PART I
Item 1. Business
Overview
We are a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel therapeutics based on our
proprietary Safely Metabolized And Rationally Targeted, or SMART, linker drug discovery platform. Our SMART linker drug discovery platform enables us to engineer product candidates that can
simultaneously modulate multiple targets in a disease. Our proprietary product candidates impact pathways that are central to diseases where efficacy may be optimized by a multiple target approach. We
have applied our SMART linker drug discovery platform to build an internal pipeline of product candidates for rare diseases, our primary focus, and plan to pursue partnerships to develop additional
product candidates.
Our
lead product candidate is edasalonexent, formerly known as CAT-1004, an oral small molecule. Based on its mechanism of action, the inhibition of
NF-
k
B, or nuclear factor kappa-light-chain-enhancer of activated B cells, we believe edasalonexent has the potential to be a disease-modifying therapy for all
patients affected by Duchenne muscular dystrophy, or DMD, regardless of the underlying dystrophin mutation. DMD is an ultimately fatal genetic disorder involving progressive muscle degeneration. The
United States Food and Drug Administration, or FDA, has granted orphan drug, fast track and rare pediatric disease designations to edasalonexent for the treatment of DMD. The European Commission, or
EC, has granted orphan medicinal product designation to edasalonexent for the treatment of DMD.
We
are currently conducting the MoveDMD
®
Phase 1/2 trial of edasalonexent in ambulatory boys with DMD between ages four and seven. The
MoveDMD trial is a three-part clinical trial investigating the safety and efficacy of edasalonexent in DMD. We previously reported positive safety, tolerability, pharmacokinetics and biomarker results
from Part A of the MoveDMD trial. We reported top-line Part B results in January 2017, indicating that the primary efficacy endpoint of average change from baseline to week 12 in the
magnetic resonance imaging, or MRI, T2 composite measure of lower leg muscles for the pooled edasalonexent treatment groups compared to placebo was not met. There were, however, consistent numerical
improvements versus placebo across all functional exploratory endpoint measures for the higher dose, as well as numerical improvement versus placebo across multiple functional exploratory endpoint
measures for the lower dose, while the lower dose had mixed results versus the higher dose. Changes in these functional measures were not statistically significant in Part B of the MoveDMD
trial, which was not powered for functional measures. We believe that the potential treatment-associated effects from these exploratory endpoints warrant further evaluation in Part C of the
MoveDMD trial, which is the ongoing open-label extension portion of the trial. We intend to transition all patients participating in Part C of the trial to the 100 mg/kg/day dose, the higher of
the two dosing levels administered in Part B, and extending Part C by an additional 24 weeks, subject to institutional review board approval. We intend to report the results from
Part C in 2017. We anticipate providing an interim update on Part C of the MoveDMD trial in the second quarter of 2017. In addition to our work in DMD, we are evaluating other diseases
where the inhibition of NF-
k
B may be beneficial for further therapeutic applications of edasalonexent. There are a number of other rare diseases where
NF-
k
B is believed to play an important role, such as Becker muscular dystrophy, which is one of nine types of muscular dystrophy and is characterized by slowly
progressive muscle weakness of the legs and pelvis, and IgA
nephropathy, a kidney disease that is believed to result from activation of mucosal immunity leading to the synthesis of aberrantly glycosylated polymeric immunoglobulin A1, or IgA1, which enters the
circulation and lodges in a patient's kidneys interfering with their proper function.
In
addition to edasalonexent, we are developing a pipeline of product candidates using our SMART linker drug discovery platform as potential treatments for rare diseases including cystic
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fibrosis,
or CF, amyotrophic lateral sclerosis, or ALS, and Friedreich's ataxia, or FA. Our pipeline includes CAT-5571 and CAT-4001, for which we are currently conducting preclinical activities. We
are developing CAT-5571 initially as a potential oral treatment for CF, with potential beneficial effects on both trafficking and function of cystic fibrosis transmembrane conductance regulator, or
CFTR, and the clearance of
Pseudomonas aeruginosa
. In CF, a malfunctioning CFTR ion channel impairs chloride secretion, with deleterious effects on
multiple organs, and particularly devastating effects on pulmonary, intestinal and pancreatic function. Patients affected with CF are also predisposed to respiratory failure caused by persistent lung
infections, notably bacteria and most commonly
Pseudomonas aeruginosa
, that are difficult to treat with standard antibiotics. CAT-5571 is a small
molecule that activates autophagy, a process that maintains cellular homeostasis and host defense mechanisms, which are known to be impaired in CF. In addition, we are developing CAT-4001 as a
potential treatment for neurodegenerative diseases such as FA and ALS, irrespective of mutation status. FA is a rare genetic disease that causes nervous system damage and compromises motor
coordination. ALS, sometimes called Lou Gehrig's disease or classical motor neuron disease, is a rapidly progressive, fatal neurological disease that attacks the nerve cells responsible for
controlling voluntary muscles. CAT-4001 is a small molecule that activates Nuclear factor (erythroid-derived 2)-like 2, or Nrf2, and inhibits NF-
k
B, two pathways
that have been implicated in FA and ALS.
We
have previously applied our SMART linker drug discovery platform to engineer our CAT-2000 series product candidates to inhibit the Sterol Regulatory Element Binding Protein, or SREBP,
pathway. Inhibitors of SREBP have been proposed for the treatment of nonalcoholic steatohepatitis, or NASH, based on the role of SREBP in lipid metabolism and known human polymorphisms associated with
NASH disease progression. NASH is characterized by the build-up of fat in the liver and chronic inflammation, which can trigger progression to fibrosis and ultimately cirrhosis and sometimes
hepatocellular carcinoma. We have advanced two CAT-2000 molecules, CAT-2003 and CAT-2054, into clinical development and intend to pursue a partnership for further development of the CAT-2000 series in
NASH, which, in addition to CAT-2003 and CAT-2054, includes other discovery-stage molecules with intermediate rates of hydrolysis.
As
of December 31, 2016, we owned five issued U.S. patents with composition of matter and method of use claims directed to edasalonexent, four issued U.S. patents with composition of
matter and method of use claims directed to the CAT-2000 series, two issued U.S. patents with composition of
matter claims generically covering CAT-5571 and two issued U.S. patents with composition of matter and method of use claims directed to CAT-4001. These patents are expected to expire between 2029 and
2031, without taking into account potential patent term extensions. In addition, our patent portfolio includes over 50 issued foreign patents, over 10 pending U.S. patent applications and over 35
pending foreign patent applications.
Our Scientific Approach
Our SMART linker drug discovery platform enables us to engineer product candidates that can simultaneously modulate multiple biological targets
in a disease. Our proprietary product candidates impact pathways that are central to diseases where efficacy may be optimized by a multiple target approach.
Multi-target
therapies have in many cases been developed to provide treatment options where single-target therapies have been ineffective. These multi-target therapies have traditionally
followed one of two approaches: either use of a single drug that binds to multiple biological targets or co-administration of two or more drugs that interact with different targets. While each of
these approaches has well-established benefits in a variety of indications, each is also characterized by significant limitations. For example, use of a single broadly targeted drug can lead to
off-target toxicities, side-effects and tolerability issues, and co-administration of two or more drugs can be confounded by differences in the pharmacokinetics and tissue distribution of the drugs,
thereby
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reducing
the likelihood of each agent being simultaneously active in the same cell. Our SMART linker drug discovery platform is designed to address these issues.
Our
aim is to leverage the growing body of knowledge associated with disease pathways, and to rationally design orally bioavailable product candidates that simultaneously interact with
multiple biological targets in a disease. While other technologies exist to conjugate or combine two bioactives, we believe that our SMART linker drug discovery platform provides substantial
improvements over previous approaches to bioactive conjugation.
SMART Linker Drug Discovery Platform
We have leveraged our SMART linker drug discovery platform to engineer molecules that can simultaneously modulate multiple biological targets in
a disease. Our drug discovery platform includes a broad array of linkers that we use to engineer molecular series. The linkers used in our drug discovery platform are small chemicals designed to join
two separate bioactives into a single conjugate molecule, and some linkers are also bioactives. In systemic circulation, our SMART linker conjugates are typically stable and inactive, potentially
reducing off-target toxicities and side-effects. Certain of our conjugates are designed to be cleaved by specific enzymes exclusively within cells in order to release the two bioactives inside the
cells. By releasing the bioactive components of the conjugate molecule inside cells, the SMART linker allows the bioactives to reach their targets more efficiently and have greater efficacy than if
the bioactives were dosed independently or in combination.
To
create a conjugate using our SMART linker drug discovery platform, we begin by analyzing pathways that are disrupted in a disease. We then select two bioactive molecules known for
their clinical safety and demonstrated effect along one or more of these biological pathways. We then design a SMART linker that will conjugate the two selected bioactives, allow the conjugate
molecule to be carried to biological tissues and, following entry into cells, be cleaved by enzymes resident in the cells to release the bioactives.
We
have SMART linker conjugates that are designed to be stable with oral dosing, as well as stable in both the lumen of the intestine and in systemic circulation, which we have now
observed in clinical trials for two product candidate series. We can design the SMART linker to chemically link the two bioactive molecules through their pharmacophores, the regions of the bioactive
molecules that are responsible for carrying out their biological activity, resulting in inactivation of the bioactives while conjugated. Once the conjugate enters a cell, the SMART linker may be
cleaved by specific enzymes which reside only within cells, releasing the two bioactives to interact with their biological targets. Simultaneous delivery of the bioactives through the SMART linker
conjugate into the cell results in the two bioactives having the same pharmacokinetics and tissue distribution. As a result, our SMART linker conjugates can simultaneously modulate two biological
targets in diseases of interest within the same cell. In addition, release of the bioactives inside cells can potentially reduce or eliminate off-target, extracellular activity of the bioactives,
which may improve safety and tolerability.
We
have observed in multiple preclinical studies that our SMART linker conjugates achieved greater efficacy than administration of the two bioactives either independently or in
combination. In clinical trials, SMART linker conjugates have demonstrated significant improvements in activity on disease pathways and tolerability relative to equivalent doses of the two bioactives
delivered in combination. We also have observed statistically significant pharmacological effects with SMART linker conjugates at dose levels significantly lower than the prescribed doses of the two
component bioactives, as further described below under "Our Product CandidatesEdasalonexentEdasalonexent Clinical DevelopmentCompleted Clinical
Trials". We are developing a pipeline of preclinical
assets using our SMART linker drug discovery platform to potentially treat rare diseases including CF, ALS, FA, and others.
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We
believe that our SMART linker drug discovery platform has the potential to:
-
-
enhance activity on diseases through modulation of multiple biological targets;
-
-
improve efficacy by matching the pharmacokinetics and tissue distribution of the component bioactives; and
-
-
improve safety and tolerability by releasing the component bioactives within cells.
Our Product Candidates
The following chart summarizes key information regarding our product candidates. We hold rights to all of our product candidates throughout the
world.
Edasalonexent
Edasalonexent is a SMART linker conjugate of salicylic acid and the omega-3 fatty acid docosahexaenoic acid, or DHA, a naturally occurring
unsaturated fatty acid with anti-inflammatory properties. We designed edasalonexent to inhibit NF-
k
B, a protein that is activated in DMD and that drives
inflammation, fibrosis and muscle degeneration, and suppresses muscle regeneration. We reported results from Part A of the MoveDMD trial in January 2016 and reported top-line safety and
efficacy results for Part B of the trial in January 2017. Results from both Part A and Part B of the MoveDMD trial are described further below under "Edasalonexent
Clinical Development". In July 2016, we initiated an open-label extension, Part C of the MoveDMD trial, which is expected to provide safety and efficacy data on edasalonexent when administered
for up to 48 weeks. The FDA has granted edasalonexent orphan drug, fast track and rare pediatric disease designations for the treatment of DMD. The EC has granted orphan medicinal product designation
to edasalonexent for the treatment of DMD.
In
September 2016, we announced a pre-clinical joint research collaboration with Sarepta Therapeutics, Inc., or Sarepta, a commercial stage developer of RNA targeted therapeutics,
established to explore a combination drug treatment approach for DMD. In the Catabasis and Sarepta
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collaboration,
increased dystrophin protein expression was seen with an exon-skip modality in combination with edasalonexent in the designated mouse model of DMD.
Overview of DMD
DMD is a rare pediatric disorder involving progressive muscle degeneration that eventually leads to death. DMD is caused by various mutations in
the dystrophin gene that result in a lack of functional dystrophin in muscle fibers, which renders muscle fibers more susceptible to mechanical stress. Dystrophin is a protein that resides in the
membrane of muscle cells and is critical to the structural and membrane stability of muscle fibers in skeletal, including diaphragm, and cardiac muscle. When muscles contract or stretch during normal
use, the absence of normally functioning dystrophin results in activation of the NF-
k
B pathway, triggering inflammation in the muscles, resulting in muscle damage
and reducing the ability of muscles to regenerate. As muscle damage progresses, connective and adipose tissues replace muscle fibers, resulting in inexorable muscle weakness.
DMD
occurs almost exclusively in males, occurring in approximately 1 in 3,500 live male births. Based on this incidence rate, we estimate that DMD affects a total of approximately 15,000
patients in the United States and approximately 19,000 patients in the European Union.
Children
with DMD typically begin to show symptoms of disease between ages two and five, when they develop a waddling gait, frequently fall and have difficulty rising from the floor.
Progressive weakness then develops in the voluntary muscles in the arms, legs and trunk. This muscle weakness is accompanied by fixations, or contractures, of joints, such as knees, hips and elbows.
By age eight, most patients have difficulty ascending stairs. Patients typically lose walking ability between the ages of ten and fourteen and, by about twelve years of age, most people with DMD are
unable to walk and need to use a power wheelchair on a regular basis. Patients' cardiac and respiratory muscles are also adversely affected, typically requiring use of ventilators in their late teens.
Progressive weakening of cardiac and respiratory muscles of DMD patients eventually results in death, generally in their mid-twenties.
The Role of NF-
k
B in Duchenne Muscular Dystrophy
NF-
k
B plays an important role in regulating skeletal muscle health and appears to be especially important
in regulating skeletal muscle mass in chronic diseases such as DMD. Activated NF-
k
B promotes the degradation of specific muscle proteins and leads to the
induction of pro-inflammatory mediators such as cytokines, including tumor necrosis factor alpha, or TNF-
a
, interleukin 6, or IL-6, and interleukin-1 beta, or
IL-1
b
; chemokines; cell adhesion molecules; and
tissue degrading enzymes, such as matrix metallopeptidase 9, or MMP-9. In addition, activated NF-
k
B suppresses muscle stem cell differentiation that is required
for muscle regeneration by preventing satellite stem cells from differentiating into myoblasts, progenitor cells that differentiate, to give rise to muscle cells. Activation of
NF-
k
B is observed in muscle tissues of patients with DMD prior to the onset of other clinical manifestations, and activated
NF-
k
B is persistently elevated in the immune cells and degenerating muscle fibers of patients with DMD. Moreover, evidence exists that mechanical stress activates
NF-
k
B in muscles and increases levels of activated NF-
k
B by a factor of three to four times and drives
NF-
k
B mediated inflammation. Muscles with increased mechanical stress and inflammation, such as quadriceps and hamstrings, show the greatest progression of
disease.
Unaddressed Market Opportunity
There are currently only two therapies approved in the United States for the treatment of DMD: Sarepta's drug Exondys 51, also known as
eteplirsen, an exon skipping therapy targeting the skipping of exon 51, that was granted accelerated approval by the FDA, and Marathon Pharmaceuticals' EMFLAZA, also known as deflazacort,
a corticosteroid, which is indicated for the treatment of DMD
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in
patients five years of age and older. Corticosteroid therapy, including treatment with prednisone, is often prescribed to treat the inflammation underlying DMD and to delay loss of ambulation.
Corticosteroids have demonstrated efficacy in DMD patients, which is believed to be driven by reductions in activated NF-
k
B. However, corticosteroids primarily
act through another pathway called the glucocorticoid receptor-mediated pathway, and also can cause significant complications including growth suppression, excessive weight gain, behavioral changes,
reduction in bone strength and compromise of the immune system. Over time, corticosteroids induce chronic myopathy in many diseases through induction of muscle protein breakdown, which ultimately
leads to muscle damage. DMD patients treated with corticosteroids typically show an initial improvement in measures of muscle function but then resume a progressive decline. Approximately half of DMD
patients treated with steroids lose the ability to walk by age thirteen and the vast majority are in wheelchairs by age sixteen. DMD patients typically live until their mid-twenties, despite the
availability of corticosteroids.
Additionally,
there are several treatments for DMD that are approved or under review in the European Union or are expected to be under review by regulatory agencies in the near future.
Santhera Pharmaceuticals, or Santhera, has filed a marketing authorization application with the European Medicines Agency, or EMA, for Raxone
®
, also known
as idebenone, for the treatment of DMD in patients with respiratory function decline and not taking concomitant glucocorticoids. Sarepta's Exondys 51 is under review by the EMA, and PTC Therapeutics'
ataluren is conditionally approved in the European Union and several other countries for treatment of nonsense mutation DMD under the trade name Translarna. PTC Therapeutics also re-filed
a new drug application, or NDA, with the FDA in March 2017. Exondys 51 and ataluren target mechanisms to increase levels of dystrophin in muscles. Each of these agents addresses a specific type of
genetic mutation in order to produce a partially functional dystrophin protein. The therapeutic goal of these product candidates is to reduce disease severity and extend survival in those DMD patients
who are candidates for therapy with these agents. Based on the prevalence of the specific mutations that Exondys 51 and ataluren are designed to address, they would be expected to be effective in an
aggregate of approximately 26% of DMD patients. We believe that DMD patients, including those treated with these dystrophin therapies, will continue to require treatments to reduce muscle inflammation
and degeneration and enhance muscle regeneration.
Edasalonexent for the Treatment of Duchenne Muscular Dystrophy
Based
on the mechanism of action by which edasalonexent suppresses NF-
k
B and the results that we have seen in preclinical models
of DMD, we believe that edasalonexent has the potential to combine reduction of inflammation and muscle degeneration with positive effects on muscle regeneration, all of which may allow patients to
retain muscle function longer. In addition, we believe that edasalonexent has the potential to be an effective therapy in all DMD patients, regardless of the underlying mutation, and to provide
significant benefit to patients, both as monotherapy and when used in combination with other therapies, including dystrophin-targeted therapies and agents targeting utrophin. We intend to
commercialize edasalonexent in North America ourselves and commercialize edasalonexent outside of North America either ourselves or with a collaborator.
Edasalonexent Clinical Development
Our MoveDMD Phase 1/2 trial enrolled ambulatory boys between ages four and seven with a genetically confirmed diagnosis of DMD who were steroid
naive or had not used steroids for at least six months prior to the trial. Boys enrolled in the trial are not limited to any specific dystrophin mutations. The MoveDMD trial is designed to be
conducted in three sequential parts, Part A and Part B, both of which have been completed, and Part C, an open-label extension initiated in July 2016, which is on-going.
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In
Part A of the MoveDMD trial, which was conducted at three sites in the United States, we assessed the safety, tolerability and pharmacokinetics of edasalonexent in 17 patients,
following seven days of dosing, across three dosing levels: 33 mg/kg/day, taken in a single daily dose, 67 mg/kg/day, taken in two daily doses, and 100 mg/kg/day, taken in three daily doses. We also
compared edasalonexent exposure levels to exposure levels achieved in previous edasalonexent clinical trials in adults where inhibition of NF-
k
B was observed. In
January 2016, we reported that all three doses of edasalonexent tested were generally well tolerated with no safety signals observed. The majority of adverse events were mild, and the most common
adverse events were gastrointestinal, primarily diarrhea. There were no serious adverse events and no drug discontinuations. For the 67 mg/kg/day and 100 mg/kg/day dosing levels, pharmacokinetic
results demonstrated edasalonexent plasma exposure levels consistent with those previously observed in adults at which inhibition of NF-
k
B was observed, and
edasalonexent significantly reduced the expression of a set of genes that are controlled by NF-
k
B. We subsequently reported results with positive
NF-
k
B biomarker data that supported NF-
k
B target engagement via statistically significant reduction in
NF-
k
B controlled gene expression for the 67 mg/kg/day and 100 mg/kg/day dosing levels. These two dosing levels were advanced to Part B of the trial.
Thirty-one
boys enrolled in Part B of the MoveDMD trial and all completed Part B of the trial. Both dose levels of edasalonexent evaluated were well tolerated with no
safety signals observed. The majority of adverse events were mild in nature and the most common treatment-related adverse events were gastrointestinal, primarily mild diarrhea and vomiting. There were
no treatment-related serious adverse events, no drug discontinuations and no dose reductions. Edasalonexent plasma exposure in Part B of the MoveDMD trial was consistent with that observed in
Part A.
In
Part B of the MoveDMD trial, we assessed the effects of edasalonexent using MRI T2 as an early biomarker at 12 weeks in a randomized, double-blind, placebo-controlled trial.
Part B of the MoveDMD trial was conducted at five sites in the United States, and we believe that it was the first Phase 2 trial in DMD to use MRI as a primary endpoint. MRI is a non-invasive
imaging technique that allows investigators to view muscle structure and composition and measure disease status in children with DMD. Changes in MRI measures, particularly fat fraction, have been
correlated in natural history studies with longer-term changes in clinically meaningful measures of functional activity. We used MRI T2 as the primary endpoint to serve as an early biomarker
for demonstrating a benefit on muscle composition that potentially would allow us to see an effect of edasalonexent at 12 weeks of treatment, as has been seen by others with corticosteroids. We
announced in January 2017 that the primary efficacy endpoint of average change from baseline to week 12 in the MRI T2 composite measure of lower leg muscles for the pooled edasalonexent treatment
groups compared to placebo was not met (0.37 milliseconds for the pooled edasalonexent treatment groups versus 0.47 milliseconds for placebo; a smaller increase in MRI T2 is believed to correlate with
less muscle inflammation). Although we did not see a similar treatment effect as corticosteroids on the MRI T2 composite measure at 12 weeks, we observed potential treatment-associated functional
effects at both dose levels of edasalonexent on the exploratory endpoints described below, as well as continued to observe acceptable safety, tolerability and plasma exposure data in Part B of
the MoveDMD trial. Therefore, as planned, we are measuring the effects of edasalonexent on patients with DMD in the MoveDMD trial in Part C to see if signals strengthen in the longer-term data
from the ongoing open-label extension.
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Exploratory endpoints also included the following functional tests in Parts B and C of the MoveDMD trial: timed function tests best suited for the age group of
the trial subjects, including the 10-meter walk/run, 4-stair climb and time-to-stand tests; the North Star Ambulatory Assessment; assessments of muscle strength; and the Pediatrics Outcomes Data
Collection Instrument, a parent-proxy measure of functional ability. The trial is not powered to detect statistically significant changes in any of the exploratory endpoints during Part B or Part C,
and no significant changes were detected in these measures for those dosed with edasalonexent versus placebo at 12 weeks. Top-line results from Part B demonstrated that the edasalonexent 100 mg/kg/day
treatment group, whose patients took 33mg/kg capsules three times a day, consistently showed numerical improvement versus placebo across all measures of the functional test exploratory endpoints,
although the changes were not statistically significant. Similarly, the 67 mg/kg/day treatment group, whose patients took 33mg/kg capsules twice a day, consistently showed numerical improvement versus
placebo across multiple measures of the functional test exploratory endpoints, although the changes were not statistically significant and were mixed compared to the 100 mg/kg/day treatment group.
Compared to the placebo group, patients in the edasalonexent 100 mg/kg/day group had characteristics of more advanced disease at baseline. This was indicated by the age at onset, age at diagnosis and
the baseline values for time to complete the 4-stair climb and time-to-stand. In addition, baseline assessments were performed at the beginning of Part A and Part B of the MoveDMD trial
to compare changes in functional measures in this control period to those observed in Part B and Part C. There were twelve boys who participated in Part A and received active
treatment in Part B, and the rate of decline in functional measures for these boys generally showed numerical improvement over the active treatment period compared to the control period. We
believe that the top-line results from the functional exploratory endpoints and additional functional assessments warrant further evaluation as planned in Part C of the MoveDMD trial. We intend to
transition all patients participating in Part C of the trial to the 100 mg/kg/day dose and extending Part C by an additional 24 weeks, subject to institutional review board approval, so that we have
the opportunity to assess the higher dose in all of the boys in Part C and so that the boys that started the open-label extension since July last year are able to continue to receive edasalonexent
treatment. We intend to report the results from Part C in 2017. We anticipate providing an interim update on Part C of the MoveDMD trial in the second quarter of 2017.
Following
additional assessment of the effects in patients of edasalonexent in Part C of the MoveDMD trial, we will determine next steps for the edasalonexent program in DMD.
To date, we have studied edasalonexent in three completed Phase 1 clinical trials, in addition to Part A of the MoveDMD trial, which is
described above. The design for each of these other clinical trials are discussed below.
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EdasalonexentCompleted Phase 1 Clinical Trials
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Subjects
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Trial
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Description
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Duration
Of
Dosing
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Total
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Treated
with
edasalonexent
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CAT-1004-101
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Randomized, double-blind, placebo-controlled, single ascending dose clinical trial to evaluate safety, tolerability and pharmacokinetics of edasalonexent in healthy subjects
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1 day
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52
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39
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CAT-1004-102
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Randomized, double-blind, placebo-controlled multiple ascending dose clinical trial to evaluate safety, tolerability,
pharmacokinetics and pharmacodynamics of edasalonexent in adults with Type 2 diabetes
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14 days
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44
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32
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CAT-1004-103
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Single-blind biomarker trial in healthy adults to compare activity of edasalonexent, a combination of salicylate and DHA, or
placebo on activated NF-
k
B
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1 day
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9
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8
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Phase 1 Single Ascending Dose Trial (CAT-1004-101):
We conducted a randomized, double-blind, placebo-controlled, single ascending dose
Phase 1
clinical trial in 52 healthy volunteers at a single site
in the United States to assess the safety, tolerability and pharmacokinetics of edasalonexent in both fasted and fed states. The participants were randomized to receive edasalonexent or placebo.
Edasalonexent was administered orally in soft gelatin capsules at doses ranging from 300 mg to 6000 mg.
Single
doses of edasalonexent, administered to subjects in both fed and fasted conditions, appeared to be well tolerated. Subjects in the fasted state reported few adverse events, with
the most commonly reported adverse events being headache, diarrhea and dizziness. Of the 44 subjects in the fasted state, five reported headache, three reported diarrhea and two reported dizziness.
The majority of the adverse events in the fasted state were mild in severity. Of the 35 subjects in the fed state, six reported diarrhea, six reported headache and four reported abdominal pain. The
most common adverse events in the fed state were diarrhea, headache and abdominal pain, and all of the adverse events in the fed state were mild in severity. Subjects in the fed state receiving single
doses of edasalonexent of 4000 mg or more reported gastrointestinal adverse events more frequently than subjects receiving lower doses. No treatment-related severe adverse events were reported. There
were no observed trends in laboratory, vital signs or electrocardiogram results following edasalonexent administration in either the fasted or fed state.
Edasalonexent
was rapidly absorbed in plasma, with mean maximum and overall plasma exposure generally increasing with edasalonexent dose levels. Neither component bioactive, salicylate
or DHA, was detected in plasma at levels above background, consistent with intracellular cleavage of edasalonexent and intracellular delivery of the component bioactives. Administration of a high-fat
meal increased edasalonexent mean maximum and overall exposure by approximately three- to eight-fold.
Phase 1 Multiple Ascending Dose Trial (CAT-1004-102):
We conducted a randomized, double-blind, placebo-controlled, multiple ascending
dose Phase 1
clinical trial in 44 subjects at a single center in the United States to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of edasalonexent. These subjects had Type 2 diabetes and
mild background inflammation, which enabled us to assess the activity of edasalonexent on activated NF-
k
B. Subjects were randomized to receive
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edasalonexent
or placebo. edasalonexent was administered orally in soft gelatin capsules at total daily doses ranging from 300 mg to 4000 mg.
Edasalonexent
administered for two weeks appeared to be well tolerated. The adverse events reported in more than one subject were each reported by two subjects. These adverse events were
diarrhea (both
instances reported by subjects receiving 4000 mg daily doses of edasalonexent), gastroenteritis (one instance reported by a subject in the placebo group and the other by a subject receiving 1000 mg
daily doses of edasalonexent) and upper respiratory tract infection (both instances reported by subjects receiving 4000 mg daily doses of edasalonexent). The majority of the adverse events were mild
in severity. No treatment-related severe adverse events were reported.
Edasalonexent
was rapidly absorbed in plasma, with mean maximum and overall plasma exposure generally increasing with escalating single or multiple doses of edasalonexent. Neither
component bioactive, salicylate or DHA, was detected in plasma at levels above background, again consistent with intracellular cleavage of edasalonexent and intracellular delivery of the component
bioactives.
In
the Phase 1 multiple ascending dose trial, we observed by two methods that edasalonexent inhibited activated NF-
k
B. For the first method, we
stimulated NF-
k
B activity
ex vivo
in whole blood from subjects treated with edasalonexent or placebo, and then
observed NF-
k
B activity in monocytes, or immune cells, that we isolated from the whole blood. NF-
k
B activity was reduced in
a majority of subjects following two weeks of edasalonexent treatment but not following treatment with placebo. For the second method, we performed gene expression analyses on whole blood taken from
subjects prior to treatment and after two weeks of treatment with edasalonexent or placebo. Edasalonexent significantly reduced the expression of a set of genes that are controlled by
NF-
k
B. In contrast, treatment with placebo for two weeks did not significantly reduce expression of NF-
k
B regulated genes.
Phase 1 NF-
k
B Biomarker Trial (CAT-1004-103):
We conducted a
single-blind, crossover Phase 1 clinical trial with edasalonexent in nine healthy adult volunteers at a single center in the United States to compare activity of a single dose of 2000 mg of
edasalonexent on activated NF-
k
B to a combination of salicylate and DHA or placebo. No adverse events were reported in this clinical trial. The salicylate and DHA
were dosed at approximately equivalent amounts to those contained in the edasalonexent conjugate. We assessed NF-
k
B activity in peripheral blood mononuclear
cells, or PBMCs, isolated from subjects before dosing and two hours after dosing. PBMCs are circulating immune cells that can mount an NF-
k
B response and migrate
into tissue such as muscle and drive inflammation. Prior to the determination of NF-
k
B activity, we stimulated whole blood with lipopolysaccharide, or LPS, to
activate the NF-
k
B pathway. Treatment of subjects with edasalonexent significantly reduced the level of activated NF-
k
B, as
measured by nuclear p65, a surrogate marker for activated NF-
k
B. In contrast, no change in the level of activated NF-
k
B was
observed upon treatment with the combination of salicylate and DHA, or upon treatment with placebo. In this trial, edasalonexent, which is a SMART linker conjugate of salicylate and DHA, exhibited
greater activity on the NF-
k
B pathway than the combination of its component bioactives.
Edasalonexent Preclinical Development
In preclinical studies, we have observed that edasalonexent inhibited NF-
k
B activity
in vitro
and
in vivo
, and produced disease-modifying effects in two established animal models of DMD,
the
mdx
mouse model and the Golden Retriever muscular dystrophy, or GRMD, dog model.
We have created several SMART linker conjugates that inhibit activated NF-
k
B. Two of these conjugates,
edasalonexent and CAT-1041, exhibit very similar effects on NF-
k
B activity in cell based assays, in animal studies and on functional activity in animal models.
CAT-1041 is a closely related analog of edasalonexent in which the DHA component of the salicylate-DHA conjugate has been
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replaced
with the omega-3 fatty acid eicosapentaenoic acid, or EPA. In some preclinical studies, we used CAT-1041 as a surrogate for edasalonexent. Both edasalonexent and CAT-1041 produced
disease-modifying efficacy in established animal models of DMD. We decided to advance edasalonexent into clinical trials rather than CAT-1041 based on scientific literature suggesting that DHA has
superior anti-inflammatory activity compared to EPA.
mdx Mouse Model.
We examined the potential therapeutic effects of edasalonexent using the
mdx
mouse
model of DMD. We observed that four weeks of treatment with edasalonexent or prednisolone, a steroid, reduced muscle inflammation and the number of degenerating muscle fibers in
mdx
mice. However, only
edasalonexent-treated animals showed preservation of muscle mass and an increase in the number of regenerating fibers,
suggesting that chronic treatment with edasalonexent can protect muscle from the damage expected to occur over time in
mdx
mice.
In
a long-term
mdx
mouse study, we observed that, compared to the control group of
mdx
mice, six months of treatment with CAT-1041 significantly improved muscle endurance as measured by mean weekly and total running distance determined based upon cumulative revolutions on a running
wheel. Improvements in muscle endurance following CAT-1041 treatment versus control were also observed in post-mortem assessments of twitch force, tetanic force and specific force generation, each of
which is an established measurement of muscle endurance, in excised diaphragm muscle.
We
also observed in this same study that
mdx
mice treated with CAT-1041 showed significantly increased mass of two major leg muscles, the
gastrocnemius and quadriceps. These increases were independent of changes in total body weight. CAT-1041 treated mice also had a statistically significant reduction in cardiac mass and fibrosis,
suggesting that chronic treatment with CAT-1041 may have reduced the dilated cardiomyopathy typically observed in
mdx
mice.
In
this study, we also observed that edasalonexent and CAT-1041 exhibited similar activity on muscle contractions of the extensor digitorum longus muscle in
mdx
mice with significant preservation of muscle
function compared to control. Finally, in this study we observed a reduction in diaphragm and quadricep
muscle fibrosis in
mdx
mice treated with CAT-1041 in comparison to control.
Golden Retriever Dog Model.
We also evaluated the effects of edasalonexent in the GRMD dog model. A single oral dose of edasalonexent
inhibited
basal, or unstimulated, NF-
k
B activity by 48% in GRMD dogs. Edasalonexent also inhibited LPS-stimulated NF-
k
B activity by
75% and LPS-stimulated plasma levels of TNF
a
protein, a key marker of inflammatory response, by 77%. Together, these data suggest that a single oral dose of
edasalonexent achieves sufficient exposure levels to inhibit activated NF-
k
B in a dog model of DMD.
In an
in vitro
study in a mouse macrophage cell line, we observed that edasalonexent inhibited
LPS-stimulated NF-
k
B activity to a greater extent than either of its components, salicylate and DHA, alone or in combination. We also observed that edasalonexent
inhibited LPS-stimulated NF-
k
B activity in human PBMCs, which are a potential target tissue for edasalonexent. In studies performed with a mouse macrophage cell
line, edasalonexent reduced the LPS-stimulated expression of a set of genes that encode pro-inflammatory
mediators and whose expression is controlled by NF-
k
B.
Edasalonexent Orphan Drug, Fast Track and Rare Pediatric Disease Designations
The FDA has granted edasalonexent orphan drug, fast track and rare pediatric disease designations for the treatment of DMD. A product may be
designated by the FDA as an "orphan drug" if it is intended to treat a rare disease or condition affecting fewer than 200,000 individuals in the United States. If a product with orphan status receives
the first FDA approval for the disease or condition for which it has such designation, the FDA will not approve another sponsor's marketing
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application
for the same product for the same use or indication before the expiration of seven years, except in certain limited circumstances. The FDA fast track process is designed to expedite the
development and review of drugs to treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs. Companies that receive fast track designation are allowed
to submit NDAs on a rolling basis, expediting the FDA review process, and benefiting from more frequent communication with the FDA to discuss all aspects of clinical development. In addition, drugs
that receive fast track designation are eligible for accelerated approval and priority review if certain criteria are met. The FDA's rare pediatric disease designation gives us the potential to
receive a priority review voucher if edasalonexent is approved. However, the rare pediatric disease program is set to expire in September 2020.
The
EC has granted orphan medicinal product designation to edasalonexent for the treatment of DMD. Similar to the FDA orphan drug designation, the EC may designate a product as an orphan
medicinal product if it is intended for the treatment of a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons. In Europe, marketing
authorization for an orphan medicinal product generally leads to up to a ten-year period of market exclusivity if the product candidate is granted marketing authorization in the European Union.
CAT-5571
CAT-5571 is a SMART linker conjugate that contains cysteamine, a naturally occurring molecule that is a degradation product of the amino acid
cysteine, and DHA. We are developing CAT-5571 initially as a potential oral treatment for CF with potential effects on both the CFTR and on the clearance of
Pseudomonas
aeruginosa
. CAT-5571 is a small molecule that activates autophagy, a process that maintains cellular homeostasis and host defense mechanisms, which are known to be impaired in
CF.
We
have shown in preclinical studies that CAT-5571 synergistically activates autophagy in cultured primary human bronchial epithelial cells isolated from patients with CF. In addition,
we have shown in
ex vivo
preclinical studies that CAT-5571, in combination with lumacaftor/ivacaftor, a combination drug that consists of lumacaftor,
which increases CFTR proteins that are trafficked to the cell surface, and ivacaftor, which increases the activity of the CFTR protein at the surface of epithelial cell, enhances cell-surface
trafficking and function of CFTR with the F508del mutation, which is the most frequent CFTR mutation and is present in 86% of patients included in the Cystic Fibrosis Foundation United States Patient
Registry. We have also shown that CAT-5571 enhances the clearance of
Pseudomonas aeruginosa
infection in preclinical models of CF, irrespective of CFTR
mutation status. We are conducting additional preclinical activities with CAT-5571.
In
2017, we plan to continue preclinical evaluation of CAT-5571 in animal models of CF, and to conduct investigational new drug, or IND, application-enabling activities for CAT-5571. If
we are successful in these activities, we intend to advance CAT-5571 into a Phase 1 clinical trial in 2018.
Cystic Fibrosis
Cystic fibrosis is a rare, chronic, genetic, life-shortening orphan disease that affects over 70,000 patients worldwide, predominantly in the
Caucasian population. In CF, a malfunctioning CFTR ion channel impairs chloride secretion, with deleterious effects on multiple organs, and particularly devastating effects on pulmonary, intestinal
and pancreatic function. Patients affected with CF are also predisposed to respiratory failure caused by persistent lung infections, notably bacteria and most commonly
Pseudomonas aeruginosa,
that are
difficult to treat with standard antibiotics. CF patients have frequent pulmonary exacerbations due to their inability
to clear the persistent lung infections. Advancement in research and treatments have extended the life expectancy for those living with CF, however, there is currently no cure.
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CAT-4001
CAT-4001 is a SMART linker conjugate that we designed to combine the potentially beneficial activities of monomethyl fumarate and DHA on the
Nrf2 and NF-
k
B pathways. CAT-4001 is a small molecule designed to activate the Nrf2 pathway and inhibit the NF-
k
B pathway.
We are developing CAT-4001 initially for the treatment of severe, rare neurodegenerative diseases, such as FA and ALS, two diseases of the central nervous system in which the Nrf2 and
NF-
k
B pathways have been implicated, irrespective of mutation status. Nrf2 is a gene transcription factor, a protein that works inside of cells to control the
expression of genes, that control the body's response to cellular stress and oxidative damage. We are conducting preclinical activities with CAT-4001.
We
have shown that CAT-4001 modulates the Nrf2 and NF-
k
B pathways in both cellular assays and animal models. In these studies, we have also observed
that the activity produced by CAT-4001 was greater than that produced by the individual bioactives, monomethyl fumarate and DHA, either alone or in combination at approximately equivalent amounts to
those contained in the CAT-4001 conjugate. Oxidative stress and neuroinflammation are believed to play a central role in a number of neurodegenerative diseases, including FA and ALS. In addition,
monomethyl fumarate is the circulating form of the active ingredient of Biogen's Tecfidera (dimethyl fumarate), an FDA-approved treatment for multiple sclerosis, another neurodegenerative disease. We
believe that this known therapeutic effectiveness of monomethyl fumarate offers further support for the potential for CAT-4001 to be developed for the treatment of neurodegenerative diseases.
Based
on its mechanism of action, we believe that CAT-4001 has the potential to be a disease modifying agent in certain neurodegenerative diseases. In 2017, we plan to continue
preclinical evaluation of CAT-4001 in animal models of FA as well as ALS.
Friedreich's Ataxia
Friedreich's ataxia is a rare genetic disease that causes nervous system damage and compromises motor coordination. FA is caused by a defect in
the frataxin gene, which regulates iron levels in the mitochondria. In the majority of cases, the genetic defect in FA causes a reduction in the production of the frataxin protein and iron levels in
mitochondria become poorly regulated. In FA, iron overload in mitochondria affects metabolism, causing oxidative stress and ultimately damaging mitochondrial DNA. Progressive degeneration of central
and peripheral nervous systems in FA patients causes impaired gait and coordination, muscle loss and fatigue. Disease progression varies, but generally, the patient is confined to a wheelchair within
10 to 20 years after the appearance of the first symptoms. Patients may become completely incapacitated in later stages of the disease.
FA
occurs in both males and females and is estimated to affect 1 in 50,000 individuals. Based on this prevalence rate, we believe there are up to 6,000 patients with FA in the US and up
to 15,000 FA patients in the European Union.
The
Friedreich's Ataxia Research Alliance announced in January 2016 that we were the recipient of the Kyle Bryant Translational Research Award. The Kyle Bryant Translational Research
Award specifically focuses on pre-clinical and clinical investigations that target treatments for FA.
Amyotrophic Lateral Sclerosis
ALS, sometimes called Lou Gehrig's disease or classical motor neuron disease, is a rapidly progressive, fatal neurological disease that attacks
the nerve cells responsible for controlling voluntary muscles. Eventually, muscle weakness and atrophy occur. People with ALS lose the ability to stand and walk, and use their hands and arms. In later
stages of the disease, individuals have difficulty breathing as the muscles of the respiratory system weaken. Although ventilation support can enable breathing and
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prolong
survival, it does not affect the progression of ALS. Most people with ALS die from respiratory failure, usually within three to five years of diagnosis.
According
to the ALS Association, approximately 5,600 people in the United States are diagnosed with ALS each year. The incidence of ALS is two per 100,000 people, and it is estimated
that as many as 30,000 Americans may have the disease at any given time. ALS occurs throughout the world and affects all racial, ethnic and socioeconomic groups.
CAT-2000 Series
Our CAT-2000 compounds are SMART linker conjugates of nicotinic acid and EPA. The linkers for our CAT-2000 series compounds are cleaved through
intracellular enzymatic hydrolysis, to release the component bioactives to inhibit SREBP. By using different linkers, we have produced product candidates within the CAT-2000 series that possess
different hydrolysis rates, resulting in distinct pharmacokinetics, biodistribution and pharmacology. We have been able to demonstrate enzymatic hydrolysis and inhibition of SREBP in
in vitro
studies
with CAT-2000 molecules. In addition,
in vivo
, CAT-2000 molecules have demonstrated
efficacy in multiple preclinical models of hyperlipidemias and NASH. We believe that our portfolio of CAT-2000 molecules, which includes the clinical-stage molecules CAT-2003 and CAT-2054 and other
discovery-stage molecules with intermediate rates of hydrolysis, provides an opportunity to develop a therapy for NASH. We intend to pursue a partnership for further development of the CAT-2000 series
in NASH.
Sales and Marketing
Given our stage of development, we have not yet established a commercial organization or distribution capabilities, nor have we entered into any
collaboration or co-promotion arrangements. If we are able to progress our edasalonexent program, we intend to commercialize edasalonexent in North America ourselves and commercialize edasalonexent
outside of North America either ourselves or with a collaborator. In addition, we intend to expand the drug development applications of our SMART linker drug discovery platform through selective
collaborations with leading biotechnology and pharmaceutical companies.
Manufacturing and Supply
Each of our SMART linker conjugate product candidates is a small molecule compound manufactured from component raw materials. The omega-3 fatty
acid materials that we use as bioactives are purified from natural sources by established pharmaceutical fine chemicals manufacturers. The other bioactive and linker raw materials that we use are also
readily available from established pharmaceutical intermediate manufacturers. The components are conjugated to form the SMART linker product candidate using well understood, conventional chemistries.
We
currently have no manufacturing facilities and limited personnel with manufacturing experience. We rely on contract manufacturers to produce both drug substance and drug product
required for our clinical trials. We plan to continue to rely upon contract manufacturers and, potentially, collaborators to manufacture commercial quantities of our products, if approved.
Competition
The development and commercialization of new drugs is highly competitive. If we successfully develop and commercialize any of our product
candidates, we and any future collaborators will face competition from pharmaceutical and biotechnology companies worldwide. Many of the entities developing and marketing potentially competing
products have significantly greater financial resources and expertise than we do in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory
approvals and marketing. Our commercial opportunity will be reduced or eliminated if our competitors develop and commercialize products that are more effective, have fewer side effects, are more
convenient or are less expensive than any products that we may develop.
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The key competitive factors affecting the success of our product candidates, if approved, are likely to be their efficacy, safety, convenience, price and the
availability of coverage and reimbursement from government and other third-party payors.
Edasalonexent for Duchenne Muscular Dystrophy
There are currently only two therapies approved in the United States for the treatment of DMD. Sarepta's drug Exondys 51, also known as
eteplirsen, was approved by the FDA for the treatment of DMD under the accelerated approval pathway in September 2016 for patients who have a confirmed mutation of the DMD gene that is amenable to
exon 51 skipping. In addition, in February 2017, Marathon Pharmaceuticals, LLC announced that the FDA granted approval of EMFLAZA, also known as deflazacort, a corticosteroid, for the
treatment of DMD in patients five years and older. Outside of the United States, PTC Therapeutics' drug ataluren, also known as Translarna, has been conditionally approved within the
European Union
Member States, Iceland, Liechtenstein, Norway, Israel and South Korea for the treatment of nonsense mutation DMD. Although not previously approved for the treatment of DMD, corticosteroid therapy,
including prednisone, is considered standard of care and is often prescribed to treat the inflammation underlying DMD and to delay loss of ambulation.
A
number of companies are developing therapies to treat DMD in patients with specific mutations in the dystrophin gene. In addition to eteplirsen, Sarepta has two additional
exon-skipping therapies for DMD in Phase 3 clinical development. These agents, SRP-4053 and SRP-4045, target skipping of exons 53 and 45, respectively. Daiichi-Sankyo is developing an exon-skipping
product candidate for DMD patients with out-of-frame deletion mutations amenable to exon 45 skipping, and announced in February 2016 that it began its first Phase 1/2 clinical trial for its product
candidate, DS-5141b, in Japan. NS Pharma has a compound, NS-065/NCNP-01, in Phase 2 clinical development in the United States and Japan for patients with mutations amenable to exon 53 skipping. Based
on the prevalence of the specific mutations that these product candidates being developed by Sarepta, Daiichi-Sankyo and NS-Pharma are designed to address, they would be expected to have the potential
to be effective in an aggregate of approximately 16% of DMD patients. In addition to these clinical stage programs, BioMarin has announced its intent to continue to explore the development of next
generation oligonucleotides for the treatment of DMD, and Wave Life Sciences is developing an exon 51 skipping candidate, WVE-210201, for which it has announced plans to enter the clinic in the second
half of 2017.
In
addition to exon-skipping therapies, other companies have alternative therapeutic approaches to the treatment of DMD in late stage clinical development. Santhera announced in
September 2016 that it enrolled its first patient in its Phase 3 trial (SIDEROS) that will assess the efficacy of its drug Raxone
®
, also known as
idebenone, in slowing the rate of respiratory function decline in DMD patients receiving concomitant glucocorticoids. Santhera has stated that successful completion of the SIDEROS trial will provide
the necessary data to support an NDA filing with FDA for Raxone. Santhera has filed a marketing authorization application with the EMA for Raxone for the treatment of DMD in patients with respiratory
function decline and not taking concomitant glucocorticoids. PTC Therapeutics' ataluren provides another alternative therapeutic approach to treating DMD, already approved outside of the United States
as mentioned above. Ataluren is designed to enable the formation of a functioning dystrophin protein in patients with DMD caused by a nonsense mutation. In February 2016, PTC Therapeutics received a
Refuse to File letter for ataluren from the FDA and appealed this decision, and this appeal was subsequently denied by the FDA in October 2016. PTC Therapeutics filed a new ataluren NDA for nonsense
mutation DMD over protest with the FDA in March 2017. A number of companies also have products candidates in clinical development for DMD, including Akashi Therapeutics, Bristol-Myers Squibb, Capricor
Therapeutics, Cardero Therapeutics, Italfarmaco SpA, Pfizer, Phrixus Pharmaceuticals, Reveragen, Summit Plc and Taiho Pharmaceuticals. If successfully
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developed,
some of these alternative therapeutic approaches may be applicable to all DMD patients regardless of underlying mutation status.
Intellectual Property
We strive to protect the proprietary technologies that we believe are important to our business, including pursuing and maintaining patent
protection intended to cover the composition of matter of our product candidates, their methods of use, related technologies and other inventions that are important to our business. In addition to
patent protection, we also rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection, including certain aspects
of our SMART linker drug discovery platform.
Our
commercial success depends in part upon our ability to obtain and maintain patent and other proprietary protection for commercially important technologies, inventions and know-how
related to our business, defend and enforce our intellectual property rights, in particular, our patent rights, preserve the confidentiality of our trade secrets and operate without infringing valid
and enforceable intellectual property rights of others.
The
patent positions for biotechnology and pharmaceutical companies like us are generally uncertain and can involve complex legal, scientific and factual issues. In addition, the
coverage claimed in a patent application can be significantly reduced before a patent is issued, and its scope can be reinterpreted and even challenged after issuance. As a result, we cannot guarantee
that any of our product candidates will be protected or remain protectable by enforceable patents. We cannot predict whether the patent applications we are currently pursuing will issue as patents in
any particular jurisdiction or whether the claims of any issued patents will provide sufficient proprietary protection from competitors. Any patents that we hold may be challenged, circumvented or
invalidated by third parties.
As
of December 31, 2016, our patent estate included over 20 issued U.S. patents, over 50 issued foreign patents, over 10 pending U.S. patent applications and over 35 pending foreign
patent applications.
With
regard to edasalonexent, we have five issued U.S. patents with composition of matter and method of use claims directed to edasalonexent and its use. The issued U.S. patents are
expected to expire in 2029, without taking a potential patent term extension into account. In addition, we have patents that have been granted in various countries including Australia, China, Europe,
Japan, Mexico and New Zealand, which are expected to expire in 2029, without taking potential patent term extensions into account, and at least five pending patent applications in various other
countries and regions in North America, South America, and Asia, which, if issued, are expected to expire in 2029, without taking potential patent term extensions into account.
With
regard to CAT-5571, we have two granted U.S. patents with composition of matter claims generically covering CAT-5571, which are scheduled to expire in 2030, without taking potential
patent term extensions into account. We also have a pending international patent application with claims covering CAT-5571 and related compounds and their use, including their use in the treatment of
cystic fibrosis.
With
regard to CAT-4001, we have two granted U.S. patents with composition of matter and method of use claims directed to CAT-4001 and its use. These U.S. patent are scheduled to expire
in 2031, without taking a potential patent term extension into account. In addition, we have patents that have been granted in various countries including Australia, China, Japan, Mexico, New Zealand
and Taiwan, which are expected to expire in 2031, without taking potential patent term extensions into account, and at least 5 pending patent applications in various other countries and regions in
North
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America,
South America, Europe and Asia, which, if issued, are expected to expire in 2031, without taking potential patent term extensions into account.
With
regard to CAT-2003 and CAT-2054, we have four issued U.S. patents with composition of matter and method of use claims directed to CAT-2003 and CAT-2054 and their use. These U.S.
patents are scheduled to expire in 2030 and 2031, without taking potential patent term extensions into account. In addition, we have patents that have been granted in several different countries
including Australia, Mexico, China, Japan and New Zealand, which are expected to expire in 2030, without taking potential patent term extensions into account and at least 20 pending applications in
various other countries and regions including North and South America, Europe, and Asia, which, if issued, are expected to expire in 2030, without taking patent term extensions into account. In
addition, we have a pending U.S. patent application covering CAT-2054, which, if issued, is expected to expire in 2033, without taking a potential patent term extension into account. We have at least
10 counterpart patent applications pending in various countries and regions in North America, South America, Europe and Asia, which, if issued, are expected to expire in 2033, without taking potential
patent term extensions into account.
The
term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which we file, the patent term is 20 years
from the earliest date of filing a non-provisional patent application.
In
the United States, the term of a patent covering an FDA-approved drug may be eligible for a patent term extension under the Hatch-Waxman Act as compensation for the loss of patent
term during the FDA regulatory review process. The period of extension may be up to five years beyond the expiration of the patent, but cannot extend the remaining term of a patent beyond a total of
14 years from the
date of product approval. Only one patent among those eligible for an extension may be extended. Similar provisions are available in Europe and in certain other jurisdictions to extend the term of a
patent that covers an approved drug. It is possible that issued U.S. patents covering edasalonexent, CAT-5571, CAT-4001, CAT-2003 and CAT-2054 may be entitled to patent term extensions. If our product
candidates receive FDA approval, we intend to apply for patent term extensions, if available, to extend the term of patents that cover the approved product candidates. We also intend to seek patent
term extensions in any jurisdictions where they are available, however, there is no guarantee that the applicable authorities, including the FDA, will agree with our assessment of whether such
extensions should be granted, and even if granted, the length of such extensions.
In
addition to patent protection, we also rely on trade secret protection for our proprietary information that is not amenable to, or that we do not consider appropriate for, patent
protection, including, for example, certain aspects of our manufacturing processes and conjugate selection methodologies. However, trade secrets can be difficult to protect. Although we take steps to
protect our proprietary information, including restricting access to our premises and our confidential information, as well as entering into agreements with our employees, consultants, advisors and
potential collaborators, third parties may independently develop the same or similar proprietary information or may otherwise gain access to our proprietary information. As a result, we may be unable
to meaningfully protect our trade secrets and proprietary information.
Government Regulation and Product Approvals
Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the
European Union, extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising,
promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products. The processes for obtaining regulatory approvals in the United States and
in foreign countries and jurisdictions, along with subsequent
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compliance
with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.
Review and Approval of Drugs in the United States
In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA, and implementing regulations. The failure
to comply with applicable U.S. requirements at any time during the product development process, approval process or after approval may subject an applicant and/or sponsor to a variety of
administrative or judicial sanctions, including refusal by the FDA to approve pending applications, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters and other
types of letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement of
profits, or civil or criminal investigations and penalties brought by the FDA and the Department of Justice or other governmental entities.
An
applicant seeking approval to market and distribute a new drug product in the United States must typically undertake the following:
-
-
completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA's good laboratory practice, or
GLP, regulations;
-
-
submission to the FDA of an IND, which must take effect before human clinical trials may begin;
-
-
approval by an independent institutional review board, or IRB, representing each clinical site before each clinical trial may be initiated;
-
-
performance of adequate and well-controlled human clinical trials in accordance with good clinical practices, or GCP, to establish the safety
and efficacy of the proposed drug product for each indication;
-
-
preparation and submission to the FDA of an NDA;
-
-
review of the product by an FDA advisory committee, where appropriate or if applicable;
-
-
satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof,
are produced to assess compliance with current Good Manufacturing Practices, or cGMP, requirements and to assure that the facilities, methods and controls are adequate to preserve the product's
identity, strength, quality and purity;
-
-
satisfactory completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data;
-
-
payment of user fees and securing FDA approval of the NDA; and
-
-
compliance with any post-approval requirements, including Risk Evaluation and Mitigation Strategies, or REMS, and post-approval studies
required by the FDA.
Preclinical Studies
Preclinical studies include laboratory evaluation of the purity and stability of the manufactured drug substance or active pharmaceutical
ingredient and the formulated drug or drug product, as well as
in vitro
and animal studies to assess the safety and activity of the drug for initial
testing in humans and to establish a rationale for therapeutic use. The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations. The results of the
preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical trials, among other things, are submitted to the FDA as
part of an IND. Some long-term
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preclinical
testing, such as chronic toxicity and carcinogenicity assessments, may continue after the IND is submitted.
Companies
usually must complete some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, and must also develop additional information
about the chemistry and physical characteristics of the investigational product and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The
manufacturing process must be capable of consistently producing quality batches of the candidate product and, among other things, the manufacturer must develop methods for testing the identity,
strength, quality and purity of the final product. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the candidate product
does not undergo unacceptable deterioration over its shelf life.
The IND and IRB Processes
An IND is an exemption from the FDCA that allows an unapproved drug to be shipped in interstate commerce for use in an investigational clinical
trial and a request for FDA authorization to administer an investigational drug to humans. Such authorization must be secured prior to interstate shipment and administration of any new drug that is
not the subject of an approved NDA. In support of a request for an IND, applicants must submit a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as
part of the IND. In addition, the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical trials,
among other things, are submitted to the FDA as part of an IND. The FDA requires a 30-day waiting period after the filing of each IND before clinical trials may begin. This waiting period is designed
to allow the FDA to review the IND to determine whether human research subjects will be exposed to unreasonable health risks. At any time during this 30-day period, the FDA may raise concerns or
questions about the conduct of the trials as
outlined in the IND and impose a clinical hold. In this case, the IND sponsor and the FDA must resolve any outstanding concerns before clinical trials can begin.
Following
commencement of a clinical trial under an IND, the FDA may also place a clinical hold or partial clinical hold on that trial. A clinical hold is an order issued by the FDA to
the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. A partial clinical hold is a delay or suspension of only part of the clinical work requested under the
IND. For example, a specific protocol or part of a protocol is not allowed to proceed, while other protocols may do so. No more than 30 days after imposition of a clinical hold or partial clinical
hold, the FDA will provide the sponsor a written explanation of the basis for the hold. Following issuance of a clinical hold or partial clinical hold, an investigation may only resume after the FDA
has notified the sponsor that the investigation may proceed. The FDA will base that determination on information provided by the sponsor correcting the deficiencies previously cited or otherwise
satisfying the FDA that the investigation can proceed.
A
sponsor may choose, but is not required, to conduct a foreign clinical study under an IND. When a foreign clinical study is conducted under an IND, all FDA IND requirements must be met
unless waived. When the foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with FDA certain regulatory requirements in order to use the study as
support for an IND or application for marketing approval. Specifically, on April 28, 2008, the FDA amended its regulations governing the acceptance of foreign clinical studies not conducted under an
investigational new drug application as support for an IND or a new drug application. The final rule provides that such studies must be conducted in accordance with GCP, including review and approval
by an independent ethics committee and informed consent from subjects. The GCP requirements in the final rule encompass both ethical and data integrity standards for clinical studies. The FDA's
regulations are intended to help ensure the protection of human subjects enrolled in non-IND foreign clinical studies,
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as
well as the quality and integrity of the resulting data. They further help ensure that non-IND foreign studies are conducted in a manner comparable to that required for IND studies.
In
addition to the foregoing IND requirements, an IRB representing each institution participating in the clinical trial must review and approve the plan for any clinical trial before it
commences at that institution, and the IRB must conduct continuing review and reapprove the study at least annually. The IRB must review and approve, among other things, the study protocol and
informed consent information to be provided to study subjects. An IRB must operate in compliance with FDA regulations. An IRB can suspend or terminate approval of a clinical trial at its institution,
or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB's requirements or if the product candidate has been associated with unexpected serious harm to
patients.
Additionally,
some trials are overseen by an independent group of qualified experts organized by the trial sponsor, known as a data safety monitoring board or committee. This group
provides authorization for whether or not a trial may move forward at designated check points based on access that only the group maintains to available data from the study. Suspension or termination
of development during any phase of clinical trials can occur if it is determined that the participants or patients are being exposed to an unacceptable health risk. Other reasons for suspension or
termination may be made by us based on evolving business objectives and/or competitive climate.
Information
about certain clinical trials must be submitted within specific timeframes to the National Institutes of Health for public dissemination on its ClinicalTrials.gov website.
Human Clinical Trials in Support of an NDA
Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in
accordance with GCP requirements, which include, among other things, the requirement that all research subjects provide their informed consent in writing before their participation in any clinical
trial. Clinical trials are conducted under written study protocols detailing, among other things, the inclusion and exclusion criteria, the objectives of the study, the parameters to be used in
monitoring safety and the effectiveness criteria to be evaluated.
Human
clinical trials are typically conducted in the following sequential phases, which may overlap or be combined:
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Phase 1.
The drug is initially
introduced into healthy human subjects or, in certain indications such as cancer, patients with the target disease or condition and tested for safety, dosage tolerance, absorption, metabolism,
distribution, excretion and, if possible, to gain an early indication of its effectiveness and to determine optimal dosage.
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Phase 2.
The drug is administered
to a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage
tolerance and optimal dosage.
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-
Phase 3.
The drug is administered
to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to statistically evaluate the efficacy and
safety of the product for approval, to establish the overall risk-benefit profile of the product and to provide adequate information for the labeling of the product.
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Phase 4.
Post-approval studies,
which are conducted following initial approval, are typically conducted to gain additional experience and data from treatment of patients in the intended therapeutic indication.
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Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur.
In addition, IND safety reports must be submitted to the FDA for any of the following: serious and unexpected suspected adverse reactions; findings from other studies or animal or
in vitro
testing that
suggest a significant risk in humans exposed to the drug; and any clinically important increase in the case of a serious suspected
adverse reaction over that listed in the protocol or investigator brochure. Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, or at all.
Furthermore, the FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health
risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the
IRB's requirements or if the drug has been associated with unexpected serious harm to patients. The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the
integrity of the clinical data submitted.
Concurrent
with clinical trials, companies often complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the
drug as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing
quality batches of the drug candidate and, among other things, must develop methods for testing the identity, strength,
quality, purity, and potency of the final drug. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the drug candidate does not
undergo unacceptable deterioration over its shelf life.
Submission of an NDA to the FDA
Assuming successful completion of required clinical testing and other requirements, the results of the preclinical studies and clinical trials,
together with detailed information relating to the product's chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA requesting approval
to market the drug product for one or more indications. Under federal law, the submission of most NDAs is additionally subject to an application user fee, which for federal fiscal year 2017 is
$2,038,100. The sponsor of an approved NDA is also subject to annual product and establishment user fees, which for fiscal year 2017 are $97,750 per product and $512,200 per establishment.
The
FDA conducts a preliminary review of an NDA within 60 days of its receipt and informs the sponsor by the 74th day after the FDA's receipt of the submission to determine whether the
application is sufficiently complete to permit substantive review. The FDA may request additional information rather than accept an NDA for filing. In this event, the application must be resubmitted
with the additional information. The resubmitted application is also subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth
substantive review. The FDA has agreed to certain performance goals in the review process of NDAs. Most such applications are meant to be reviewed within ten months from the date of filing, and most
applications for "priority review" products are meant to be reviewed within six months of filing. The review process may be extended by the FDA for three additional months to consider new information
or clarification provided by the applicant to address an outstanding deficiency identified by the FDA following the original submission.
Before
approving an NDA, the FDA typically will inspect the facility or facilities where the product is or will be manufactured. These pre-approval inspections may cover all facilities
associated with an NDA submission, including drug component manufacturing (such as active pharmaceutical ingredients), finished drug product manufacturing and control testing laboratories. The FDA
will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the
product within required
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specifications.
Additionally, before approving an NDA, the FDA will typically inspect one or more clinical sites involved with the conduct of the Phase 3 clinical trials to assure compliance with GCP.
If compliance or data integrity is called into question due to inspection finding, this may cause a delay or affect the likelihood of drug approval.
In
addition, as a condition of approval, the FDA may require an applicant to develop a REMS. REMS use risk minimization strategies beyond the professional labeling to ensure that the
benefits of the product outweigh the potential risks. To determine whether a REMS is needed, the FDA will consider the size of the population likely to use the product, seriousness of the disease,
expected benefit of the product, expected duration of treatment, seriousness of known or potential adverse events, and whether the product is a new molecular entity. REMS can include medication
guides, physician communication plans for healthcare professionals, and elements to assure safe use, or ETASU. ETASU may include, but are not limited to, special training or certification for
prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries. The FDA may require a REMS before approval or post-approval if it becomes
aware of a serious risk associated with use of the product. The requirement for a REMS can materially affect the potential market and profitability of a product.
The
FDA is required to refer an application for a novel drug to an advisory committee or explain why such referral was not made. Typically, an advisory committee is a panel of
independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what
conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
Fast Track, Breakthrough Therapy, Priority Review and Regenerative Advanced Therapy Designations
The FDA is authorized to designate certain products for expedited review if they are intended to address an unmet medical need in the treatment
of a serious or life-threatening disease or condition. These programs are referred to as fast track designation, breakthrough therapy designation, priority review designation and regenerative advanced
therapy designation.
Specifically,
the FDA may designate a product for Fast Track review if it is intended, whether alone or in combination with one or more other products, for the treatment of a serious or
life-threatening disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition. For Fast Track products, sponsors may have greater interactions
with the FDA
and the FDA may initiate review of sections of a Fast Track product's application before the application is complete. This rolling review may be available if the FDA determines, after preliminary
evaluation of clinical data submitted by the sponsor, that a Fast Track product may be effective. The sponsor must also provide, and the FDA must approve, a schedule for the submission of the
remaining information and the sponsor must pay applicable user fees. However, the FDA's time period goal for reviewing a Fast Track application does not begin until the last section of the application
is submitted. In addition, the Fast Track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process.
Second,
a product may be designated as a Breakthrough Therapy if it is intended, either alone or in combination with one or more other products, to treat a serious or life-threatening
disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such
as substantial treatment effects observed early in clinical development. The FDA may take certain actions with respect to Breakthrough Therapies, including holding meetings with the sponsor throughout
the development process; providing timely advice to the product sponsor regarding development and
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approval;
involving more senior staff in the review process; assigning a cross-disciplinary project lead for the review team; and taking other steps to design the clinical trials in an efficient
manner.
Third,
the FDA may designate a product for priority review if it is a product that treats a serious condition and, if approved, would provide a significant improvement in safety or
effectiveness. The FDA determines, on a case- by-case basis, whether the proposed product represents a significant improvement when compared with other available therapies. Significant improvement may
be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting product reaction, documented enhancement of patient
compliance that may lead to improvement in serious outcomes, and evidence of safety and effectiveness in a new subpopulation. A priority designation is intended to direct overall attention and
resources to the evaluation of such applications, and to shorten the FDA's goal for taking action on a marketing application from ten months to six months.
Finally,
with passage of the 21st Century Cures Act, or the Cures Act, in December 2016, Congress authorized the FDA to accelerate review and approval of products designated as
regenerative advanced therapies. A product is eligible for this designation if it is a regenerative medicine therapy that is intended to treat, modify, reverse or cure a serious or life-threatening
disease or condition and preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition. The benefits of a regenerative advanced
therapy designation include early interactions with FDA to expedite development and review, benefits available to breakthrough therapies, potential eligibility for priority review and accelerated
approval based on surrogate or intermediate endpoints.
Accelerated Approval Pathway
The FDA may grant accelerated approval to a drug for a serious or life-threatening condition that provides meaningful therapeutic advantage to
patients over existing treatments based upon a determination that the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. The FDA may also grant
accelerated approval for such a condition when the product has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, or
IMM, and that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and
the availability or lack of alternative treatments. Drugs granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval.
For
the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to
predict clinical benefit, but is not itself a measure of clinical benefit. Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints. An intermediate clinical
endpoint is a measurement of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on IMM. There is limited experience with accelerated
approvals by the FDA based on intermediate clinical endpoints. However, the FDA has indicated that such endpoints generally may support accelerated approval where the therapeutic effect measured by
the endpoint is not itself a clinical benefit and basis for traditional approval, if there is a basis for concluding that the therapeutic effect is reasonably likely to predict the ultimate clinical
benefit of a drug.
The
accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended period of time is required to measure the intended clinical
benefit of a drug, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly. Thus, accelerated approval has been used extensively in the development and approval of drugs
for treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity and the
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duration
of the typical disease course requires lengthy and sometimes large trials to demonstrate a clinical or survival benefit.
The
accelerated approval pathway is usually contingent on a sponsor's agreement to conduct, in a diligent manner, additional post-approval confirmatory studies to verify and describe the
drug's clinical benefit. As a result, a drug candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase 4 or post-approval
clinical trials to confirm the effect on the clinical endpoint. Failure to conduct required post-approval studies, or confirm a clinical benefit during post-marketing studies, would allow the FDA to
withdraw the drug from the market on an expedited basis. All promotional materials for drug candidates approved under accelerated regulations are subject to prior review by the FDA.
The FDA's Decision on an NDA
On the basis of the FDA's evaluation of the NDA and accompanying information, including the results of the inspection of the manufacturing
facilities, the FDA may issue an approval letter or a complete response letter. An approval letter authorizes commercial marketing of the product with specific prescribing information for specific
indications. A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing or information in order for the FDA to reconsider the
application. If and when those deficiencies have been addressed to the FDA's satisfaction in a resubmission of the NDA, the FDA may issue an approval letter. The FDA has committed to reviewing such
resubmissions in two or six months depending on the type of information included. Even with submission of this additional information, the FDA ultimately may decide that the application does not
satisfy the regulatory criteria for approval. The FDA, and other foreign regulatory agencies, have substantial discretion in the approval process.
If
the FDA approves a product, it may limit the approved indications for use for the product, require that contraindications, warnings or precautions be included in the product labeling,
require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess the drug's safety after approval, require testing and surveillance programs to monitor the product
after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, including REMS, which can materially affect the potential market and
profitability of the product. The FDA may prevent or limit further marketing of a product based on the results of post-market studies or surveillance programs. After approval, many types of changes to
the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further testing requirements and FDA review and approval.
Post-Approval Requirements
Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among
other things, requirements relating
to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product. After approval, most changes to the approved
product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval. There also are continuing, annual user fee requirements for any marketed products and
the establishments at which such products are manufactured, as well as new application fees for supplemental applications with clinical data.
In
addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and state
agencies, and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements. Changes to the manufacturing process are strictly regulated and
often require prior FDA approval before being implemented. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and documentation requirements
upon
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the
sponsor and any third-party manufacturers that the sponsor may decide to use. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality
control to maintain cGMP compliance.
Once
an approval is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches
the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with
regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical trials to assess new safety risks; or imposition
of distribution or other restrictions under a REMS program. Other potential consequences include, among other things:
-
-
restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls;
-
-
fines, warning letters or holds on post-approval clinical trials;
-
-
refusal of the FDA to approve pending NDAs or supplements to approved NDAs, or suspension or revocation of product license approvals;
-
-
product seizure or detention, or refusal to permit the import or export of products; or
-
-
injunctions or the imposition of civil or criminal penalties.
The
FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market. Drugs may be promoted only for the approved indications and in
accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to
have improperly promoted off-label uses may be subject to significant liability.
In
addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act, or PDMA, which regulates the distribution of drugs and drug
samples at the federal level, and sets minimum standards for the registration and regulation of drug distributors by the states. Both the PDMA and state laws limit the distribution of prescription
pharmaceutical product samples and impose requirements to ensure accountability in distribution.
Abbreviated New Drug Applications for Generic Drugs
In 1984, with passage of the Hatch-Waxman Amendments to the FDCA, Congress authorized the FDA to approve generic drugs that are the same as
drugs previously approved by the FDA under the NDA provisions of the statute. To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application, or ANDA, to the
agency. In support of such applications, a generic manufacturer may rely on the preclinical and clinical testing previously conducted for a drug product previously approved under an NDA, known as the
reference-listed drug, or RLD.
Specifically,
in order for an ANDA to be approved, the FDA must find that the generic version is identical to the RLD with respect to the active ingredients, the route of administration,
the dosage form, and the strength of the drug. At the same time, the FDA must also determine that the generic drug is "bioequivalent" to the innovator drug. Under the statute, a generic drug is
bioequivalent to a RLD if "the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug..."
Upon
approval of an ANDA, the FDA indicates whether the generic product is "therapeutically equivalent" to the RLD in its publication "Approved Drug Products with Therapeutic Equivalence
Evaluations," also referred to as the "Orange Book." Physicians and pharmacists consider a therapeutic
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equivalent
generic drug to be fully substitutable for the RLD. In addition, by operation of certain state laws and numerous health insurance programs, the FDA's designation of therapeutic equivalence
often results in substitution of the generic drug without the knowledge or consent of either the prescribing physician or patient.
Under
the Hatch-Waxman Amendments, the FDA may not approve an ANDA until any applicable period of non-patent exclusivity for the RLD has expired. The FDCA provides a period of five years
of non-patent data exclusivity for a new drug containing a new chemical entity. For the purposes of this provision, a new chemical entity, or NCE, is a drug that contains no active moiety that has
previously been approved by the FDA in any other NDA. An active moiety is the molecule or ion responsible for the physiological or pharmacological action of the drug substance. In cases where such NCE
exclusivity has been granted, an ANDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV certification, in which case the applicant
may submit its application four years following the original product approval.
The
FDCA also provides for a period of three years of exclusivity if the NDA includes reports of one or more new clinical investigations, other than bioavailability or bioequivalence
studies, that were conducted by or for the applicant and are essential to the approval of the application. This three-year exclusivity period often protects changes to a previously approved drug
product, such as a new dosage form, route of administration, combination or indication. Three-year exclusivity would be available for a drug product that contains a previously approved active moiety,
provided the statutory requirement for a new clinical investigation is satisfied. Unlike five-year NCE exclusivity, an award of three-year exclusivity does not block the FDA from accepting ANDAs
seeking approval for generic versions of the drug as of the date of approval of the original drug product. The FDA typically makes decisions about awards of data exclusivity shortly before a product
is approved.
Hatch-Waxman Patent Certification and the 30-Month Stay
Upon approval of an NDA or a supplement thereto, NDA sponsors are required to list with the FDA each patent with claims that cover the
applicant's product or an approved method of using the product. Each of the patents listed by the NDA sponsor is published in the Orange Book. When an ANDA applicant files its application with the
FDA, the applicant is required to certify to the FDA concerning any patents listed for the reference product in the Orange Book, except for patents covering methods of use for which the ANDA applicant
is not seeking approval. To the extent that the Section 505(b)(2) applicant is relying on studies conducted for an already approved product, the applicant is required to certify to the FDA
concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA applicant would.
Specifically,
the applicant must certify with respect to each patent that:
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-
the required patent information has not been filed;
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-
the listed patent has expired;
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-
the listed patent has not expired, but will expire on a particular date and approval is sought after patent expiration; or
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the listed patent is invalid, unenforceable or will not be infringed by the new product.
A
certification that the new product will not infringe the already approved product's listed patents or that such patents are invalid or unenforceable is called a Paragraph IV
certification. If the applicant does not challenge the listed patents or indicates that it is not seeking approval of a patented method
of use, the ANDA application will not be approved until all the listed patents claiming the referenced product have expired (other than method of use patents involving indications for which the ANDA
applicant is not seeking approval).
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If
the ANDA applicant has provided a Paragraph IV certification to the FDA, the applicant must also send notice of the Paragraph IV certification to the NDA and patent holders once the
ANDA has been accepted for filing by the FDA. The NDA and patent holders may then initiate a patent infringement lawsuit in response to the notice of the Paragraph IV certification. The filing of a
patent infringement lawsuit within 45 days after the receipt of a Paragraph IV certification automatically prevents the FDA from approving the ANDA until the earlier of 30 months after the receipt of
the Paragraph IV notice, expiration of the patent, or a decision in the infringement case that is favorable to the ANDA applicant.
Pediatric Studies and Exclusivity
Under the Pediatric Research Equity Act of 2003, an NDA or supplement thereto must contain data that are adequate to assess the safety and
effectiveness of the drug product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product
is safe and effective. With enactment of the Food and Drug Administration Safety and Innovation Act, or FDASIA, in 2012, sponsors must also submit pediatric study plans prior to the assessment data.
Those plans must contain an outline of the proposed pediatric study or studies the applicant plans to conduct, including study objectives and design, any deferral or waiver requests, and other
information required by regulation. The applicant, the FDA, and the FDA's internal review committee must then review the information submitted, consult with each other, and agree upon a final plan.
The FDA or the applicant may request an amendment to the plan at any time.
The
FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults,
or full or partial waivers from the pediatric data requirements. Additional requirements and procedures relating to deferral requests and requests for extension of deferrals are contained in FDASIA.
Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation.
Pediatric
exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted, provides for the attachment of an additional six months of marketing
protection to the term of any existing regulatory exclusivity, including the non-patent and orphan exclusivity. This six-month exclusivity may be granted if an NDA sponsor submits pediatric data that
fairly respond to a written request from the FDA for such data. The data do not need to show the product to be effective in the pediatric population studied; rather, if the clinical trial is deemed to
fairly respond to the FDA's request, the additional protection is granted. If reports of requested pediatric studies are submitted to and accepted by the FDA within the statutory time limits, whatever
statutory or regulatory periods of exclusivity or patent protection cover the product are extended by six months. This is not a patent term extension, but it effectively extends the regulatory period
during which the FDA cannot approve another application.
Orphan Drug Designation and Exclusivity
Under the Orphan Drug Act, the FDA may designate a drug product as an "orphan drug" if it is intended to treat a rare disease or condition
(generally meaning that it affects fewer than 200,000 individuals in the United States, or more in cases in which there is no reasonable expectation that the cost of developing and making a drug
product available in the United States for treatment of the disease or condition will be recovered from sales of the product). A company must request orphan product designation before submitting an
NDA. If the request is granted, the FDA will disclose the identity of the therapeutic agent and its potential use. Orphan product designation does not convey any advantage in or shorten the duration
of the regulatory review and approval process.
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If
a product with orphan status receives the first FDA approval for the disease or condition for which it has such designation or for a select indication or use within the rare disease
or condition for which it was designated, the product generally will be receiving orphan product exclusivity. Orphan product exclusivity means that the FDA may not approve any other applications for
the same product for the same indication for seven years, except in certain limited circumstances, such as if the later product is shown to be clinically superior to our product or due to an inability
to assure a sufficient quantity of the orphan drug. Competitors may receive approval of different products for the indication for which the orphan product has exclusivity and may obtain approval for
the same product but for a different indication. If a drug or drug product designated as an orphan product ultimately receives marketing approval for an indication broader than what was designated in
its orphan product application, it may not be entitled to exclusivity.
Patent Term Restoration and Extension
A patent claiming a new drug product may be eligible for a limited patent term extension under the Hatch-Waxman Act, which permits a patent
restoration of up to five years for patent term lost during product development and the FDA regulatory review. The restoration period granted is typically one-half the time between the effective date
of an IND and the submission date of an NDA, plus the time between the submission date of an NDA and the ultimate approval date. Patent term restoration cannot be used to extend the remaining term of
a patent past a total of 14 years from the product's approval date. Only one patent applicable to an approved drug product is eligible for the extension, and the application for the extension must be
submitted prior to the expiration of the patent in question. A patent that covers multiple drugs for which approval is sought can only be extended in connection with one of the approvals. The U.S.
Patent and Trademark Office reviews and approves the application for any patent term extension or restoration in consultation with the FDA.
Rare Pediatric Disease Priority Review Voucher Program
With enactment of the FDASIA in 2012, Congress authorized the FDA to award priority review vouchers to sponsors of certain rare pediatric
disease product applications that meet the criteria specified in the law. This provision is designed to encourage development of new drug and biological products for prevention and treatment of
certain rare pediatric diseases. Specifically, under this program, a sponsor who receives an approval for a drug or biologic for a "rare pediatric disease" may qualify for a voucher that can be
redeemed to receive a priority review of a subsequent marketing application for a different product. The sponsor of a rare pediatric disease drug product receiving a priority review voucher may
transfer (including by sale) the voucher to another sponsor. The voucher may be further transferred any number of times before the voucher is used, as long as the sponsor making the transfer has not
yet submitted the application.
For
the purposes of this program, a "rare pediatric disease" is a (a) serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect
individuals aged from birth to 18 years, including age groups often called neonates, infants, children, and adolescents; and (b) rare disease or conditions within the meaning of the Orphan Drug
Act. A sponsor may choose to request rare pediatric disease designation, but the designation process is entirely voluntary; requesting designation is not a prerequisite to requesting or receiving a
priority review voucher. In addition, sponsors who choose not to submit a rare pediatric disease designation request may nonetheless receive a priority review voucher if they request such a voucher in
their original marketing application and meet all of the eligibility criteria. Under the Cures Act, the Rare Pediatric Disease Priority Review Voucher program was reauthorized until 2020. However, if
a drug is designated before October 1, 2020, it is eligible to receive a voucher if approved before October 2022.
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The 21st Century Cures Act
On December 13, 2016, President Obama signed the Cures Act into law. The Cures Act is designed to modernize and personalize healthcare, spur
innovation and research, and streamline the discovery and development of new therapies through increased federal funding of particular programs. It authorizes increased funding for the FDA to spend on
innovation projects. The new law also amends the Public Health Service Act to reauthorize and expand funding for the National Institutes of Health. The Act establishes the NIH Innovation Fund to pay
for the cost of development and implementation of a strategic plan, early stage investigators and research. It also charges NIH with leading and coordinating expanded pediatric research. Further, the
Cures Act directs the Centers for Disease Control and Prevention to expand surveillance of neurological diseases.
With
amendments to the FDCA and the Public Health Service Act, or PHSA, Title III of the Cures Act seeks to accelerate the discovery, development and delivery of new medicines and
medical technologies. To that end, and among other provisions, the Cures Act reauthorizes the existing priority review voucher program for certain drugs intended to treat rare pediatric diseases until
2020; creates a new priority review voucher program for drug applications determined to be material national security threat medical countermeasure applications; revises the FDCA to streamline review
of combination product applications; requires FDA to evaluate the potential use of "real world evidence" to help support approval of new indications for approved drugs; provides a new "limited
population" approval pathway for antibiotic and antifungal drugs intended to treat serious or life-threatening infections; and authorizes FDA to designate a drug as a "regenerative advanced therapy,"
thereby making it eligible for certain expedited review and approval designations.
Review and Approval of Drug Products in the European Union
In order to market any product outside of the United States, a company must also comply with numerous and varying regulatory requirements of
other countries and jurisdictions regarding quality, safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of products.
Whether or not it obtains FDA approval for a product, the company would need to obtain the necessary approvals by the comparable foreign regulatory authorities before it can commence clinical trials
or marketing of the product in those
countries or jurisdictions. The approval process ultimately varies between countries and jurisdictions and can involve additional product testing and additional administrative review periods. The time
required to obtain approval in other countries and jurisdictions might differ from and be longer than that required to obtain FDA approval. Regulatory approval in one country or jurisdiction does not
ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others.
Procedures Governing Approval of Drug Products in the European Union
Pursuant to the European Clinical Trials Directive, a system for the approval of clinical trials in the European Union has been implemented
through national legislation of the member states. Under this system, an applicant must obtain approval from the competent national authority of a European Union member state in which the clinical
trial is to be conducted. Furthermore, the applicant may only start a clinical trial after a competent ethics committee has issued a favorable opinion. Clinical trial application must be accompanied
by an investigational medicinal product dossier with supporting information prescribed by the European Clinical Trials Directive and corresponding national laws of the member states and further
detailed in applicable guidance documents.
To
obtain marketing approval of a product under European Union regulatory systems, an applicant must submit a marketing authorization application, or MAA, either under a centralized or
decentralized procedure. The centralized procedure provides for the grant of a single marketing
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authorization
by the EC that is valid for all European Union member states. The centralized procedure is compulsory for specific products, including for medicines produced by certain biotechnological
processes, products designated as orphan medicinal products, advanced therapy products and products with a new active substance indicated for the treatment of certain diseases. For products with a new
active substance indicated for the treatment of other diseases and products that are highly innovative or for which a centralized process is in the interest of patients, the centralized procedure may
be optional.
Under
the centralized procedure, the Committee for Medicinal Products for Human Use, or the CHMP, established at the EMA is responsible for conducting the initial assessment of a
product. The CHMP is also responsible for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing marketing authorization. Under the
centralized procedure in the European Union, the maximum timeframe for the evaluation of an MAA is 210 days, excluding clock stops, when additional information or written or oral explanation is to be
provided by
the applicant in response to questions of the CHMP. Accelerated evaluation might be granted by the CHMP in exceptional cases, when a medicinal product is of major interest from the point of view of
public health and in particular from the viewpoint of therapeutic innovation. In this circumstance, the EMA ensures that the opinion of the CHMP is given within 150 days.
The
decentralized procedure is available to applicants who wish to market a product in various European Union member states where such product has not received marketing approval in any
European Union member states before. The decentralized procedure provides for approval by one or more other, or concerned, member states of an assessment of an application performed by one member
state designated by the applicant, known as the reference member state. Under this procedure, an applicant submits an application based on identical dossiers and related materials, including a draft
summary of product characteristics, and draft labeling and package leaflet, to the reference member state and concerned member states. The reference member state prepares a draft assessment report and
drafts of the related materials within 210 days after receipt of a valid application. Within 90 days of receiving the reference member state's assessment report and related materials, each concerned
member state must decide whether to approve the assessment report and related materials.
If
a member state cannot approve the assessment report and related materials on the grounds of potential serious risk to public health, the disputed points are subject to a dispute
resolution mechanism and may eventually be referred to the EC, whose decision is binding on all member states.
Clinical Trial Approval
Requirements for the conduct of clinical trials in the European Union, including GCP, are set forth in the Clinical Trials
Directive 2001/20/EC and the GCP Directive 2005/28/EC. Pursuant to Directive 2001/20/EC and Directive 2005/28/EC, as amended, a system for the approval of clinical trials
in the European Union has been implemented through national legislation of the European Union member states. Under this system, approval must be obtained from the competent national authority of each
European Union member state in which a study is planned to be conducted. To this end, a Clinical Trial Application is submitted, which must be supported by an investigational medicinal product
dossier, or IMPD, and further supporting information prescribed by Directive 2001/20/EC and Directive 2005/28/EC and other applicable guidance documents. Furthermore, a clinical trial
may only be started after a competent ethics committee has issued a favorable opinion on the clinical trial application in that country.
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In April 2014, the European Union passed the new Clinical Trials Regulation, (EU) No 536/2014, which will replace the current Clinical Trials
Directive 2001/20/EC. To ensure that the rules for clinical trials are identical throughout the European Union, the new European Union clinical trials legislation was passed as a regulation
that is directly applicable in all European Union member states. All clinical trials performed in the European Union are required to be conducted in accordance with the Clinical Trials
Directive 2001/20/EC until the new Clinical Trials Regulation (EU) No 536/2014 becomes applicable. According to the current plans of the EMA, the new Clinical Trials Regulation will become
applicable in October 2018. The Clinical Trials Directive 2001/20/EC will, however, still apply three years from the date of entry into application of the Clinical Trials Regulation to (i)
clinical trials applications submitted before the entry into application and (ii) clinical trials applications submitted within one year after the entry into application if the sponsor opts for old
system.
The
new Clinical Trials Regulation aims to simplify and streamline the approval of clinical trial in the European Union. The main characteristics of the regulation include: a streamlined
application procedure via a single entry point, the European Union portal; a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures that
will spare sponsors from submitting broadly identical information separately to various bodies and different member states; a harmonized procedure for the assessment of applications for clinical
trials, which is divided in two parts. Part I is assessed jointly by all member states concerned. Part II is assessed
separately by each member state concerned; strictly defined deadlines for the assessment of clinical trial applications; and the involvement of the ethics committees in the assessment procedure in
accordance with the national law of the member state concerned but within the overall timelines defined by the Clinical Trials Regulation.
Data and Market Exclusivity in the European Union
In the European Union, new chemical entities qualify for eight years of data exclusivity upon marketing authorization and an additional two
years of market exclusivity. This data exclusivity, if granted, prevents regulatory authorities in the European Union from referencing the innovator's data to assess a generic (abbreviated)
application for eight years, after which generic marketing authorization can be submitted, and the innovator's data may be referenced, but not approved for two years. The overall ten-year period will
be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications
which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies. Even if a compound is considered to be a
new chemical entity and the sponsor is able to gain the prescribed period of data exclusivity, another company nevertheless could also market another version of the product if such company can
complete a full MAA with a complete database of pharmaceutical test, preclinical tests and clinical trials and obtain marketing approval of its product.
In
order to market any product outside of the United States, a company must also comply with numerous and varying regulatory requirements of other countries and jurisdictions regarding
quality, safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of drug products. Whether or not it obtains FDA approval for
a product, the company would need to obtain the necessary approvals by the comparable foreign regulatory authorities before it can commence clinical trials or marketing of the product in those
countries or jurisdictions. The approval process ultimately varies between countries and jurisdictions and can involve additional product testing and additional administrative review periods. The time
required to obtain approval in other countries and jurisdictions might differ from and be longer than that required to obtain FDA approval. Regulatory approval in one country or jurisdiction does not
ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others.
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Periods of Authorization and Renewals
Marketing authorization is valid for five years in principle and the marketing authorization may be renewed after five years on the basis of a
re-evaluation of the risk-benefit balance by the EMA or by the competent authority of the authorizing member state. To this end, the marketing authorization holder must provide the EMA or the
competent authority with a consolidated version of the file in respect of quality, safety and efficacy, including all variations introduced since the marketing authorization was granted, at least six
months before the marketing authorization ceases to be valid. Once renewed, the marketing authorization is valid for an unlimited period, unless the EC or the competent authority decides, on justified
grounds relating to pharmacovigilance, to proceed with one additional five-year renewal. Any authorization which is not followed by the actual placing of the drug on the European Union market (in case
of centralized procedure) or on the market of the authorizing member state within three years after authorization ceases to be valid (the so-called sunset clause).
Orphan Drug Designation and Exclusivity
Regulation 141/2000 provides that a drug shall be designated as an orphan drug if its sponsor can establish: that the product is intended for
the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the European Community when the application
is made, or that the product is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the European Community and that
without incentives it is unlikely that the marketing of the drug in the European Community would generate sufficient return to justify the necessary investment. For either of these conditions, the
applicant must demonstrate that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized in the European Community or, if such
method exists, the drug will be of significant benefit to those affected by that condition.
Regulation
847/2000 sets out criteria and procedures governing designation of orphan drugs in the European Union. Specifically, an application for designation as an orphan product can be
made any time prior to the filing of an application for approval to market the product. Marketing authorization for an orphan drug leads to a ten-year period of market exclusivity. This period may,
however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan drug designation, for example because the product is
sufficiently profitable not to justify market exclusivity. Market exclusivity can be revoked only in very selected cases, such as consent from the marketing authorization holder, inability to supply
sufficient quantities of the product, demonstration of "clinically relevant superiority" by a similar medicinal product, or, after a review by the Committee for Orphan Medicinal Products, requested by
a member state in the fifth year of the marketing exclusivity period (if the designation criteria are believed to no longer apply). Medicinal products designated as orphan drugs pursuant to Regulation
141/2000 shall be eligible for incentives
made available by the European Community and by the member states to support research into, and the development and availability of, orphan drugs.
Brexit and the Regulatory Framework in the United Kingdom
On June 23, 2016, the electorate in the United Kingdom voted in favor of leaving the European Union, which is commonly referred to as "Brexit".
The withdrawal of the U.K. from the European Union will take effect either on the effective date of the withdrawal agreement or, in the absence of agreement, two years after the U.K. provides a notice
of withdrawal pursuant to the European Union Treaty. The U.K. Prime Minister has stated that notice of withdrawal will be given by the end of March 2017. Since the regulatory framework for
pharmaceutical products in the U.K. covering quality, safety and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales and distribution of pharmaceutical
products is derived from European Union directives and regulations,
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Brexit
could materially impact the future regulatory regime which applies to products and the approval of product candidates in the U.K. It remains to be seen how, if at all, Brexit will impact
regulatory requirements for product candidates and products in the U.K.
Pharmaceutical Coverage, Pricing and Reimbursement
Significant uncertainty exists as to the coverage and reimbursement status of products approved by the FDA and other government authorities.
Sales of products will depend, in part, on the extent to which third-party payors, including government health programs in the United States such as Medicare and Medicaid, commercial health insurers
and managed care organizations, provide coverage, and establish adequate reimbursement levels for, such products. The process for determining whether a payor will provide coverage for a product may be
separate from the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is approved. Third-party payors are increasingly challenging the prices
charged for medical products and services and imposing controls to manage costs. Third-party payors may limit coverage to specific products on an approved list, or formulary, which might not include
all of the approved products for a particular indication.
In
order to secure coverage and reimbursement for any product that might be approved for sale, a company may need to conduct expensive pharmacoeconomic studies in order to demonstrate
the medical necessity and cost-effectiveness of the product, in addition to the costs required to obtain FDA or other comparable regulatory approvals. A payor's decision to provide coverage for a drug
product does not imply that an adequate reimbursement rate will be approved. Third-party reimbursement may not be sufficient to maintain price levels high enough to realize an appropriate return on
investment in product development.
The
containment of healthcare costs also has become a priority of federal, state and foreign governments and the prices of drugs have been a focus in this effort. Governments have shown
significant interest in implementing cost-containment programs, including price controls, restrictions on reimbursement and requirements for substitution of generic products. Adoption of price
controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit our net revenue and results.
Outside
the United States, ensuring adequate coverage and payment for our product candidates will face challenges. Pricing of prescription pharmaceuticals is subject to governmental
control in many countries. Pricing negotiations with governmental authorities can extend well beyond the receipt of regulatory marketing approval for a product and may require us to conduct a clinical
trial that compares the cost effectiveness of our product candidates or products to other available therapies. The conduct of such a clinical trial could be expensive and result in delays in our
commercialization efforts.
In
the European Union, pricing and reimbursement schemes vary widely from country to country. Some countries provide that drug products may be marketed only after a reimbursement price
has been agreed. Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular drug candidate to currently available therapies. For example, the
European Union provides options for its member states to restrict the range of drug products for which their national health insurance systems provide reimbursement and to control the prices of
medicinal products for human use. European Union member states may approve a specific price for a drug product or it may instead adopt a system of direct or indirect controls on the profitability of
the company placing the drug product on the market. Other member states allow companies to fix their own prices for drug products, but monitor and control company profits. The downward pressure on
health care costs in general, particularly prescription drugs, has become intense. As a result, increasingly high barriers are being erected to the entry of new products. In addition, in some
countries, cross-border imports from low-priced markets exert competitive pressure that may reduce pricing within a country. Any country that has price controls or reimbursement limitations for drug
products may not allow favorable reimbursement and pricing arrangements.
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Healthcare Law and Regulation
Healthcare providers, physicians and third-party payors play a primary role in the recommendation and prescription of drug products that are
granted marketing approval. Arrangements with third-party payors and customers are subject to broadly applicable fraud and abuse and other healthcare laws and regulations. Such restrictions under
applicable federal and state healthcare laws and regulations, include the following:
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-
the federal Anti-Kickback Statute, which prohibits, among other things, persons and entities from knowingly and willfully soliciting, offering,
receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, order or recommendation of, any good or
service, for which payment may be made, in whole or in part, under a federal healthcare program such as Medicare and Medicaid;
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-
the federal civil and criminal false claims laws, including the civil False Claims Act, and civil monetary penalties laws, which prohibit
individuals or entities from, among other things, knowingly presenting, or causing to be presented, to the federal government, claims for payment that are false or fraudulent or making a false
statement to avoid, decrease or conceal an obligation to pay money to the federal government;
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-
the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created federal criminal laws that prohibit, among
other things, knowingly and willingly executing, or attempting to execute, a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;
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-
HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act and its implementing regulations, which also
imposes obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;
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the federal false statements statute, which prohibits knowingly and willfully falsifying, concealing or covering up a material fact or making
any materially false statement in connection with the delivery of or payment for healthcare benefits, items or services;
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-
the federal transparency requirements under the Patient Protection and Affordable Care Act, as amended by the Health Care Education
Reconciliation Act, or the Affordable Care Act, which requires certain manufacturers of drugs, devices, biologics and medical supplies to report to the Department of Health and Human Services
information related to payments and other transfers of value to physicians and teaching hospitals and physician ownership and investment interests; and
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analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws, which may apply to healthcare items or
services that are reimbursed by non-governmental third-party payors, including private insurers.
Some
state laws require pharmaceutical companies to comply with the pharmaceutical industry's voluntary compliance guidelines and the relevant compliance guidance promulgated by the
federal government in addition to requiring drug manufacturers to report information related to payments to physicians and other health care providers or marketing expenditures. State and foreign laws
also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating
compliance efforts.
Healthcare Reform
A primary trend in the United States healthcare industry and elsewhere is cost containment. There have been a number of federal and state
proposals during the last few years regarding the pricing of
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pharmaceutical
and biopharmaceutical products, limiting coverage and reimbursement for drugs and other medical products, government control and other changes to the healthcare system in the United
States.
In
March 2010, the United States Congress enacted the Affordable Care Act, which, among other things, includes changes to the coverage and payment for drug products under government
health care programs. The Affordable Care Act:
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-
expanded manufacturers' rebate liability under the Medicaid Drug Rebate Program by increasing the minimum rebate for both branded and generic
drugs and revising the definition of "average manufacturer price," or AMP, for calculating and reporting Medicaid drug rebates on outpatient prescription drug prices;
-
-
addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are
inhaled, infused, instilled, implanted or injected;
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-
expanded the types of entities eligible for the 340B drug discount program; and
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established the Medicare Part D coverage gap discount program by requiring manufacturers to provide a 50% point-of-sale-discount off the
negotiated price of applicable brand drugs to eligible beneficiaries during their coverage gap period as a condition for the manufacturers' outpatient drugs to be covered under Medicare Part D.
Other
legislative changes have been proposed and adopted in the United States since the Affordable Care Act was enacted. In August 2011, the Budget Control Act of 2011, among other
things, created measures for spending reductions by Congress. A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the
years 2013 through 2021,
was unable to reach required goals, thereby triggering the legislation's automatic reduction to several government programs. This includes aggregate reductions of Medicare payments to providers up to
2% per fiscal year, which went into effect in April 2013 and will remain in effect through 2024 unless additional Congressional action is taken. In January 2013, President Obama signed into law the
American Taxpayer Relief Act of 2012, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and
increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
With
the new Presidential Administration and Congress, there will likely be additional legislative changes, including repeal and replacement of certain provisions of the Affordable Care
Act. In January 2017, Congress voted to adopt a budget resolution for fiscal year 2017, or the Budget Resolution, that authorizes the implementation of legislation that would repeal portions of the
Affordable Care Act. The Budget Resolution is not a law, however, it is widely viewed as the first step toward the passage of legislation that would repeal certain aspects of the Affordable Care Act.
Further, on January 20, 2017, President Trump signed an Executive Order directing federal agencies with authorities and responsibilities under the Affordable Care Act to waive, defer, grant exemptions
from, or delay the implementation of any provision of the Affordable Care Act that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or
manufacturers of pharmaceuticals or medical devices.
The
President and Congressional leaders have expressed interest in repealing certain Affordable Care Act provisions and replacing them with alternatives that may be less costly and
provide state Medicaid programs and private health plans more flexibility. It is possible that these repeal and replacement initiatives, if enacted into law, could ultimately result in fewer
individuals having health insurance coverage or in individuals having insurance coverage with less generous benefits. The scope of potential future legislation to repeal and replace Affordable Care
Act provisions is highly uncertain in many respects, and it is possible that some of the Affordable Care Act provisions that generally are not favorable for the research-based pharmaceutical industry
could also be repealed along with
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Affordable
Care Act coverage expansion provisions. However, at this time the coverage expansion provisions of the Affordable Care Act appear most likely to be repealed and replaced.
Employees
As of December 31, 2016, we had 38 employees, 29 of whom were primarily engaged in research and development activities. A total of 19
employees have Ph.D. degrees. None of our employees is represented by a labor union and we believe our relations with our employees are good.
Our Corporate Information
We were incorporated under the laws of the State of Delaware on June 26, 2008 under the name Catabasis Pharmaceuticals, Inc. Our
executive offices are located at One Kendall Square, Bldg. 1400E, Suite B14202, Cambridge, Massachusetts 02139, and our telephone number is (617) 349-1971. Our website address is
www.catabasis.com. The information contained on, or that can be accessed through, our website is not a part of this Annual Report on Form 10-K. We have included our website address in this Annual
Report on Form 10-K solely as an inactive textual reference.
Available Information
Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any amendments to these
reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, are available free of charge on our website located at www.catabasis.com as
soon as reasonably practicable after they are filed with or furnished to the Securities and Exchange Commission (the "SEC"). These reports are also available at the SEC's Internet website at
www.sec.gov. The public may also read and copy any materials filed with the SEC at the SEC's Public Reference Room at 100 F Street, N.E., Washington D.C. 20549. Information on the operation of
the Public Reference Room may be obtained by calling the SEC at 1-800-SEC-0330.
A
copy of our Corporate Governance Guidelines, Code of Business Conduct and Ethics and the charters of the Audit Committee, Compensation Committee and Nominating and Corporate Governance
Committee are posted on our website, www.catabasis.com, under "Corporate Governance" and are available in print to any person who requests copies by contacting us by calling (617) 349-1971 or
by writing to Catabasis Pharmaceuticals, Inc., One Kendall Square, Bldg. 1400E, Suite B14202, Cambridge, Massachusetts 02139.
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Item 1A. Risk Factors
We operate in a dynamic and rapidly changing business environment that involves risks and substantial uncertainty. The
following discussion addresses risks and uncertainties that could cause, or contribute to causing, actual results to differ from expectations in material ways. In evaluating our business, investors
should pay particular attention to the risks and uncertainties described below and in other sections of this Annual Report on Form 10-K and in our subsequent filings with the Securities and Exchange
Commission, or SEC. These risks and uncertainties, or other events that we do not currently anticipate or that we currently deem immaterial also may affect our results of operations, cash flows and
financial condition. The trading price of our common stock could also decline due to any of these risks, and you could lose all or part of your investment.
Risks Related to Our Financial Position and Need for Additional Capital
We have incurred significant losses since inception and expect to incur significant losses for at least the
next several years. We may never achieve or maintain profitability.
We have incurred significant annual net operating losses in every year since our inception. We expect to continue to incur significant operating
losses for at least the next several years. Our net losses were $36.1 million, $32.6 million and $21.9 million for the years ended December 31, 2016, 2015 and 2014, respectively. As of December 31,
2016, we had an accumulated deficit of $144.1 million. We have not generated any revenues from product sales, have not completed the development of any product candidate and may never have a product
candidate approved for commercialization. We have financed our operations to date primarily through private placements of our preferred stock, registered offerings of our common stock, including our
initial public offering, or IPO, as well as a secured debt financing, and have devoted substantially all of our financial resources and efforts to research and development, including preclinical
studies and our clinical development programs. Our net losses may fluctuate significantly from quarter to quarter and year to year. Net losses and negative cash flows have had, and will continue to
have, an adverse effect on our stockholders' equity and working capital.
We
anticipate that our expenses will increase substantially if and to the extent we:
-
-
continue to develop and conduct clinical trials with respect to our lead product candidate edasalonexent, including an ongoing Phase 1/2
clinical trial of edasalonexent for the treatment of Duchenne muscular dystrophy, or DMD;
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initiate and continue research and preclinical and clinical development efforts for our other product candidates;
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-
seek to identify and develop additional product candidates;
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-
seek regulatory and marketing approvals for our product candidates that successfully complete clinical trials, if any;
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establish sales, marketing, distribution and other commercial infrastructure in the future to commercialize various products for which we may
obtain marketing approval, if any;
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-
require the manufacture of larger quantities of product candidates for clinical development and potentially commercialization;
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-
maintain, expand and protect our intellectual property portfolio;
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-
hire and retain additional personnel, such as clinical, quality control and scientific personnel;
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add operational, financial and management information systems and personnel, including personnel to support our product development and help us
comply with our obligations as a public company; and
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-
add equipment and physical infrastructure to support our research and development programs.
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Our
ability to become and remain profitable depends on our ability to generate revenue. We do not expect to generate significant revenue unless and until we are, or any future
collaborator is, able to obtain marketing approval for, and successfully commercialize, one or more of our product candidates. This will require our, or any of our future collaborators', success in a
range of challenging activities, including completing clinical trials of our product candidates, obtaining marketing approval for these product candidates, manufacturing, marketing and selling those
products for which we, or any of our future collaborators, may obtain marketing approval, satisfying any post-marketing requirements and obtaining reimbursement for our products from private insurance
or government payors. Because of the uncertainties and risks associated with these activities, we are unable to accurately predict the timing and amount of increased expenses, and if or when we might
achieve profitability. We and any future collaborators may never succeed in these activities and, even if we do, or any future collaborators does, we may never generate revenues that are large enough
for us to achieve profitability. Even if we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis. Our failure to become and remain
profitable would decrease the value of our company and could impair our ability to raise capital, expand our business, maintain our research and development efforts, diversify our pipeline of product
candidates or continue our operations. A decline in the value of our company could cause you to lose all or part of your investment.
We have a limited operating history and no history of commercializing pharmaceutical products, which may make
it difficult to evaluate the prospects for our future viability.
We began operations in 2008. Our operations to date have been limited to financing and staffing our company and developing our technology and
conducting preclinical research and early-stage clinical trials for our product candidates. We have not yet demonstrated an ability to successfully conduct pivotal clinical trials, obtain marketing
approvals, manufacture a commercial scale product, or arrange for a third party to do so on our behalf, or conduct sales and marketing activities necessary for successful product commercialization.
Accordingly, our investors should consider our prospects in light of the costs, uncertainties, delays and difficulties frequently encountered by companies in the early stages of development,
especially clinical-stage biopharmaceutical companies such as ours. Predictions about our future success or viability may not be as accurate as they could be if we had a longer operating history or a
history of successfully developing and commercializing pharmaceutical products.
We will need substantial additional funding. If we are unable to raise capital when needed, we could be
forced to delay, reduce or eliminate our product development programs or commercialization efforts.
Developing pharmaceutical products, including conducting preclinical studies and clinical trials, is a very time-consuming, expensive and
uncertain process that takes years to complete. We expect our expenses to increase, if and to the extent of certain ongoing activities, particularly if we initiate new clinical trials of, initiate new
research and preclinical development efforts for and seek marketing approval for, our product candidates. In addition, if we obtain marketing approval for any of our product candidates, we may incur
significant commercialization expenses related to product sales, marketing, manufacturing and distribution to the extent that such sales, marketing, manufacturing and distribution are not the
responsibility of a future collaborator. Furthermore, we have incurred and will continue to incur significant additional costs associated with operating as a public company. Accordingly, we will need
to obtain substantial additional funding in connection with our continuing operations. If we are unable to raise capital when needed or on attractive terms, we may be forced to delay, reduce or
eliminate our research and development programs or any future commercialization efforts.
We
will be required to expend significant funds in order to advance the development of edasalonexent, as well as our other product candidates. In addition, while we may seek one or more
collaborators for future development of our product candidates or programs, such as our CAT-2000
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program
in nonalcoholic steatohepatitis, or NASH, or for our platform technology, we may not be able to enter into a collaboration for any of our product candidates or programs or for our platform
technology on suitable terms or at all. In any event, our existing cash and cash equivalents will not be sufficient to fund all of the efforts that we plan to undertake or to fund the completion of
development of any of our product candidates. Accordingly, we will be required to obtain further funding through public or private equity offerings, debt financings, collaborations and licensing
arrangements or other sources. We do not have any committed external source of funds.
Adequate
additional financing may not be available to us on acceptable terms, on a timely basis or at all. Further, our ability to obtain additional debt financing may be limited by
covenants we have made under our loan and security agreement with MidCap Financial Trust, or MidCap, Flexpoint MCLS SPV LLC, or Flexpoint, and Square 1 Bank, or Square 1, including our negative pledge
with respect to intellectual property in favor of Flexpoint and Square 1, as well as our pledge to MidCap, Flexpoint and Square 1 of substantially all of our assets, other than our intellectual
property, as collateral. Our failure to raise capital on acceptable terms as and when needed would have a material adverse effect on our business, results of operations, and our financial condition
and our ability to pursue our business strategy.
We
believe that our existing cash and cash equivalents and available-for-sale securities as of December 31, 2016 will enable us to fund our operating expenses, and debt service and
capital expenditure requirements based on our current operating plan through March 31, 2018, assuming that we are not required to make unscheduled payments of indebtedness prior to such date. As our
current lenders have the ability to call our existing debt prior to the maturity date, that condition could affect our ability to continue as a going concern for a period of one year from the date of
this Annual Report on Form 10-K. We believe that the condition is mitigated by our management's plans, which include the ability to reduce or delay expenditures including expenditures for employee
incentive compensation and direct program expenses. However, such actions to reduce or delay expenditures, if taken, could require us to delay, limit, reduce or terminate our product development
efforts or other activities or undertake a restructuring of our workforce. Our estimate as to how long we expect our cash and cash equivalents to be able to fund our operations is based on assumptions
that may prove to be wrong, and we could use our available capital resources sooner than we currently expect. Further, changing circumstances, some of which may be beyond our control, could cause us
to consume capital significantly faster than we currently anticipate, and we may need to seek additional funds sooner than planned. Our future funding requirements, both short-term and long-term, will
depend on many factors, including:
-
-
the progress, timing, costs and results of clinical trials of, and research and preclinical development efforts for, our product candidates and
potential product candidates, including current and future clinical trials;
-
-
our ability to enter into and the terms and timing of any additional collaborations, licensing or other arrangements that we may establish;
-
-
the number and characteristics of future product candidates that we pursue and their development requirements;
-
-
the outcome, timing and costs of seeking regulatory approvals;
-
-
the costs of commercialization activities for any of our product candidates that receive marketing approval to the extent such costs are not
the responsibility of any future collaborators, including the costs and timing of establishing product sales, marketing, distribution and manufacturing capabilities;
-
-
subject to receipt of marketing approval, revenue, if any, received from commercial sales of our product candidates;
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-
-
our headcount growth and associated costs as we expand our research and development and establish a commercial infrastructure;
-
-
the costs of preparing, filing and prosecuting patent applications, maintaining and protecting our intellectual property rights and defending
against intellectual property related claims; and
-
-
the costs of operating as a public company.
Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to
relinquish rights to our technologies or product candidates.
We expect that significant additional capital will be needed in the future to continue our planned operations. To the extent that we raise
additional capital through the sale of common stock, convertible securities or other equity securities, our existing stockholders' ownership
interest may be substantially diluted, and the terms of these securities could include liquidation or other preferences and anti-dilution protections that could adversely affect your rights as a
common stockholder. Additional debt financing, if available, would result in increased fixed payment obligations and may involve agreements that include restrictive covenants that limit our ability to
take specific actions, such as incurring additional debt, making capital expenditures, creating liens, redeeming stock or declaring dividends, that could adversely impact our ability to conduct our
business. For example, our credit facility with MidCap, Flexpoint and Square 1 contains restrictive covenants that, among other things and subject to certain exceptions, prohibit us from transferring
any of our material assets, exclusively licensing our intellectual property (subject to certain exceptions), merging with or acquiring another entity, entering into a transaction that would result in
a change of control, incurring additional indebtedness, creating any lien on our property, making investments in third parties or redeeming stock or paying dividends. Future debt securities or other
financing arrangements could contain similar or more restrictive negative covenants. In addition, securing additional financing could require a substantial amount of time and attention from our
management and may divert a disproportionate amount of their attention away from day-to-day activities, which may adversely affect our management's ability to oversee the development of our product
candidates.
If
we raise additional funds through collaborations or marketing, distribution or licensing arrangements with third parties, we may have to relinquish valuable rights to our
technologies, future revenue streams or product candidates or grant licenses on terms that may not be favorable to us. If we are unable to raise additional funds when needed, we may be required to
delay, limit, reduce or terminate our product development or future commercialization efforts or grant rights to develop and market product candidates that we would otherwise prefer to develop and
market ourselves.
Our existing and any future indebtedness could adversely affect our ability to operate our business.
As of December 31, 2016, we had $5.8 million of outstanding principal payments under our credit facility with MidCap, Flexpoint and Square 1. We
are required to repay principal and interest on these borrowings in monthly installments through October 2018. Subject to the restrictions in this existing credit facility, we could in the future
incur additional indebtedness beyond our borrowings from MidCap, Flexpoint and Square 1.
Our
outstanding indebtedness, including any additional indebtedness beyond our borrowings from MidCap, Flexpoint and Square 1, combined with our other financial obligations and
contractual commitments could have significant adverse consequences, including:
-
-
requiring us to dedicate a portion of our cash resources to the payment of interest and principal, reducing money available to fund working
capital, capital expenditures, product development and other general corporate purposes;
-
-
increasing our vulnerability to adverse changes in general economic, industry and market conditions;
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-
-
subjecting us to restrictive covenants that may reduce our ability to take certain corporate actions or obtain further debt or equity
financing;
-
-
limiting our flexibility in planning for, or reacting to, changes in our business and the industry in which we compete; and
-
-
placing us at a competitive disadvantage compared to our competitors that have less debt or better debt servicing options.
We
intend to satisfy our current and future debt service obligations with our existing cash and cash equivalents. However, we may not have sufficient funds, and may be unable to arrange
for additional financing, to pay the amounts due under our existing debt instruments. Failure to make payments or comply with other covenants under our existing debt instruments could result in an
event of default and acceleration of amounts due. Under our loan and security agreement with MidCap, Flexpoint and Square 1, the occurrence of an event that would reasonably be expected to have a
material adverse effect on our business, operations, assets or condition is an event of default. If an event of default occurs and the lenders accelerate the amounts due, we may not be able to make
accelerated payments, and the lenders could seek to enforce security interests in the collateral securing such indebtedness, which includes substantially all of our assets other than our intellectual
property. In addition, the covenants under our credit facility, the pledge of our assets as collateral and the negative pledge with respect to our intellectual property could limit our ability to
obtain additional debt financing.
Risks Related to the Discovery, Development and Commercialization of Our Product Candidates
Our approach to the discovery and development of product candidates based on our SMART linker drug discovery
platform is unproven, and we do not know whether we will be able to develop any products of commercial value.
We are focused on discovering and developing novel small molecule drugs by applying our Safely Metabolized And Rationally Targeted, or SMART,
linker drug discovery platform. We have not yet succeeded and may never succeed in demonstrating efficacy and safety for any of our product candidates in later stage clinical trials or in obtaining
marketing approval thereafter. For example, although we have discovered and evaluated numerous compounds using our SMART linker drug discovery platform, we have not yet advanced a compound into Phase
3 clinical development and no product created using the SMART linker drug discovery platform has ever been approved for sale.
We are dependent on the success of our product candidate edasalonexent. If we are unable to complete the
clinical development of, obtain marketing approval for or successfully commercialize this product candidate, either alone or with a collaborator, or if we experience significant delays in doing so,
our business could be substantially harmed.
We currently have no products approved for sale and are investing a significant portion of our efforts and financial resources in the
development of edasalonexent for the treatment of DMD. Our prospects are substantially dependent on our ability, or that of any future collaborator, to develop, obtain marketing approval for and
successfully commercialize edasalonexent.
The
success of edasalonexent will depend on several factors, including the following:
-
-
completion of the ongoing open-label extension of our MoveDMD clinical trial;
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-
initiation and successful enrollment and completion of additional clinical trials;
-
-
safety, tolerability and efficacy profiles that are satisfactory to the U.S. Food and Drug Administration, or FDA, or any comparable foreign
regulatory authority for marketing approval;
-
-
timely receipt of marketing approvals from applicable regulatory authorities;
-
-
the performance of our future collaborators, if any;
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-
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the extent of any required post-marketing approval commitments to applicable regulatory authorities;
-
-
establishment of supply arrangements with third-party raw materials suppliers and manufacturers;
-
-
establishment of arrangements with third-party manufacturers to obtain finished drug products that are appropriately packaged for sale;
-
-
obtaining and maintaining patent, trade secret protection and regulatory exclusivity, both in the United States and internationally;
-
-
protection of our rights in our intellectual property portfolio;
-
-
successful launch of commercial sales following any marketing approval;
-
-
a continued acceptable safety profile following any marketing approval;
-
-
commercial acceptance by patients, the medical community and third-party payors following any marketing approval; and
-
-
our ability to compete with other therapies, including therapies targeting dystrophin, utrophin, myostatin and inflammatory mediators.
Many
of these factors are beyond our control, including the outcome of clinical development, the regulatory submission process, potential threats to our intellectual property rights and
the manufacturing, marketing and sales efforts of any future collaborator. If we are unable to develop, receive marketing approval for and successfully commercialize edasalonexent, on our own or with
any future collaborator, or experience delays as a result of any of these or other factors, our business could be substantially harmed.
Our SMART linker drug discovery platform may fail to help us discover and develop additional potential
product candidates.
A significant portion of the research that we are conducting involves the development of new compounds using our SMART linker drug discovery
platform. The drug discovery that we are conducting using our SMART linker drug discovery platform may not be successful in creating compounds that have commercial value or therapeutic utility. Our
SMART linker drug discovery platform may initially show promise in identifying potential product candidates, yet fail to yield viable product candidates for clinical development or commercialization
for a number of reasons, including:
-
-
compounds created through our SMART linker drug discovery platform may not demonstrate improved efficacy, safety or tolerability;
-
-
potential product candidates may, on further study, be shown to have harmful side effects or other characteristics that indicate that they are
unlikely to receive marketing approval and achieve market acceptance;
-
-
competitors may develop alternative therapies that render our potential product candidates non-competitive or less attractive; or
-
-
a potential product candidate may not be capable of being produced at an acceptable cost.
Our
research programs to identify new product candidates will require substantial technical, financial and human resources, and we may be unsuccessful in our efforts to identify new
product candidates. If we are unable to identify suitable additional compounds for preclinical and clinical development, our ability to develop product candidates and obtain product revenues in future
periods
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could
be compromised, which could result in significant harm to our financial position and adversely impact our stock price.
We have never obtained marketing approval for a product candidate and we may be unable to obtain, or may be
delayed in obtaining, marketing approval for any of our product candidates.
We have never obtained marketing approval for a product candidate. It is possible that the FDA may refuse to accept for substantive review any
new drug applications, or NDAs, that we submit for our product candidates or may conclude after review of our data that our application is insufficient to obtain marketing approval of our product
candidates. If the FDA does not accept or approve our NDAs for either of our most advanced product candidates, it may require that we conduct additional clinical, nonclinical or manufacturing
validation studies and submit that data before it will reconsider our applications. Depending on the extent of these or any other FDA-required studies, approval of any NDA or application that we
submit may be delayed by several years, or may require us to expend more resources than we have available. It is also possible that additional studies, if performed and completed, may not be
considered sufficient by the FDA to approve our NDAs.
Any
delay in obtaining, or an inability to obtain, marketing approvals would prevent us from commercializing our product candidates, generating revenues and achieving and sustaining
profitability. If any of these outcomes occur, we may be forced to abandon our development efforts for our product candidates, which could significantly harm our business.
Results of preclinical studies and early clinical trials may not be predictive of results of future clinical
trials.
The outcome of preclinical studies and early clinical trials may not be predictive of the success of later clinical trials, and interim results
of clinical trials do not necessarily predict success in future clinical trials. Many companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage
clinical trials after achieving positive results in earlier development, and we cannot be certain that we will not face similar setbacks. The design of a clinical trial can determine whether its
results will support approval of a product and flaws in the design of a clinical trial may not become apparent until the clinical trial is well advanced. We have limited experience in designing
clinical trials and may be unable to design and execute a clinical trial to support marketing approval. In addition, preclinical and clinical data are often susceptible to varying
interpretations and analyses. Many companies that believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing
approval for the product candidates. Even if we, or any future collaborators, believe that the results of clinical trials for our product candidates warrant marketing approval, the FDA or comparable
foreign regulatory authorities may disagree and may not grant marketing approval of our product candidates.
In
some instances, there can be significant variability in safety or efficacy results between different clinical trials of the same product candidate due to numerous factors, including
changes in trial procedures set forth in protocols, differences in the size and type of the patient populations, changes in and adherence to the dosing regimen and other clinical trial protocols and
the rate of dropout among clinical trial participants. For example, while we observed positive NF-
k
B biomarker data in Part A of our MoveDMD Phase 1/2 clinical
trial of edasalonexent for the treatment of DMD that demonstrated NF-
k
B target engagement via statistically significant reduction in
NF-
k
B controlled gene expression for the 67 mg/kg/day and 100 mg/kg/day dosing levels, the primary efficacy endpoint in Part B of the trial for the same dosing
levels was not met. If we fail to receive positive results in clinical trials of our product candidates, the development timeline and regulatory approval and commercialization prospects for our most
advanced product candidates, and, correspondingly, our business and financial prospects would be negatively impacted.
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Because we are developing edasalonexent for the treatment of DMD, a disease for which regulatory authorities
have not issued definitive guidance as to how to measure and demonstrate efficacy, there is increased risk that the outcome of our clinical trials will not be satisfactory for marketing approval.
There are currently only two therapies approved in the United States for the treatment of DMD. In addition, there has been limited historical
clinical trial experience for the development of drugs to treat the underlying cause of DMD. As a result, the design and conduct of clinical trials for this disease, particularly for drugs to address
the underlying cause of this disease, is subject to increased risk. In particular, while a general FDA Guidance for Industry on developing drugs for the treatment of DMD has been issued, regulatory
authorities in the United States have not issued definitive direction as to how to measure and demonstrate efficacy. For example, we chose the primary endpoint in our MoveDMD Phase 1/2 clinical trial
of edasalonexent for the treatment of DMD as change in muscle inflammation as measured by magnetic resonance imaging, or MRI, of leg muscles, which we believe had not previously been used as a primary
endpoint for a Phase 2 or Phase 3 trial in DMD. We also included as exploratory endpoints the timed function tests best suited for this age group, specifically the 10-meter walk/run, 4-stair climb and
time-to-stand tests, as well as other strength and functional measures, including the North Star ambulatory assessment questionnaire and the pediatric outcome data collection instrument. However,
there is no definitive guidance from regulatory authorities that any of these endpoints, if met in a Phase 3 trial for DMD, would be satisfactory for
marketing approval. In addition, since we believe we were the first company to use MRI T2 at 12 weeks as a primary endpoint in a DMD clinical trial, it is unclear whether the failure of edasalonexent
to meet this efficacy endpoint is indicative of edasalonexent not having a treatment effect over the 12-week period, or if MRI T2 is an appropriate measure of treatment effect over a 12-week period.
The regulatory approval processes for product candidates that target rare diseases, including DMD, cystic
fibrosis, Friedreich's ataxia and ALS, are uncertain.
Due to the lack of precedent, broad discretion of regulatory authorities, and a multitude of unique factors that impact the regulatory approval
process, the likelihood of the approval of any of our product candidates that target rare diseases, such as DMD, cystic fibrosis, Friedreich's Ataxia and ALS, is uncertain, and we may not be able to
anticipate, prepare for or satisfy requests or requirements from regulatory authorities, including completing and submitting planned investigational new drug applications and NDAs for our product
candidates, in a timely manner, or at all. For example, DMD is a rare disease for which there are only two FDA approved therapeutics. Further, the FDA may determine, after evaluation of our data and
analyses, that such data and analyses do not support an NDA submission, filing or approval. Due to this lack of predictability, we may not have the resources necessary to meet regulatory requirements
and successfully complete a potentially protracted, expensive and wide-ranging approval process for commercialization of product candidates for rare diseases.
We may expend our limited resources to pursue a particular product candidate or indication and fail to
capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success.
Because we have limited financial and managerial resources, we intend to focus on developing product candidates for specific indications that we
identify as most likely to succeed, in terms of both their potential for marketing approval and commercialization. As a result, we may forego or delay pursuit of opportunities with other product
candidates or for other indications that may prove to have greater commercial potential.
Our
resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities. Our spending on current and future research and
development programs and product candidates for specific indications may not yield any commercially viable product candidates. If we do not accurately evaluate the commercial potential or target
market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which it would have
been more advantageous for us to retain sole development and commercialization rights to the product candidate.
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Clinical drug development involves a lengthy and expensive process with an uncertain outcome.
Clinical testing is expensive, time-consuming and uncertain as to outcome. We cannot guarantee that any clinical trials will be conducted as
planned or completed on schedule, or at all. Further, the clinical development of our product candidates is susceptible to the risk of failure at any stage of drug development, including failure to
demonstrate efficacy in a clinical trial or across a broad population of patients, the occurrence of adverse events that are severe or medically or commercially unacceptable, failure to comply with
protocols or applicable regulatory requirements and determination by the FDA or any comparable foreign regulatory authority that a product candidate may not continue development or is not approvable.
It is possible that even if one or more of our product candidates has a beneficial effect, that effect will not be detected during clinical evaluation as a result of one or more of a variety of
factors, including the size, duration, design, measurements, conduct or analysis of our clinical trials. Conversely, as a result of the same factors, our clinical trials may indicate an apparent
positive effect of a product candidate that is greater than the actual positive effect, if any. Similarly, in our clinical trials we may fail to detect toxicity of or intolerability caused by our
product candidates, or mistakenly believe that our product candidates are toxic or not well tolerated when that is not in fact the case.
In
addition to the risk of failure inherent in drug development, certain of the compounds that we are developing and may develop in the future using our SMART linker drug discovery
platform may be particularly susceptible to failure to the extent they are based on compounds that others have previously studied or tested, but did not progress in development due to safety,
tolerability or efficacy concerns or otherwise. Our failure to successfully complete clinical trials of our product candidates and to demonstrate the efficacy and safety necessary to obtain regulatory
approval to market any of our product candidates would significantly harm our business.
If clinical trials of our product candidates fail to satisfactorily demonstrate safety and efficacy to the
FDA and other comparable foreign regulators, we, or any future collaborators, may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and
commercialization of these product candidates.
We, and any future collaborators, are not permitted to commercialize, market, promote or sell any product candidate in the United States without
obtaining marketing approval from the FDA. Comparable foreign regulatory authorities, such as the European Medicines Agency, or the EMA, impose similar restrictions. We, and any future collaborators,
may never receive such approvals. We, and any future collaborators, must complete extensive preclinical development and clinical trials to demonstrate the safety and efficacy of our product candidates
in humans before we, or they, will be able to obtain these approvals.
Clinical
testing is expensive, difficult to design and implement, can take many years to complete and is inherently uncertain as to outcome. We have not previously submitted an NDA to
the FDA or similar drug approval filings to comparable foreign regulatory authorities for any of our product candidates. Any inability to complete preclinical and clinical development successfully
could result in additional costs to us, or any future collaborators, and impair our ability to generate revenues from product sales, regulatory and commercialization milestones and royalties.
Moreover, if (1) we, or any future collaborators, are required to modify our trial designs, such as required modifications with respect to patient populations, endpoints, comparators or trial
duration, (2) we, or any future collaborators, are required to conduct additional clinical trials or other testing of our product candidates beyond the trials and testing that we, or they contemplate,
(3) we, or any future collaborators, are unable to successfully complete clinical trials of our product candidates or other testing, (4) the results of these trials or tests are unfavorable, uncertain
or are only modestly favorable,
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or
(5) there are unacceptable safety concerns associated with our product candidates, we, or any future collaborators, may:
-
-
be delayed in obtaining marketing approval for our product candidates;
-
-
not obtain marketing approval at all;
-
-
obtain approval for indications or patient populations that are not as broad as intended or desired;
-
-
obtain approval with labeling that includes significant use or distribution restrictions or significant safety warnings, including boxed
warnings;
-
-
be subject to additional post-marketing testing or other requirements; or
-
-
be required to remove the product from the market after obtaining marketing approval.
Adverse events or undesirable side effects caused by, or other unexpected properties of, any of our product
candidates may be identified during development that could delay or prevent their marketing approval or limit their use.
Adverse events or undesirable side effects caused by, or other unexpected properties of, our product candidates could cause us, any future
collaborators, an institutional review board or regulatory authorities to interrupt, delay or halt clinical trials of one or more of our product candidates and could result in a more restrictive label
or the delay or denial of marketing approval by the FDA or comparable foreign regulatory authorities. For example, in 2014, in our clinical trials of CAT-2003 we observed gastrointestinal tolerability
issues, including nausea, diarrhea and vomiting, and in some cases these adverse events led to dose reductions or discontinuations. If any of our product candidates is associated with adverse events
or undesirable side effects or has properties that are unexpected, we, or any future collaborators, may need to abandon development or limit development of that product candidate to certain uses or
subpopulations in which the undesirable side effects or other characteristics are less prevalent, less severe or more acceptable from a risk-benefit perspective. Many compounds that initially showed
promise in clinical or earlier stage testing have later been found to cause undesirable or unexpected side effects that prevented further development of the compound.
If we, or any future collaborators, experience any of a number of possible unforeseen events in connection
with clinical trials of our product candidates, potential marketing approval or commercialization of our product candidates could be delayed or prevented.
We, or any future collaborators, may experience numerous unforeseen events during, or as a result of, clinical trials that could delay or
prevent marketing approval or commercialization of our product candidates, including:
-
-
clinical trials of our product candidates may produce unfavorable or inconclusive results, such as occurred in our MoveDMD Phase 1/2 clinical
trial of edasalonexent for the treatment of DMD, where the primary efficacy endpoint was not met;
-
-
we, or any future collaborators, may decide, or regulators may require us or them, to conduct additional clinical trials or abandon product
development programs;
-
-
the number of patients required for clinical trials of our product candidates may be larger than we, or any future collaborators, anticipate,
patient enrollment in these clinical trials may be slower than we, or any future collaborators, anticipate or participants may drop out of these clinical trials at a higher rate than we, or any future
collaborators, anticipate;
-
-
the cost of planned clinical trials of our product candidates may be greater than we anticipate;
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-
-
our third-party contractors or those of any future collaborators, including those manufacturing our product candidates or components or
ingredients thereof or conducting clinical trials on our behalf or on behalf of any future collaborators, may fail to comply with regulatory requirements or meet their contractual obligations to us or
any future collaborators in a timely manner or at all;
-
-
regulators or institutional review boards may not authorize us, any future collaborators or our or their investigators to commence a clinical
trial or conduct a clinical trial at a prospective trial site;
-
-
we, or any future collaborators, may have delays in reaching or fail to reach agreement on acceptable clinical trial contracts or clinical
trial protocols with prospective trial sites;
-
-
patients that enroll in a clinical trial may misrepresent their eligibility to do so or may otherwise not comply with the clinical trial
protocol, resulting in the need to drop the patients from the clinical trial, increase the needed enrollment size for the clinical trial or extend the clinical trial's duration;
-
-
we, or any future collaborators, may have to delay, suspend or terminate clinical trials of our product candidates for various reasons,
including a finding that the participants are being exposed to unacceptable health risks, undesirable side effects or other unexpected characteristics of the product candidate, such as the delay we
experienced in 2014 in one of our Phase 2 clinical trials of CAT-2003 while we reformulated CAT-2003 in a coated capsule and evaluated its tolerability;
-
-
regulators or institutional review boards may require that we, or any future collaborators, or our or their investigators suspend or terminate
clinical research for various reasons, including noncompliance with regulatory requirements or their standards of conduct, a finding that the participants are being exposed to unacceptable health
risks, undesirable side effects or other unexpected characteristics of the product candidate or findings of undesirable effects caused by a chemically or mechanistically similar drug or drug
candidate;
-
-
the FDA or comparable foreign regulatory authorities may disagree with our, or any future collaborators', clinical trial designs or our or
their interpretation of data from preclinical studies and clinical trials;
-
-
the FDA or comparable foreign regulatory authorities may fail to approve or subsequently find fault with the manufacturing processes or
facilities of third-party manufacturers with which we, or any future collaborators, enter into agreements for clinical and commercial supplies;
-
-
the supply or quality of raw materials or manufactured product candidates or other materials necessary to conduct clinical trials of our
product candidates may be insufficient, inadequate or not available at an acceptable cost, or we may experience interruptions in supply; and
-
-
the approval policies or regulations of the FDA or comparable foreign regulatory authorities may significantly change in a manner rendering our
clinical data insufficient to obtain marketing approval.
Product
development costs for us, or any future collaborators, will increase if we, or they, experience delays in testing or pursuing marketing approvals and we, or they, may be required
to obtain additional funds to complete clinical trials and prepare for possible commercialization of our product candidates. We do not know whether any preclinical tests or clinical trials will begin
as planned, will need to be restructured, or will be completed on schedule or at all. Significant preclinical or clinical trial delays also could shorten any periods during which we, or any future
collaborators, may have the exclusive right to commercialize our product candidates or allow our competitors, or the competitors of any future collaborators, to bring products to market before we, or
any future
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collaborators,
do and impair our ability, or the ability of any future collaborators, to successfully commercialize our product candidates and may harm our business and results of operations. In
addition, many of the factors that lead to clinical trial delays may ultimately lead to the denial of marketing approval of any of our product candidates.
If we, or any future collaborators, experience delays or difficulties in the enrollment of patients in
clinical trials, our or their receipt of necessary regulatory approvals could be delayed or prevented.
We, or any future collaborators, may not be able to initiate or continue clinical trials for any of our product candidates if we, or they, are
unable to locate and enroll a sufficient number of eligible patients to participate in clinical trials as required by the FDA or comparable foreign regulatory authorities, such as the EMA. Patient
enrollment is a significant factor in the timing of clinical trials, and is affected by many factors, including:
-
-
the size and nature of the patient population;
-
-
the severity of the disease under investigation;
-
-
the proximity of patients to clinical sites;
-
-
the eligibility criteria for the trial;
-
-
the design of the clinical trial;
-
-
efforts to facilitate timely enrollment;
-
-
competing clinical trials; and
-
-
clinicians' and patients' perceptions as to the potential advantages and risks of the drug being studied in relation to other available
therapies, including any new drugs that may be approved for the indications we are investigating.
In
particular, the successful completion of our clinical development program for edasalonexent for the treatment of DMD is dependent upon our ability to enroll a sufficient number of
patients with DMD. DMD is a rare disease with a small patient population. Further, there are only a limited number of specialist physicians that regularly treat patients with DMD and major clinical
centers that support DMD treatment are concentrated in a few geographic regions. In addition, other companies are conducting clinical trials and have announced plans for future clinical trials that
are seeking, or are likely to seek, to enroll patients with DMD and patients are generally only able to enroll in a single
trial at a time. The small population of patients, competition for these patients and the limited trial sites may make it difficult for us to enroll enough patients to complete our clinical trials for
edasalonexent in a timely and cost-effective manner.
The
clinical trials that we conduct may also have inclusion criteria that further limit the population of patients that we are able to enroll. For example, further clinical trials for
edasalonexent may require that the enrolled boys be between certain ages and not on certain co-medications. These inclusion criteria could further limit the available patient pool and present
challenges to clinical trial enrollment.
Our
inability, or the inability of any future collaborators, to enroll a sufficient number of patients for our, or their, clinical trials could result in significant delays or may
require us or them to abandon one or more clinical trials altogether. Enrollment delays in our, or their, clinical trials may result in increased development costs for our product candidates, delay or
halt the development of and approval processes for our product candidates and jeopardize our, or any future collaborators', ability to commence sales of and generate revenues from our product
candidates, which could cause the value of our company to decline.
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If any of our product candidates receives marketing approval and we, or others, later discover that the drug
is less effective than previously believed or causes undesirable side effects that were not previously identified, our ability, or that of any future collaborators, to market the drug could be
compromised.
Clinical trials of our product candidates are conducted in carefully defined subsets of patients who have agreed to enter into clinical trials.
Consequently, it is possible that our clinical trials, or those of any future collaborator, may indicate an apparent positive effect of a product candidate that is greater than the actual positive
effect, if any, or alternatively fail to identify undesirable side effects. If, following approval of a product candidate, we, or others, discover that the drug is less effective than previously
believed or causes undesirable side effects that were not previously identified, any of the following adverse events could occur:
-
-
regulatory authorities may withdraw their approval of the drug or seize the drug;
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we, or any future collaborators, may be required to recall the drug, change the way the drug is administered or conduct additional clinical
trials;
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-
additional restrictions may be imposed on the marketing of, or the manufacturing processes for, the particular drug;
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we may be subject to fines, injunctions or the imposition of civil or criminal penalties;
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-
regulatory authorities may require the addition of labeling statements, such as a "black box" warning or a contraindication;
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we, or any future collaborators, may be required to create a Medication Guide outlining the risks of the previously unidentified side effects
for distribution to patients;
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we, or any future collaborators, could be sued and held liable for harm caused to patients;
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the drug may become less competitive; and
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our reputation may suffer.
Any
of these events could have a material and adverse effect on our operations and business and could adversely impact our stock price.
Even if one of our product candidates receives marketing approval, it may fail to achieve the degree of
market acceptance by physicians, patients, third-party payors and others in the medical community necessary for commercial success and the market opportunity for the product candidate may be smaller
than we estimate.
We have never commercialized a product. Even if one of our product candidates is approved by the appropriate regulatory authorities for
marketing and sale, it may nonetheless fail to gain sufficient market acceptance by physicians, patients, third-party payors and others in the medical community. For example, physicians are often
reluctant to switch their patients from existing therapies even when new and potentially more effective or convenient treatments enter the market. Further, patients often acclimate to the therapy that
they are currently taking and do not want to switch unless their physicians recommend switching products or they are required to switch therapies due to lack of reimbursement for existing therapies.
Efforts
to educate the medical community and third-party payors on the benefits of our product candidates may require significant resources and may not be successful. If any of our
product candidates is approved but does not achieve an adequate level of market acceptance, we may not generate significant revenues and we may not become profitable. The degree of market acceptance
of our product candidates, if approved for commercial sale, will depend on a number of factors, including:
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the efficacy and safety of the product;
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the potential advantages of the product compared to alternative treatments;
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the prevalence and severity of any side effects;
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the clinical indications for which the product is approved;
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whether the product is designated under physician treatment guidelines as a first-line therapy or as a second- or third-line therapy;
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limitations or warnings, including distribution or use restrictions, contained in the product's approved labeling;
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our ability, or the ability of any future collaborators, to offer the product for sale at competitive prices;
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the product's convenience and ease of administration compared to alternative treatments;
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the willingness of the target patient population to try, and of physicians to prescribe, the product;
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the strength of sales, marketing and distribution support;
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the approval of other new products for the same indications;
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changes in the standard of care for the targeted indications for the product;
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the timing of market introduction of our approved products as well as competitive products;
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availability and amount of reimbursement from government payors, managed care plans and other third-party payors;
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adverse publicity about the product or favorable publicity about competitive products; and
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potential product liability claims.
The
potential market opportunities for our product candidates are difficult to estimate precisely. Our estimates of the potential market opportunities are predicated on many assumptions,
including industry knowledge and publications, third-party research reports and other surveys. While we believe that our internal assumptions are reasonable, these assumptions involve the exercise of
significant judgment on the part of our management, are inherently uncertain and the reasonableness of these assumptions has
not been assessed by an independent source. If any of the assumptions proves to be inaccurate, the actual markets for our product candidates could be smaller than our estimates of the potential market
opportunities.
If we are unable to establish sales, marketing and distribution capabilities or enter into sales, marketing
and distribution arrangements with third parties, we may not be successful in commercializing any product candidates that we develop if and when those product candidates are approved.
We do not have a sales, marketing or distribution infrastructure and have no experience in the sale, marketing or distribution of pharmaceutical
products. To achieve commercial success for any approved product, we must either develop a sales and marketing organization or outsource these functions to third parties. We plan to use a combination
of focused in-house sales and marketing capabilities and third-party collaboration, licensing and distribution arrangements to sell any of our products that receive marketing approval.
We
generally plan to seek to retain full commercialization rights for products that we can commercialize with a specialized sales force and to retain co-promotion or similar rights when
feasible in indications requiring a larger commercial infrastructure. The development of sales, marketing and distribution capabilities will require substantial resources, will be time-consuming and
could delay any
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product
launch. If the commercial launch of a product for which we recruit a sales force and establish marketing and distribution capabilities is delayed or does not occur for any reason, we could
have prematurely or unnecessarily incurred these commercialization costs. This may be costly, and our investment could be lost if we cannot retain or reposition our sales and marketing personnel. In
addition, we may not be able to hire or retain a sales force that is sufficient in size or has adequate expertise in the medical markets that we plan to target. If we are unable to establish or retain
a sales force and marketing and distribution capabilities, our operating results may be adversely affected. If a potential partner has development or commercialization expertise that we believe is
particularly relevant to one of our products, then we may seek to collaborate with that potential partner even if we believe we could otherwise develop and commercialize the product independently.
We
may collaborate with third parties for commercialization of any products that require a large sales, marketing and product distribution infrastructure. We intend to potentially
commercialize our product candidates through collaboration, licensing and distribution arrangements with third parties. As a result of entering into arrangements with third parties to perform sales,
marketing and distribution services, our product revenues or the profitability of these product revenues may be lower, perhaps substantially
lower, than if we were to directly market and sell products in those markets. Furthermore, we may be unsuccessful in entering into the necessary arrangements with third parties or may be unable to do
so on terms that are favorable to us. In addition, we may have little or no control over such third parties, and any of them may fail to devote the necessary resources and attention to sell and market
our products effectively.
If
we do not establish sales, marketing and distribution capabilities, either on our own or in collaboration with third parties, we will not be successful in commercializing any of our
product candidates that receive marketing approval.
We face substantial competition from other pharmaceutical and biotechnology companies, and our operating
results may suffer if we fail to compete effectively.
The development and commercialization of new drug products is highly competitive. We expect that we, and any future collaborators, will face
significant competition from major pharmaceutical companies, specialty pharmaceutical companies and biotechnology companies worldwide with respect to any of our product candidates that we, or they,
may seek to develop or commercialize in the future. Specifically, there are a number of large pharmaceutical and biotechnology companies that currently market and sell products or are pursuing the
development of product candidates for the treatment of the key indication of our most advanced program, DMD.
There
are currently two therapies approved for the treatment of DMD in the United States, Sarepta Therapeutics' drug Exondys 51, also known as eteplirsen, and Marathon Pharmaceuticals'
EMFLAZA, also known as deflazacort, a corticosteroid. Additionally, corticosteroid therapy, including prednisone, is often prescribed to treat the inflammation underlying DMD and to delay
loss of ambulation. In addition, a number of companies are developing therapies to treat DMD, one of which is already on the market in Europe and others are in the process of registration or late
stage clinical development, including, PTC Therapeutics, Santhera Pharmaceuticals and Sarepta Therapeutics.
Our
competitors may succeed in developing, acquiring or licensing technologies and drug products that are more effective, have fewer or more tolerable side effects or are less costly
than any product candidates that we are currently developing or that we may develop, which could render our product candidates obsolete and noncompetitive.
Our
commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects,
are more convenient or are less expensive than any products that we, or any future collaborators, may develop. Our competitors also may obtain FDA or other marketing approval for their products before
we, or
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any
future collaborators, are able to obtain approval for ours, which could result in our competitors establishing a strong market position before we, or any future collaborators, are able to enter
the market.
Many
of our existing and potential future competitors have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing,
conducting clinical trials, obtaining marketing approvals and marketing approved products than we do. Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even
more resources being concentrated among a smaller number of our competitors. Smaller or early stage companies may also prove to be significant competitors, particularly through collaborative
arrangements with large and established companies. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial
sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.
If the FDA or comparable foreign regulatory authorities approve generic versions of any of our products that
receive marketing approval, or such authorities do not grant our products appropriate periods of data exclusivity before approving generic versions of our products, the sales of our products could be
adversely affected.
Once an NDA is approved, the product covered thereby becomes a "reference-listed drug" in the FDA's publication, "Approved Drug Products with
Therapeutic Equivalence Evaluations." Manufacturers may seek approval of generic versions of reference-listed drugs through submission of abbreviated new drug applications, or ANDAs, in the United
States. In support of an ANDA, a generic manufacturer need not conduct clinical studies. Rather, the applicant generally must show that its product has the same active ingredient(s), dosage form,
strength, route of administration and conditions of use or labeling as the reference-listed drug and that the generic version is bioequivalent to the reference-listed drug, meaning it is absorbed in
the body at the same rate and to the same extent. Generic products may be significantly less costly to bring to market than the reference-listed drug and companies that produce generic products are
generally able to offer them at lower prices. Thus, following the introduction of a generic drug, a significant percentage of the sales of any branded product or reference-listed drug may be typically
lost to the generic product.
The
FDA may not approve an ANDA for a generic product until any applicable period of non-patent exclusivity for the reference-listed drug has expired. The Federal Food, Drug, and
Cosmetic Act, or FDCA, provides a period of five years of non-patent exclusivity for a new drug containing a new chemical entity, or NCE. Specifically, in cases where such exclusivity has been
granted, an ANDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a
Paragraph IV certification that a patent covering the reference-listed drug is either invalid or will not be infringed by the generic product, in which case the applicant may submit its application
four years following approval of the reference-listed drug. It is unclear whether the FDA will treat the active ingredients in our product candidates as NCEs and, therefore, afford them five years of
NCE data exclusivity if they are approved. If any product we develop does not receive five years of NCE exclusivity, the FDA may approve generic versions of such product three years after its date of
approval. Manufacturers may seek to launch these generic products following the expiration of the applicable marketing exclusivity period, even if we still have patent protection for our product.
Competition
that our products may face from generic versions of our products could materially and adversely impact our future revenue, profitability and cash flows and substantially
limit our ability to obtain a return on the investments we have made in those product candidates.
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Even if we, or any future collaborators, are able to commercialize any product candidate that we, or they,
develop, the product may become subject to unfavorable pricing regulations, third-party payor reimbursement practices or healthcare reform initiatives that could harm our business.
The commercial success of our product candidates will depend substantially, both domestically and abroad, on the extent to which the costs of
our product candidates will be paid by third-party payors, including government health administration authorities and private health coverage insurers. If coverage and reimbursement is not available,
or reimbursement is available only to limited levels, we, or any future collaborators, may not be able to successfully commercialize our product candidates. Even if coverage is provided, the approved
reimbursement amount may not be high enough to allow us, or any future collaborators, to establish or maintain pricing sufficient to realize a sufficient return on our or their investments. In the
United States, no uniform policy of coverage and reimbursement for products exists among third-party payors and coverage and reimbursement for products can differ significantly from payor to payor.
There
is significant uncertainty related to third-party payor coverage and reimbursement of newly approved drugs. Marketing approvals, pricing and reimbursement for new drug products
vary widely from country to country. Some countries require approval of the sale price of a drug before it can be marketed. In many countries, the pricing review period begins after marketing or
product licensing approval is granted. In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted. As a
result, we, or any future collaborators, might obtain marketing approval for a product in a particular country, but then be subject to price regulations that delay commercial launch of the product,
possibly for lengthy time periods, which may negatively impact the revenues we are able to generate from the sale of the product
in that country. Adverse pricing limitations may hinder our ability or the ability of any future collaborators to recoup our or their investment in one or more product candidates, even if our product
candidates obtain marketing approval.
Patients
who are provided medical treatment for their conditions generally rely on third-party payors to reimburse all or part of the costs associated with their treatment. Therefore,
our ability, and the ability of any future collaborators, to commercialize any of our product candidates will depend in part on the extent to which coverage and reimbursement for these products and
related treatments will be available from third-party payors. Third-party payors decide which medications they will cover and establish reimbursement levels. The healthcare industry is acutely focused
on cost containment, both in the United States and elsewhere. Government authorities and other third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement
for particular medications, which could affect our ability or that of any future collaborators to sell our product candidates profitably. These payors may not view our products, if any, as
cost-effective, and coverage and reimbursement may not be available to our customers, or those of any future collaborators, or may not be sufficient to allow our products, if any, to be marketed on a
competitive basis. Cost-control initiatives could cause us, or any future collaborators, to decrease the price we, or they, might establish for products, which could result in lower than anticipated
product revenues. If the prices for our products, if any, decrease or if governmental and other third-party payors do not provide coverage or adequate reimbursement, our prospects for revenue and
profitability will suffer.
There
may also be delays in obtaining coverage and reimbursement for newly approved drugs, and coverage may be more limited than the indications for which the drug is approved by the FDA
or comparable foreign regulatory authorities. Moreover, eligibility for reimbursement does not imply that any drug will be paid for in all cases or at a rate that covers our costs, including research,
development, manufacture, sale and distribution. Reimbursement rates may vary, by way of example, according to the use of the drug and the clinical setting in which it is used. Reimbursement rates may
also be based on reimbursement levels already set for lower cost drugs or may be incorporated into existing payments for other services.
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In
addition, increasingly, third-party payors are requiring higher levels of evidence of the benefits and clinical outcomes of new technologies and are challenging the prices charged. We
cannot be sure that coverage will be available for any product candidate that we, or any future collaborator, commercialize and, if available, that the reimbursement rates will be adequate. Further,
the net reimbursement for drug products may be subject to additional reductions if there are changes to laws that presently restrict imports of drugs from countries where they may be sold at lower
prices than in the United States. An inability to promptly obtain coverage and adequate payment rates from both government-funded and private payors for any of our product candidates for which we, or
any future collaborator, obtain marketing approval could significantly harm our operating results, our ability to raise capital needed to commercialize products and our overall financial condition.
Product liability lawsuits against us could divert our resources, cause us to incur substantial liabilities
and limit commercialization of any products that we may develop.
We face an inherent risk of product liability claims as a result of the clinical testing of our product candidates despite obtaining appropriate
informed consents from our clinical trial participants. We will face an even greater risk if we or any future collaborators commercially sell any product that we may or they may develop. For example,
we may be sued if any product we develop allegedly causes injury or is found to be otherwise unsuitable during clinical testing, manufacturing, marketing or sale. Any such product liability claims may
include allegations of defects in manufacturing, defects in design, a failure to warn of dangers inherent in the product, negligence, strict liability or a breach of warranties. Claims could also be
asserted under state consumer protection acts. If we cannot successfully defend ourselves against product liability claims, we may incur substantial liabilities or be required to limit
commercialization of our product candidates. Regardless of the merits or eventual outcome, liability claims may result in:
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decreased demand for our product candidates or products that we may develop;
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-
injury to our reputation and significant negative media attention;
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withdrawal of clinical trial participants;
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significant costs to defend resulting litigation;
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substantial monetary awards to trial participants or patients;
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loss of revenue;
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reduced resources of our management to pursue our business strategy; and
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the inability to commercialize any products that we may develop.
Although
we maintain general liability insurance of $5.0 million in the aggregate and clinical trial liability insurance of $10.0 million in the aggregate, this insurance may not fully
cover potential liabilities that we may incur. The cost of any product liability litigation or other proceeding, even if resolved in our favor, could be substantial. We will need to increase our
insurance coverage if and when we begin selling any product candidate that receives marketing approval. In addition, insurance coverage is becoming increasingly expensive. If we are unable to obtain
or maintain sufficient insurance coverage at an acceptable cost or to otherwise protect against potential product liability claims, it could prevent or inhibit the development and commercial
production and sale of our product candidates, which could adversely affect our business, financial condition, results of operations and prospects.
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Risks Related to Our Dependence on Third Parties
We expect to seek to establish collaborations and, if we are not able to establish them on commercially
reasonable terms, we may have to alter our development and commercialization plans.
Our drug development programs and the potential commercialization of our product candidates will require substantial additional cash to fund
expenses. We expect to seek one or more collaborators for the development and commercialization of one or more of our product candidates. For example, conducting clinical trials of CAT-5571 in
patients with cystic fibrosis will likely involve significant cost, and we expect that we would conduct any clinical trial of CAT-5571 in patients with cystic fibrosis in collaboration with one or
more partners. Likely collaborators may include large and mid-size pharmaceutical companies, regional and national pharmaceutical companies and biotechnology companies.
We
face significant competition in seeking appropriate collaborators. Whether we reach a definitive agreement for a collaboration will depend, among other things, upon our assessment of
the collaborator's resources and expertise, the terms and conditions of the proposed collaboration and the proposed collaborator's evaluation of a number of factors. Those factors may include the
potential differentiation of our product candidate from competing product candidates, design or results of clinical trials, the likelihood of approval by the FDA or comparable foreign regulatory
authorities and the regulatory pathway for any such approval, the potential market for the product candidate, the costs and complexities of manufacturing and delivering the product to patients and the
potential of competing products. The collaborator may also consider alternative product candidates or technologies for similar indications that may be available for collaboration and whether such a
collaboration could be more attractive than the one with us for our product candidate.
Collaborations
are complex and time-consuming to negotiate and document. Further, there have been a significant number of business combinations among large pharmaceutical companies that
have resulted in a reduced number of potential future collaborators. In addition, our loan and security agreement with MidCap, Flexpoint and Square 1 contains, and any collaboration agreements that we
enter into in the future may contain, restrictions on our ability to enter into potential collaborations or to otherwise develop specified compounds.
We
may not be able to negotiate collaborations on a timely basis, on acceptable terms, or at all. If we are unable to do so, we may have to curtail the development of the product
candidate for which we are seeking to collaborate, reduce or delay its development program or one or more of our other development programs, delay its potential commercialization or reduce the scope
of any sales or marketing activities, or increase our expenditures and undertake development or commercialization activities at our own expense. If we elect to increase our expenditures to fund
development or commercialization activities on our own, we may need to obtain additional capital, which may not be available to us on acceptable terms or at all. If we do not have sufficient funds, we
may not be able to further develop our product candidates or bring them to market and generate product revenue.
If we enter into collaborations with third parties for the development and commercialization of our product
candidates, our prospects with respect to those product candidates will depend in significant part on the success of those collaborations.
We expect to enter into collaborations for the development and commercialization of certain of our product candidates. If we enter into such
collaborations, we will have limited control over the amount and timing of resources that our collaborators will dedicate to the development or commercialization of our product candidates. Our ability
to generate revenues from these arrangements will depend on any future collaborators' abilities to successfully perform the functions assigned to them in these arrangements. In addition, any future
collaborators may have the right to abandon research or development projects and terminate applicable agreements, including funding obligations, prior to or upon the expiration of the agreed upon
terms.
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Collaborations involving our product candidates pose a number of risks, including the following:
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collaborators have significant discretion in determining the efforts and resources that they will apply to these collaborations;
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collaborators may not perform their obligations as expected;
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-
collaborators may not pursue development and commercialization of our product candidates or may elect not to continue or renew development or
commercialization programs, based on clinical trial results, changes in the collaborators' strategic focus or available funding or external factors, such as an acquisition, that divert resources or
create competing priorities;
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-
collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product
candidate, repeat or conduct new clinical trials or require a new formulation of a product candidate for clinical testing;
-
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a collaborator with marketing and distribution rights to one or more products may not commit sufficient resources to the marketing and
distribution of such product or products;
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-
disagreements with collaborators, including disagreements over proprietary rights, contract interpretation or the preferred course of
development, might cause delays or termination of the research, development or commercialization of product candidates, might lead to additional responsibilities for us with respect to product
candidates, or might result in litigation or arbitration, any of which would be time-consuming and expensive;
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collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to
invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation;
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collaborators may infringe the intellectual property rights of third parties, which may expose us to litigation and potential liability; and
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collaborations may be terminated and, if terminated, may result in a need for additional capital to pursue further development or
commercialization of the applicable product candidates.
Collaboration
agreements may not lead to development or commercialization of product candidates in the most efficient manner or at all. If any future collaborator of ours is involved in
a business combination, it could decide to delay, diminish or terminate the development or commercialization of any product candidate licensed to it by us.
We rely on third parties to conduct our clinical trials. If they do not perform satisfactorily, our business
could be significantly harmed.
We do not independently conduct clinical trials of any of our product candidates. We rely on third parties, such as contract research
organizations, clinical data management organizations, medical institutions and clinical investigators, to conduct these clinical trials and expect to rely on these third parties to conduct clinical
trials of any other product candidate that we develop. Any of these third parties may terminate their engagements with us under certain circumstances. We may not be able to enter into alternative
arrangements or do so on commercially reasonable terms. In addition, there is a natural transition period when a new contract research organization begins work. As a result, delays would likely occur,
which could materially impact our ability to meet our expected clinical development timelines and harm our business, financial condition and prospects.
Further,
our reliance on these third parties for clinical development activities limits our control over these activities, but we remain responsible for ensuring that each of our studies
is conducted in accordance with the applicable protocol, legal, regulatory and scientific standards. For example,
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notwithstanding
the obligations of a contract research organization for a trial of one of our product candidates, we remain responsible for ensuring that each of our clinical trials is conducted in
accordance with the general investigational plan and protocols for the trial. Moreover, the FDA requires us to comply with standards, commonly referred to as current Good Clinical Practices, or cGCPs,
for conducting, recording and reporting the results of clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity and confidentiality of trial
participants are protected. The FDA enforces these cGCPs through periodic inspections of trial sponsors, principal investigators, clinical trial sites and institutional review boards. If we or our
third-party contractors fail to comply with applicable cGCPs, the clinical data generated in our clinical
trials may be deemed unreliable and the FDA may require us to perform additional clinical trials before approving our product candidates, which would delay the marketing approval process. We cannot be
certain that, upon inspection, the FDA will determine that any of our clinical trials comply with cGCPs. We are also required to register clinical trials and post the results of completed clinical
trials on a government-sponsored database, ClinicalTrials.gov, within certain timeframes. Failure to do so can result in fines, adverse publicity and civil and criminal sanctions.
Furthermore,
the third parties conducting clinical trials on our behalf are not our employees, and except for remedies available to us under our agreements with such contractors, we
cannot control whether or not they devote sufficient time, skill and resources to our ongoing development programs. These contractors may also have relationships with other commercial entities,
including our competitors, for whom they may also be conducting clinical trials or other drug development activities, which could impede their ability to devote appropriate time to our clinical
programs. If these third parties do not successfully carry out their contractual duties, meet expected deadlines or conduct our clinical trials in accordance with regulatory requirements or our stated
protocols, we may not be able to obtain, or may be delayed in obtaining, marketing approvals for our product candidates. If that occurs, we will not be able to, or may be delayed in our efforts to,
successfully commercialize our product candidates. In such an event, our financial results and the commercial prospects for any product candidates that we seek to develop could be harmed, our costs
could increase and our ability to generate revenues could be impaired.
We
also rely on other third parties to store and distribute drug supplies for our clinical trials. Any performance failure on the part of our distributors could delay clinical
development or marketing approval of our product candidates or commercialization of any resulting products, producing additional losses and depriving us of potential product revenue.
We contract with third parties for the manufacture and distribution of our product candidates for clinical
trials and expect to continue to do so in connection with our future development and commercialization efforts. This reliance on third parties increases the risk that we will not have sufficient
quantities of our product candidates or such quantities at an acceptable cost, which could delay, prevent or impair our development or commercialization efforts.
We currently have no manufacturing facilities and limited personnel with manufacturing experience. We rely on contract manufacturers to produce
both drug substance and drug product required for our clinical trials. We plan to continue to rely upon contract manufacturers, and, potentially collaboration partners, to manufacture commercial
quantities of our products, if approved. Reliance on such third-party contractors entails risks, including:
-
-
manufacturing delays if our third-party contractors give greater priority to the supply of other products over our product candidates or
otherwise do not satisfactorily perform according to the terms of the agreements between us and them;
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the possible termination or nonrenewal of agreements by our third-party contractors at a time that is costly or inconvenient for us;
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the possible breach by the third-party contractors of our agreements with them;
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the failure of third-party contractors to comply with applicable regulatory requirements;
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-
the possible mislabeling of clinical supplies, potentially resulting in the wrong dose amounts being supplied or active drug or placebo not
being properly identified;
-
-
the possibility of clinical supplies not being delivered to clinical sites on time, leading to clinical trial interruptions, or of drug
supplies not being distributed to commercial vendors in a timely manner, resulting in lost sales; and
-
-
the possible misappropriation of our proprietary information, including our trade secrets and know-how.
We
currently rely, and expect to continue to rely, on a small number of third-party contract manufacturers to supply the majority of our active pharmaceutical ingredient and required
finished product for our preclinical studies and clinical trials. We do not have long-term agreements with any of these third parties. If any of our existing manufacturers should become unavailable to
us for any reason, we may incur some delay in identifying or qualifying replacements.
Any
manufacturing problem or the loss of a contract manufacturer could be disruptive to our operations, delay our clinical trials and, if our products are approved for sale, result in
lost sales. Additionally, we rely on third parties to supply the raw materials needed to manufacture our product candidates. Any reliance on suppliers may involve several risks, including a potential
inability to obtain critical materials and reduced control over production costs, delivery schedules, reliability and quality. Any unanticipated disruption to future contract manufacture caused by
problems at suppliers could delay shipment of our product candidates, increase our cost of goods sold and result in lost sales.
If
any of our product candidates are approved by any regulatory agency, we plan to enter into agreements with third-party contract manufacturers for the commercial production and
distribution of those products. It may be difficult for us to reach agreement with a contract manufacturer on satisfactory terms or in a timely manner. In addition, we may face competition for access
to manufacturing facilities as there are a limited number of contract manufacturers operating under current good manufacturing practices, or cGMPs, that are capable of manufacturing our product
candidates. Consequently, we may not be able to reach agreement with third-party manufacturers on satisfactory terms, which could delay our commercialization efforts.
Third-party
manufacturers are required to comply with cGMPs and similar regulatory requirements outside the United States. Facilities used by our third-party manufacturers must be
approved by the FDA after we submit an NDA and before potential approval of the product candidate. Similar regulations apply to manufacturers of our product candidates for use or sale in foreign
countries. We do not control the manufacturing process and are completely dependent on our third-party manufacturers for compliance with the applicable regulatory requirements for the manufacture of
our product candidates. If our manufacturers cannot successfully manufacture material that conforms to our specifications or the strict regulatory requirements of the FDA and any applicable foreign
regulatory authority, they will not be able to secure the applicable approval for their manufacturing facilities. If these facilities are not approved for commercial manufacture, we may need to find
alternative manufacturing facilities, which could result in delays in obtaining approval for the applicable product candidate.
In
addition, our manufacturers are subject to ongoing periodic inspections by the FDA and corresponding state and foreign agencies for compliance with cGMPs and similar regulatory
requirements both prior to and following the receipt of marketing approval for any of our product
candidates. Some of these inspections may be unannounced. Failure by any of our manufacturers to comply with applicable cGMPs or other regulatory requirements could result in sanctions being
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imposed
on us, including fines, injunctions, civil penalties, delays, suspensions or withdrawals of approvals, operating restrictions, interruptions in supply and criminal prosecutions, any of which
could adversely affect supplies of our product candidates and significantly harm our business, financial condition and results of operations.
Our
current and anticipated future dependence upon others for the manufacture of our product candidates may adversely affect our future profit margins and our ability to commercialize
any products that receive marketing approval on a timely and competitive basis.
Risks Related to Our Intellectual Property
If we are unable to obtain and maintain sufficient patent protection for our product candidates, or if the
scope of the patent protection is not sufficiently broad, our competitors could develop and commercialize products similar or identical to ours, and our ability to commercialize our product candidates
successfully may be adversely affected.
Our success depends in large part on our ability to obtain and maintain patent protection in the United States and other countries with respect
to our proprietary product candidates. If we do not adequately protect our intellectual property, competitors may be able to erode or negate any competitive advantage we may have, which could harm our
business and ability to achieve profitability. To protect our proprietary position, we file patent applications in the United States and abroad related to our novel product candidates that are
important to our business. The patent application and approval process is expensive and time-consuming. We may not be able to file and prosecute all necessary or desirable patent applications at a
reasonable cost or in a timely manner.
The
patent position of biotechnology and pharmaceutical companies generally is highly uncertain. No consistent policy regarding the breadth of claims allowed in biotechnology and
pharmaceutical patents has emerged to date in the United States or in many foreign jurisdictions. In addition, the determination of patent rights with respect to pharmaceutical compounds commonly
involves complex legal and factual questions, which has in recent years been the subject of much litigation. As a result, the issuance, scope, validity, enforceability and commercial value of our
patent rights are highly uncertain.
Our
pending patent applications cannot be enforced against third parties practicing the technology claimed in such applications unless and until a patent issues from such applications.
Assuming the other requirements for patentability are met, currently, the first to file a patent application is generally entitled to the patent. However, prior to March 16, 2013, in the United
States, the first to invent was entitled to the patent. Publications of discoveries in the scientific literature often lag behind the actual discoveries, and patent applications in the United States
and other jurisdictions are typically not published until 18 months after filing, or in some cases not at all. Therefore, we cannot be certain that we were the first to make the inventions claimed in
our patents or pending patent applications, or that we were the first to file for patent protection of such inventions.
Moreover,
because the issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability, our patents or pending patent applications may be challenged in
the courts or patent offices in the United States and abroad. For example, we may be subject to a third party preissuance submission of prior art to the U.S. Patent and Trademark Office, or USPTO, or
become involved in post-grant review procedures, oppositions, derivations, reexaminations, inter partes review or interference proceedings, in the United States or elsewhere, challenging our patent
rights or the patent rights of others. An adverse determination in any such challenges may result in loss of exclusivity or in patent claims being narrowed, invalidated or held unenforceable, in whole
or in part, which could limit our ability to stop others from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of our technology
and products. In addition, given the amount of time required for the development, testing and regulatory review of new product candidates,
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patents
protecting such candidates might expire before or shortly after such candidates are commercialized.
Our
pending and future patent applications may not result in patents being issued which protect our product candidates, in whole or in part, or which effectively prevent others from
commercializing competitive products. Changes in either the patent laws or interpretation of the patent laws in the United States and other countries may diminish the value of our patents or narrow
the scope of our patent protection. In addition, the laws of foreign countries may not protect our rights to the same extent or in the same manner as the laws of the United States. For example,
European patent law
restricts the patentability of methods of treatment of the human body more than United States law does.
Even
if our patent applications issue as patents, they may not issue in a form that will provide us with any meaningful protection, prevent competitors from competing with us or
otherwise provide us with any competitive advantage. Our competitors may be able to circumvent our patents by developing similar or alternative technologies or products in a non-infringing manner. Our
competitors may also seek approval to market their own products similar to or otherwise competitive with our products. Alternatively, our competitors may seek to market generic versions of any
approved products by submitting ANDAs to the FDA in which they claim that patents owned or licensed by us are invalid, unenforceable or not infringed. In these circumstances, we may need to defend or
assert our patents, or both, including by filing lawsuits alleging patent infringement. In any of these types of proceedings, a court or other agency with jurisdiction may find our patents invalid or
unenforceable, or that our competitors are competing in a non-infringing manner. Thus, even if we have valid and enforceable patents, these patents still may not provide protection against competing
products or processes sufficient to achieve our business objectives.
If we are unable to protect the confidentiality of our trade secrets, the value of our technology could be
materially adversely affected and our business would be harmed.
While we have obtained composition of matter patents with respect to our most advanced product candidates, we also rely on trade secret
protection for certain aspects of technology platform, including certain aspects of our SMART linker drug discovery platform. We seek to protect these trade secrets, in part, by entering into
non-disclosure and confidentiality agreements with parties who have access to them, such as our employees, consultants, independent contractors, advisors, contract manufacturers, suppliers and other
third parties. We also enter into confidentiality and invention or patent assignment agreements with employees and certain consultants. Any party with whom we have executed such an agreement may
breach that agreement and disclose our proprietary information, including our trade secrets, and we may not be able to obtain adequate remedies for such breaches. Enforcing a claim that a party
illegally disclosed or misappropriated a trade secret is difficult, expensive and time-consuming, and the outcome is unpredictable. In addition, if any of our trade secrets were to be lawfully
obtained or independently developed by a competitor, we would have no right to prevent such third party, or those to whom they communicate such technology or information, from using that technology or
information to compete with us. If any of our trade secrets were to be disclosed to or independently developed by a competitor, our business and competitive position could be harmed.
We may become involved in lawsuits to protect or enforce our patents or other intellectual property, which
could be expensive, time consuming and unsuccessful.
Competitors may infringe our patents, trademarks, copyrights or other intellectual property. To counter infringement or unauthorized use, we may
be required to file infringement claims, which can be expensive and time consuming and divert the time and attention of our management and scientific personnel. Any claims we assert against perceived
infringers could provoke these parties to assert counterclaims against us alleging that we infringe their patents, in addition to counterclaims asserting
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that
our patents are invalid or unenforceable, or both. In any patent infringement proceeding, there is a risk that a court will decide that a patent of ours is invalid or unenforceable, in whole or
in part, and that we do not have the right to stop the other party from using the invention at issue. There is also a risk that, even if the validity of such patents is upheld, the court will construe
the patent's claims narrowly or decide that we do not have the right to stop the other party from using the invention at issue on the grounds that our patent claims do not cover the invention. An
adverse outcome in a litigation or proceeding involving our patents could limit our ability to assert our patents against those parties or other competitors, and may curtail or preclude our ability to
exclude third parties from making and selling similar or competitive products. Any of these occurrences could adversely affect our competitive business position, business prospects and financial
condition. Similarly, if we assert trademark infringement claims, a court may determine that the marks we have asserted are invalid or unenforceable, or that the party against whom we have asserted
trademark infringement has superior rights to the marks in question. In this case, we could ultimately be forced to cease use of such trademarks.
Even
if we establish infringement, the court may decide not to grant an injunction against further infringing activity and instead award only monetary damages, which may or may not be an
adequate remedy. Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information
could be compromised by disclosure during litigation. There could also be public announcements of the results of hearings, motions or other interim proceedings or developments. If securities analysts
or investors perceive these results to be negative, it could have a material adverse effect on the price of shares of our common stock. Moreover, there can be no assurance that we will have sufficient
financial or other resources to file and pursue such infringement claims, which typically last for years before they are concluded. Even if we ultimately prevail in such claims, the monetary cost of
such litigation and the diversion of the attention of our management and scientific personnel could outweigh any benefit we receive as a result of the proceedings.
If we are sued for infringing intellectual property rights of third parties, such litigation could be costly
and time consuming and could prevent or delay us from developing or commercializing our product candidates.
Our commercial success depends, in part, on our ability to develop, manufacture, market and sell our product candidates and use our SMART linker
drug discovery platform without infringing the intellectual property and other proprietary rights of third parties. Third parties have U.S. and non-U.S. issued patents and pending patent applications
relating to compounds and methods of use for the treatment of DMD, the key indication for our most advanced program. If any third-party patents or patent applications are found to cover our product
candidates or their methods of use, we may not be free to manufacture or market our product candidates as planned without obtaining a license, which may not be available on commercially reasonable
terms, or at all.
There
is a substantial amount of intellectual property litigation in the biotechnology and pharmaceutical industries, and we may become party to, or threatened with, litigation or other
adversarial proceedings regarding intellectual property rights with respect to our product candidates, including interference proceedings before the USPTO. Third parties may assert infringement claims
against us based on existing or future intellectual property rights. The outcome of intellectual property litigation is subject to uncertainties that cannot be adequately quantified in advance. The
pharmaceutical and biotechnology industries have produced a significant number of patents, and it may not always be clear to industry participants, including us, which patents cover various types of
products or methods of use. The coverage of patents is subject to interpretation by the courts, and the interpretation is not always uniform. If we were sued for patent infringement, we would need to
demonstrate that our product candidates, products or methods either do not infringe the patent claims of the relevant patent or that the patent claims are invalid or unenforceable, and we may not be
able
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to
do this. Proving invalidity is difficult. For example, in the United States, proving invalidity requires a showing of clear and convincing evidence to overcome the presumption of validity enjoyed
by issued patents. Even if we are successful in these proceedings, we may incur substantial costs and the time and attention of our management and scientific personnel could be diverted in pursuing
these proceedings, which could significantly harm our business and operating results. In addition, we may not have sufficient resources to bring these actions to a successful conclusion.
If
we are found to infringe a third party's intellectual property rights, we could be forced, including by court order, to cease developing, manufacturing or commercializing the
infringing product candidate or product. Alternatively, we may be required to obtain a license from such third party in order to use the infringing technology and continue developing, manufacturing or
marketing the infringing product candidate. However, we may not be able to obtain any required license on commercially reasonable terms or at all. Even if we were able to obtain a license, it could be
non-exclusive, thereby giving our
competitors access to the same technologies licensed to us. In addition, we could be found liable for monetary damages, including treble damages and attorneys' fees if we are found to have willfully
infringed a patent. A finding of infringement could prevent us from commercializing our product candidates or force us to cease some of our business operations, which could materially harm our
business. Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar negative impact on our business.
Changes to the patent law in the United States and other jurisdictions could diminish the value of patents in
general, thereby impairing our ability to protect our products.
As is the case with other biopharmaceutical companies, our success is heavily dependent on intellectual property, particularly patents.
Obtaining and enforcing patents in the biopharmaceutical industry involves both technological and legal complexity and is therefore costly, time consuming and inherently uncertain. Recent patent
reform legislation in the United States and other countries, including the Leahy-Smith America Invents Act, or the Leahy-Smith Act, signed into law in September 2011, could increase those
uncertainties and costs. The Leahy-Smith Act includes a number of significant changes to U.S. patent law. These include provisions that affect the way patent applications are prosecuted, redefine
prior art and provide more efficient and cost-effective avenues for competitors to challenge the validity of patents. In addition, the Leahy-Smith Act has transformed the U.S. patent system into a
"first to file" system. The first-to-file provisions, however, only became effective in March 2013. Accordingly, it is not yet clear what, if any, impact the Leahy-Smith Act will have on the operation
of our business. However, the Leahy-Smith Act and its implementation could make it more difficult to obtain patent protection for our inventions and increase the uncertainties and costs surrounding
the prosecution of our or our collaboration partners' patent applications and the enforcement or defense of our or our collaboration partners' issued patents, all of which could harm our business,
results of operations and financial condition.
The
U.S. Supreme Court has ruled on several patent cases in recent years, either narrowing the scope of patent protection available in certain circumstances or weakening the rights of
patent owners in certain situations. Additionally, there have been recent proposals for additional changes to the patent laws of the United States and other countries that, if adopted, could impact
our ability to enforce our proprietary technology. Depending on future actions by the U.S. Congress, the U.S. courts, the USPTO and the relevant law-making bodies in other countries, the laws and
regulations governing patents could change in unpredictable ways that would weaken our ability to obtain new patents or to enforce our existing patents and patents that we might obtain in the future.
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Obtaining and maintaining our patent protection depends on compliance with various procedural, document
submissions, fee payment and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for noncompliance with these requirements.
Periodic maintenance fees on any issued patent are due to be paid to the USPTO and foreign patent agencies in several stages over the lifetime
of the patent. The USPTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent
application process. While an inadvertent lapse can in many cases be cured by payment of a late fee or by other means in accordance with the applicable rules, there are situations in which
noncompliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. Noncompliance events that
could result in abandonment or lapse of a patent or patent application include, but are not limited to, failure to respond to official actions within prescribed time limits, non-payment of fees and
failure to properly legalize and submit formal documents. If we fail to maintain the patents and patent applications covering our product candidates, our competitive position would be adversely
affected.
We may not be able to enforce our intellectual property rights throughout the world.
Filing, prosecuting and defending patents on our product candidates in all countries throughout the world would be prohibitively expensive. The
requirements for patentability may differ in certain countries, particularly in developing countries. Competitors may use our technologies in jurisdictions where we have not obtained patent protection
to develop their own products and, further, may export otherwise infringing products to territories where we may obtain patent protection, but where patent enforcement is not as strong as that in the
United States. These products may compete with our products in jurisdictions where we do not have any issued or licensed patents or where any future patent claims or other intellectual property rights
may not be effective or sufficient to prevent them from competing with us.
Moreover,
our ability to protect and enforce our intellectual property rights may be adversely affected by unforeseen changes in foreign intellectual property laws. Additionally, laws of
some countries outside of the United States and Europe do not afford intellectual property protection to the same extent as the laws of the United States and Europe. Many companies have encountered
significant problems in protecting and defending intellectual property rights in certain foreign jurisdictions. The legal systems of some countries, including India, China and other developing
countries, do not favor the enforcement of patents and other intellectual property rights. This could make it difficult for us to stop the infringement of our patents or the misappropriation of our
other intellectual property rights. For example, many foreign countries have compulsory licensing laws under which a patent owner must grant licenses to third parties. Consequently, we may not be able
to prevent third parties from practicing our inventions in certain countries outside the United States and Europe. Competitors may use our technologies in jurisdictions where we have not obtained
patent protection to develop their own products and, further, may export otherwise infringing products to territories where we have patent
protection, if our ability to enforce our patents to stop infringing activities is inadequate. These products may compete with our products, and our patents or other intellectual property rights may
not be effective or sufficient to prevent them from competing.
Proceedings
to enforce our patent rights in foreign jurisdictions, whether or not successful, could result in substantial costs and divert our efforts and resources from other aspects of
our business. Furthermore, while we intend to protect our intellectual property rights in major markets for our products, we cannot ensure that we will be able to initiate or maintain similar efforts
in all jurisdictions in which we may wish to market our products. Accordingly, our efforts to protect our intellectual property rights in such countries may be inadequate.
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Patent term may be inadequate to protect our competitive position on our products for an adequate amount of
time.
Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such
candidates might expire before or shortly after such candidates are commercialized. We expect to seek extensions of patent terms in the United States and, if available, in other countries where we are
prosecuting patents. In the United States, the Drug Price Competition and Patent Term Restoration Act of 1984 permits a patent term extension of up to five years beyond the normal expiration of the
patent, which is limited to the approved indication (or any additional indications approved during the period of extension). However, the applicable authorities, including the FDA and the USPTO in the
United States, and any equivalent regulatory authority in other countries, may not agree with our assessment of whether such extensions are available, and may refuse to grant extensions to our
patents, or may grant more limited extensions than we request. If this occurs, our competitors may be able to take advantage of our investment in development and clinical trials by referencing our
clinical and preclinical data and launch their product earlier than might otherwise be the case.
We may be subject to claims by third parties asserting that our employees or we have misappropriated their
intellectual property, or claiming ownership of what we regard as our own intellectual property.
Many of our employees, including our senior management, were previously employed at universities or at other biotechnology or pharmaceutical
companies, including our competitors or potential competitors. Some of these employees, including members of our senior
management, executed proprietary rights, non-disclosure and non-competition agreements, or similar agreements, in connection with such previous employment. Although we try to ensure that our employees
do not use the proprietary information or know-how of others in their work for us, we may be subject to claims that we or these employees have used or disclosed intellectual property, including trade
secrets or other proprietary information, of any such third party. Litigation may be necessary to defend against such claims. If we fail in defending any such claims, in addition to paying monetary
damages, we may lose valuable intellectual property rights or personnel or sustain damages. Such intellectual property rights could be awarded to a third party, and we could be required to obtain a
license from such third party to commercialize our technology or products. Such a license may not be available on commercially reasonable terms or at all. Even if we are successful in defending
against such claims, litigation could result in substantial costs and be a distraction to management.
In
addition, while we typically require our employees, consultants and contractors who may be involved in the development of intellectual property to execute agreements assigning such
intellectual property to us, we may be unsuccessful in executing such an agreement with each party who in fact develops intellectual property that we regard as our own, which may result in claims by
or against us related to the ownership of such intellectual property. If we fail in prosecuting or defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual
property rights. Even if we are successful in prosecuting or defending against such claims, litigation could result in substantial costs and be a distraction to our senior management and scientific
personnel.
Risks Related to Regulatory Approval and Other Legal Compliance Matters
Even if we complete the necessary preclinical and clinical studies, the marketing approval process is
expensive, time consuming and uncertain and may prevent us or any future collaborators from obtaining approvals for the commercialization of some or all of our product candidates. As a result, we
cannot predict when or if, and in which territories, we, or any future collaborators, will obtain marketing approval to commercialize a product candidate.
The research, testing, manufacturing, labeling, approval, selling, marketing, promotion and distribution of drug products are subject to
extensive regulation by the FDA and comparable foreign
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regulatory
authorities, which regulations differ from country to country. We, and any future collaborators, are not permitted to market our product candidates in the United States or in other
countries until we, or they, receive approval of an NDA from the FDA or marketing approval from applicable regulatory authorities outside the United States. Our product candidates are in various
stages of development and are subject to the risks of failure inherent in drug development. We have not submitted an application for or received marketing approval for any of our product candidates in
the United States or in any other jurisdiction. We have limited experience in conducting and managing the clinical trials necessary to obtain marketing approvals, including FDA approval of an NDA.
The
process of obtaining marketing approvals, both in the United States and abroad, is lengthy, expensive and uncertain. It may take many years, if approval is obtained at all, and can
vary substantially based upon a variety of factors, including the type, complexity and novelty of the product candidates involved.
In
addition, changes in marketing approval policies during the development period, changes in or the enactment or promulgation of additional statutes, regulations or guidance or changes
in regulatory review for each submitted product application, may cause delays in the approval or rejection of an application. Regulatory authorities have substantial discretion in the approval process
and may refuse to accept any application or may decide that our data are insufficient for approval and require additional preclinical, clinical or other studies. In addition, varying interpretations
of the data obtained from preclinical and clinical testing could delay, limit or prevent marketing approval of a product candidate. Any marketing approval we, or any future collaborators, ultimately
obtain may be limited or subject to restrictions or post-approval commitments that render the approved product not commercially viable.
Any
delay in obtaining or failure to obtain required approvals could materially adversely affect our ability or that of any future collaborators to generate revenue from the particular
product candidate, which likely would result in significant harm to our financial position and adversely impact our stock price.
Failure to obtain marketing approval in foreign jurisdictions would prevent our product candidates from being
marketed abroad.
In order to market and sell our products in the European Union and many other jurisdictions, we, and any future collaborators, must obtain
separate marketing approvals and comply with numerous and varying regulatory requirements. The approval procedure varies among countries and can involve additional testing. The time required to obtain
approval may differ substantially from that required to obtain FDA approval. The marketing approval process outside the United States
generally includes all of the risks associated with obtaining FDA approval. In addition, in many countries outside the United States, it is required that the product be approved for reimbursement
before the product can be approved for sale in that country. We, and any future collaborators, may not obtain approvals from regulatory authorities outside the United States on a timely basis, if at
all. Approval by the FDA does not ensure approval by regulatory authorities in other countries or jurisdictions, and approval by one regulatory authority outside the United States does not ensure
approval by regulatory authorities in other countries or jurisdictions or by the FDA.
We, or any future collaborators, may not be able to obtain orphan drug designation or orphan drug exclusivity
for our product candidates.
Regulatory authorities in some jurisdictions, including the United States and Europe, may designate drugs for relatively small patient
populations as orphan drugs. Under the Orphan Drug Act, the FDA may designate a product as an orphan drug if it is a drug intended to treat a rare disease or condition, which is generally defined as a
patient population of fewer than 200,000 individuals annually in the United States. While we have obtained orphan drug designation from the FDA and orphan
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medicinal
product designation from the European Commission for edasalonexent for the treatment of DMD, we, or any future collaborators, may seek orphan drug designations for other product candidates
or in other jurisdictions and may be unable to obtain such designations.
Even
if we, or any future collaborators, obtain orphan drug designation for a product candidate, we, or they, may not be able to obtain orphan drug exclusivity for that product
candidate. Generally, a product with orphan drug designation only becomes entitled to orphan drug exclusivity if it receives the first marketing approval for the indication for which it has such
designation, in which case the FDA or the EMA will be precluded from approving another marketing application for the same drug for that indication for the applicable exclusivity period. The applicable
exclusivity period is seven years in the United States and ten years in Europe. The European exclusivity period can be reduced to six years if a drug no longer meets the criteria for orphan drug
designation or if the drug is sufficiently profitable so that market exclusivity is no longer justified. Orphan drug exclusivity may be lost if the FDA or the EMA determines that the request for
designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the drug to meet the needs of patients with the rare disease or condition.
Even
if we, or any future collaborators, obtain orphan drug exclusivity for a product, that exclusivity may not effectively protect the product from competition because FDA has taken the
position that, under certain circumstances, another drug with the same active moiety can be approved for the same condition. Specifically, the FDA's regulations provide that it can approve another
drug with the same active moiety for the same condition if the FDA concludes that the later drug is clinically superior in that it is shown to be safer, more effective or makes a major contribution to
patient care.
Even if we, or any future collaborators, obtain marketing approvals for our product candidates, the terms of
approvals and ongoing regulation of our products may limit how we, or they, manufacture and market our products, which could materially impair our ability to generate revenue.
Once marketing approval has been granted, an approved product and its manufacturer and marketer are subject to ongoing review and extensive
regulation. We, and any future collaborators, must therefore comply with requirements concerning advertising and promotion for any of our product candidates for which we or they obtain marketing
approval. Promotional communications with respect to prescription drugs are subject to a variety of legal and regulatory restrictions and must be consistent with the information in the product's
approved labeling. Thus, we and any future collaborators will not be able to promote any products we develop for indications or uses for which they are not approved.
In
addition, manufacturers of approved products and those manufacturers' facilities are required to comply with extensive FDA requirements, including ensuring that quality control and
manufacturing procedures conform to cGMPs, which include requirements relating to quality control and quality assurance as well as the corresponding maintenance of records and documentation and
reporting requirements. We, our contract manufacturers, any future collaborators and their contract manufacturers could be subject to periodic unannounced inspections by the FDA to monitor and ensure
compliance with cGMPs.
Accordingly,
assuming we, or any future collaborators, receive marketing approval for one or more of our product candidates, we, and any future collaborators, and our and their contract
manufacturers will continue to expend time, money and effort in all areas of regulatory compliance, including manufacturing, production, product surveillance and quality control.
If
we, and any future collaborators, are not able to comply with post-approval regulatory requirements, we, and any future collaborators, could have the marketing approvals for our
products withdrawn by regulatory authorities and our, or any future collaborators', ability to market any future products could be limited, which could adversely affect our ability to achieve or
sustain profitability. Further, the cost of compliance with post-approval regulations may have a negative effect on our operating results and financial condition.
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Any of our product candidates for which we, or any future collaborators, obtain marketing approval in the
future could be subject to post-marketing restrictions or withdrawal from the market and we, or any future collaborators, may be subject to substantial penalties if we, or they, fail to comply with
regulatory requirements or if we, or they, experience unanticipated problems with our products following approval.
Any of our product candidates for which we, or any future collaborators, obtain marketing approval in the future, as well as the manufacturing
processes, post-approval studies and measures, labeling, advertising and promotional activities for such product, among other things, will be subject to continual requirements of and review by the FDA
and other regulatory authorities. These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, requirements relating to
manufacturing, quality control, quality assurance and corresponding maintenance of records and documents, requirements regarding the distribution of samples to physicians and recordkeeping. Even if
marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the product may be marketed or to the conditions of approval, including
the requirement to implement a Risk Evaluation and Mitigation Strategy.
The
FDA may also impose requirements for costly post-marketing studies or clinical trials and surveillance to monitor the safety or efficacy of a product. The FDA and other agencies,
including the Department of Justice, closely regulate and monitor the post-approval marketing and promotion of products to ensure that they are manufactured, marketed and distributed only for the
approved indications and in accordance with the provisions of the approved labeling. The FDA imposes stringent restrictions on manufacturers' communications regarding off-label use and if we, or any
future collaborators, do not market any of our product candidates for which we, or they, receive marketing approval for only their approved indications, we, or they, may be subject to warnings or
enforcement action for off-label marketing. Violation of the FDCA and other statutes, including the False Claims Act, relating to the promotion and advertising of prescription drugs may lead to
investigations or allegations of violations of federal and state health care fraud and abuse laws and state consumer protection laws.
In
addition, later discovery of previously unknown adverse events or other problems with our products or their manufacturers or manufacturing processes, or failure to comply with
regulatory requirements, may yield various results, including:
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restrictions on such products, manufacturers or manufacturing processes;
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restrictions on the labeling or marketing of a product;
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restrictions on product distribution or use;
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requirements to conduct post-marketing studies or clinical trials;
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warning letters or untitled letters;
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withdrawal of the products from the market;
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refusal to approve pending applications or supplements to approved applications that we submit;
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recall of products;
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restrictions on coverage by third-party payors;
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fines, restitution or disgorgement of profits or revenues;
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suspension or withdrawal of marketing approvals;
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refusal to permit the import or export of products;
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product seizure; or
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injunctions or the imposition of civil or criminal penalties.
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Recently enacted and future legislation may increase the difficulty and cost for us and any future
collaborators to obtain marketing approval of and commercialize our product candidates and affect the prices we, or they, may obtain.
In the United States and some foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes
regarding the healthcare system that could, among other things, prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our ability, or
the ability of any future collaborators, to profitably sell any products for which we, or they, obtain marketing approval. We expect that current laws, as well as other healthcare reform measures that
will be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we, or any future collaborators, may receive for any approved
products.
In
the United States, the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, or Medicare Modernization Act, changed the way Medicare covers and pays for
pharmaceutical products. The legislation expanded Medicare coverage for drug purchases by the elderly and introduced a new reimbursement methodology based on average sales prices for physician
administered drugs. In addition, this legislation provided authority for limiting the number of drugs that will be covered in any therapeutic class. Cost reduction initiatives and other provisions of
this legislation could decrease the coverage and price that we receive for any approved products. While the Medicare Modernization Act applies only to drug benefits for Medicare beneficiaries, private
payors often follow Medicare coverage policy and payment limitations in setting their own reimbursement rates. Therefore, any reduction in reimbursement that results from the Medicare Modernization
Act may result in a similar reduction in payments from private payors. The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Affordability Reconciliation Act, or
collectively the Affordable Care Act, or ACA, became law in 2010 and includes the following provisions of potential importance to our product candidates:
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an annual, non-deductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents;
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an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program;
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expansion of federal healthcare fraud and abuse laws, including the False Claims Act and the Anti-Kickback Statute, new government
investigative powers and enhanced penalties for noncompliance;
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a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% point-of-sale discounts off negotiated
prices;
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extension of manufacturers' Medicaid rebate liability;
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expansion of eligibility criteria for Medicaid programs;
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expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program new requirements to report
financial arrangements with physicians and teaching hospitals;
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a new requirement to annually report drug samples that manufacturers and distributors provide to physicians; and
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a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research,
along with funding for such research.
In
addition, other legislative changes have been proposed and adopted since the ACA was enacted. In August 2011, the Budget Control Act of 2011, among other things, created measures for
spending reductions by Congress. A Joint Select Committee on Deficit Reduction, tasked with recommending a
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deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation's automatic reduction to several government
programs. These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect in April 2013 and will remain in effect through 2024 unless
additional Congressional action is taken. The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers and increased the statute of limitations period
for the government to recover overpayments to providers from three to five years. These new laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the
prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used. We expect that the ACA,
as well as other healthcare reform measures that may be adopted in the future, may result in additional reductions in Medicare and other healthcare funding, more rigorous coverage criteria, new
payment methodologies and additional downward pressure on the price that we receive for any approved product and/or the level of reimbursement physicians receive for administering any approved product
we might bring to market. Reductions in reimbursement levels may negatively impact the prices we receive or the frequency with which our products are prescribed or administered. Any reduction in
reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors.
In
addition, with the new Presidential Administration and Congress, there will likely be additional legislative changes, including repeal and replacement of certain provisions of the
ACA. It remains to be seen, however, precisely what the new legislation will provide, when it will be enacted and what impact it will have on the availability of healthcare and containing or lowering
the cost of healthcare. Such reforms could have an adverse effect on anticipated revenue from product candidates that we may successfully develop and for which we may obtain marketing approval and may
affect our overall financial condition and ability to develop or commercialize product candidates. For example, the President and Congressional leaders have expressed interest in repealing certain ACA
provisions and replacing them with alternatives that may be less costly and provide state Medicaid programs and private health plans more flexibility. It is possible that these repeal and replacement
initiatives, if enacted into law, could ultimately result in fewer individuals having health insurance coverage or in individuals having insurance coverage with less generous benefits. The scope of
potential future legislation to repeal and replace ACA provisions is highly uncertain in many respects, and it is possible
that some of the ACA provisions that generally are not favorable for the research-based pharmaceutical industry could also be repealed along with ACA coverage expansion provisions.
Legislative
and regulatory proposals have been made to expand post-approval requirements and restrict sales and promotional activities for pharmaceutical products. We cannot be sure
whether additional legislative changes will be enacted, or whether the FDA regulations, guidance or interpretations will be changed, or what the impact of such changes on the marketing approvals of
our product candidates, if any, may be. In addition, increased scrutiny by the United States Congress of the FDA's approval process may significantly delay or prevent marketing approval, as well as
subject us and any future collaborators to more stringent product labeling and post-marketing testing and other requirements.
Our relationships with customers and third-party payors, among others, will be subject to applicable
anti-kickback, fraud and abuse and other healthcare laws and regulations, which could expose us to penalties, including criminal sanctions, civil penalties, contractual damages, reputational harm and
diminished profits and future earnings.
Healthcare providers and third-party payors will play a primary role in the recommendation and prescription of any products for which we obtain
marketing approval. Our arrangements with third-party payors and customers, if any, will subject us to broadly applicable fraud and abuse and other healthcare laws and regulations. The laws and
regulations may constrain the business or financial
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arrangements
and relationships through which we market, sell and distribute any products for which we obtain marketing approval. These include the following:
Anti-Kickback Statute.
The federal healthcare Anti-Kickback Statute prohibits, among other things, persons and entities from knowingly
and willfully
soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase,
order or recommendation or arranging of, any good or service, for which payment may be made under a federal healthcare program such as Medicare and Medicaid;
False Claims Laws.
The federal false claims laws impose criminal and civil penalties against individuals or entities for, among other
things,
knowingly presenting, or causing to be presented false or fraudulent claims for payment by a federal healthcare program or making a false statement or record material to payment of a false claim or
avoiding, decreasing or concealing an obligation to pay money to the federal government, with potential liability including mandatory treble damages and significant per-claim penalties;
HIPAA.
The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, imposes criminal and civil liability for,
among other
things, executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters, and, as amended by the Health Information Technology for Economic and
Clinical Health Act and its implementing regulations, also imposes obligations, including mandatory contractual terms and technical safeguards, with respect to maintaining the privacy, security and
transmission of individually identifiable health information;
Transparency Requirements.
Federal laws require applicable manufacturers of covered drugs, biologics, devices and supplies to report
payments and
other transfers of value to physicians and teaching hospitals and ownership and investment interests by physicians; and
Analogous State and Foreign Laws.
Analogous state and foreign fraud and abuse laws and regulations, such as state anti-kickback and
false claims
laws, which may be broader in scope, can apply to our business activities, including sales or marketing arrangements, and claims involving healthcare items or services and are generally broad and are
enforced by many different federal and state agencies as well as through private actions. Some state laws require pharmaceutical companies to comply with the pharmaceutical industry's voluntary
compliance guidelines and the relevant compliance guidance promulgated by the federal government and require drug manufacturers to report information related to payments and other transfers of value
to physicians and other healthcare providers or marketing expenditures. State laws also govern the privacy and security of health information in some circumstances, many of which differ from each
other in significant ways and often are not pre-empted by HIPAA, thus complicating compliance efforts.
Efforts
to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs. It is possible that
governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws
and regulations. If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and
administrative penalties, damages, fines, imprisonment, exclusion of products from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our
operations. If any of the physicians
or other healthcare providers or entities with whom we expect to do business is found to be not in compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions,
including exclusions from government funded healthcare programs.
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If we fail to comply with environmental, health and safety laws and regulations, we could become subject to
fines or penalties or incur costs that could significantly harm our business.
We are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the
handling, use, storage, treatment and disposal of hazardous materials and wastes. From time to time and in the future, our operations may involve the use of hazardous and flammable materials,
including chemicals and biological materials, and may also produce hazardous waste products. Although we contract with third parties for the disposal of these materials and waste products, we cannot
completely eliminate the risk of contamination or injury resulting from these materials. In the event of contamination or injury resulting from the use or disposal of our hazardous materials, we could
be held liable for any resulting damages, and any liability could exceed our resources. We also could incur significant costs associated with civil or criminal fines and penalties for failure to
comply with such laws and regulations.
We
maintain workers' compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials, but this
insurance may not provide adequate coverage against potential liabilities. However, we do not maintain insurance for environmental liability or toxic tort claims that may be asserted against us.
In
addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. Current or future environmental laws and
regulations may impair our research, development or production efforts, which could adversely affect our business, financial condition, results of operations or prospects. In addition, failure to
comply with these laws and regulations may result in substantial fines, penalties or other sanctions.
Governments outside the United States tend to impose strict price controls, which may adversely affect our
revenues, if any.
In some countries, such as the countries of the European Union, the pricing of prescription pharmaceuticals is subject to governmental control.
In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a product. To obtain reimbursement or pricing approval in
some countries, we, or any future collaborators, may be required to conduct a clinical trial that compares the cost-effectiveness of our product to other available therapies. If reimbursement of our
products is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our business could be materially harmed.
A fast track designation by the FDA may not actually lead to a faster development, regulatory review or
approval process.
If a product is intended for the treatment of a serious or life-threatening condition and the product demonstrates the potential to address
unmet needs for this condition, the treatment sponsor may apply for FDA fast track designation. In July 2015, the FDA notified us that we obtained fast track designation for edasalonexent for the
treatment of DMD. Fast track designation does not ensure that we will experience a faster development, regulatory review or approval process compared to conventional FDA procedures. Additionally, the
FDA may withdraw fast track designation if it believes that the designation is no longer supported by data from our clinical development program.
A rare pediatric disease designation may not lead to the receipt of a Priority Review Voucher, even if
edasalonexent is approved, due to the potential expiration of the FDA's Rare Pediatric Disease program.
The FDA has awarded rare pediatric disease Priority Review Vouchers to sponsors of drug candidates to treat rare pediatric disease products, if
the treatment sponsors apply for this designation and meet certain criteria. Under this program, upon the approval of a qualifying NDA or biologics license application, or BLA, for the treatment of a
rare pediatric disease, the sponsor of such an
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application
would be eligible for a rare pediatric disease Priority Review Voucher that can be used to obtain priority review for a subsequent NDA or BLA. The Priority Review Voucher may be sold or
transferred an unlimited number of times. In September 2015, the FDA notified us that we obtained rare pediatric disease designation for edasalonexent for the treatment of DMD. With passage of the
21st Century Cures Act in December 2016, the Rare Pediatric Disease Priority Review Voucher program was reauthorized until 2020. In addition, if a product candidate is designated before
October 1, 2020, as is the case with edasalonexent, it is eligible to receive a voucher if it is approved before October 2022. However, there is no guarantee that edasalonexent will be approved
by that date and, therefore, we may not be in a position to obtain the Priority Review Voucher prior to expiration of the program.
We are subject to anti-corruption laws, as well as export control laws, customs laws, sanctions laws and
other laws governing our operations. If we fail to comply with these laws, we could be subject to civil or criminal penalties, other remedial measures and legal expenses, which could adversely affect
our business, results of operations and financial condition.
Our operations are subject to anti-corruption laws, including the U.K. Bribery Act 2010, or Bribery Act, the U.S. Foreign Corrupt Practices Act,
or FCPA, and other anti-corruption laws that apply in countries where we do business and may do business in the future. The Bribery Act, FCPA and these other laws generally prohibit us, our officers,
and our employees and intermediaries from bribing, being bribed or making other prohibited payments to government officials or other persons to obtain or retain business or gain some other business
advantage. We may in the future operate in jurisdictions that pose a high risk of potential Bribery Act or FCPA violations, and we may participate in collaborations and relationships with third
parties whose actions could potentially subject us to liability under the Bribery Act, FCPA or local anti-corruption laws. In addition, we cannot predict the nature, scope or effect of future
regulatory requirements to which our international operations might be subject or the manner in which existing laws might be administered or interpreted.
We
are also subject to other laws and regulations governing our international operations, including regulations administered by the governments of the United Kingdom and the United
States, and authorities in the European Union, including applicable export control regulations, economic sanctions on countries and persons, customs requirements and currency exchange regulations,
which we collectively refer to as the Trade Control Laws.
There
is no assurance that we will be completely effective in ensuring our compliance with all applicable anti-corruption laws, including the Bribery Act, the FCPA or other legal
requirements, including Trade Control Laws. If we are not in compliance with the Bribery Act, the FCPA and other anti-corruption laws or Trade Control Laws, we may be subject to criminal and civil
penalties, disgorgement and other sanctions and remedial measures, and legal expenses, which could have an
adverse impact on our business, financial condition, results of operations and liquidity. Likewise, any investigation of any potential violations of the Bribery Act, the FCPA, other anti-corruption
laws or Trade Control Laws by U.K., U.S. or other authorities could also have an adverse impact on our reputation, our business, results of operations and financial condition.
Risks Related to Employee Matters and Managing Growth
Our future success depends on our ability to retain our Chief Executive Officer and to attract, retain and
motivate qualified personnel.
We are highly dependent on the pharmaceutical research and development and business development expertise of Jill C. Milne, our President and
Chief Executive Officer. Although we have entered into an employment agreement with Dr. Milne, this agreement does not prevent her from
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terminating
her employment with us at any time. In the future, we may be dependent on other members of our management, scientific and development team.
Our
ability to compete in the highly competitive biotechnology and pharmaceuticals industries depends upon our ability to attract and retain highly qualified managerial, scientific and
medical personnel. Our industry has experienced a high rate of turnover of management personnel in recent years. If we lose one or more of our executive officers or other key employees, our ability to
implement our business strategy successfully could be seriously harmed. Furthermore, replacing executive officers or other key employees may be difficult and may take an extended period of time
because of the limited number of individuals in our industry with the breadth of skills and experience required to develop, gain marketing approval of and commercialize products successfully.
Competition to hire from this limited pool is intense, and we may be unable to hire, train, retain or motivate these additional key employees on acceptable terms given the competition among numerous
pharmaceutical and biotechnology companies for similar personnel. We also experience competition for the hiring of scientific and clinical personnel from universities and research institutions.
We
rely on consultants and advisors, including scientific and clinical advisors, to assist us in formulating our research and development and commercialization strategy. Our consultants
and advisors may be employed by other entities and may have commitments under consulting or advisory contracts with those entities that may limit their availability to us. If we are unable to continue
to attract and retain highly qualified personnel, our ability to develop and commercialize our product candidates will be limited.
We expect to grow our organization, and as a result, we may encounter difficulties in managing our growth,
which could disrupt our operations.
We expect to experience significant growth in the number of our employees and the scope of our operations, particularly in the areas of drug
manufacturing, regulatory affairs and sales, marketing and distribution. To manage these growth activities, we must continue to implement and improve our managerial, operational and financial systems,
expand our facilities and continue to recruit and train additional qualified personnel. Our management may need to devote a disproportionate amount of its attention to managing these growth
activities. Due to our limited financial resources and the limited experience of our management team in managing a company with such anticipated growth, we may not be able to effectively manage the
expansion of our operations or identify, recruit and train additional qualified personnel. Our inability to manage the expansion of our operations effectively may result in weaknesses in our
infrastructure, give rise to operational mistakes, loss of business opportunities, loss of employees and reduced productivity among remaining employees. Our expected growth could also require
significant capital expenditures and may divert financial resources from other projects, such as the development of additional product candidates. If we are unable to effectively manage our expected
growth, our expenses may increase more than expected, our ability to generate revenues could be reduced and we may not be able to implement our business strategy, including the successful
commercialization of our product candidates.
Risks Related to Our Common Stock
An active trading market for our common stock may not be sustained.
Our shares of common stock began trading on The NASDAQ Global Market in June 2015. Given the limited trading history of our common stock, there
is a risk that an active trading market for our shares will not be sustained, which could put downward pressure on the market price for our common stock and thereby affect the ability of our
stockholders to sell their shares. An inactive trading market may also impair our ability to raise capital to continue to fund operations by selling shares and may impair our ability to acquire other
companies or technologies by using our shares as consideration.
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If we were to be delisted from The NASDAQ Stock Market, it could make trading in our stock more difficult.
There are various quantitative listing requirements for a company to remain listed on The NASDAQ Stock Market, including maintaining a minimum
bid price of $1.00 per share. The closing price of our common stock from February 1, 2017 to March 8, 2017 ranged from a high of $1.25 per share and a low of $1.13 per share. If in the future our
common stock fails to meet the minimum bid price requirement to remain listed on The NASDAQ Stock Market, we could be subject to delisting from The NASDAQ Stock Market. If we were to be delisted, it
could make trading in our stock more difficult.
If
the minimum bid price of our common stock were to close below $1.00 for 30 consecutive business days, we would likely receive notification from The NASDAQ Stock Market that we were
not in compliance with the $1.00 minimum bid price rule. If we do not regain compliance within the allotted compliance period, including any extensions that may be granted by The NASDAQ Stock Market,
The NASDAQ Stock Market would notify us that our common stock would be delisted from The NASDAQ Stock Market, eliminating the only established trading market for our shares. We would then be entitled
to appeal this determination to a NASDAQ Hearings Panel, which we may request review the matter in a written or an oral hearing.
In
the event we are delisted from The NASDAQ Stock Market, we would be forced to list our shares on the OTC Electronic Bulletin Board or another quotation medium, such as the pink
sheets, depending on our ability to meet the specific listing requirements of those quotation systems. As a
result, an investor might find it more difficult to trade, or to obtain accurate price quotations for, such shares. Delisting might also reduce the visibility, liquidity, and price of our common
stock.
The price of our common stock is likely to be highly volatile, which could result in substantial losses for
our stockholders.
Our stock price is likely to be highly volatile. The stock market in general and the market for smaller pharmaceutical and biotechnology
companies in particular have experienced extreme volatility that has often been unrelated to the operating performance of particular companies. As a result of this volatility, you may lose some or all
of your investment. The market price for our common stock may be influenced by many factors, including:
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the timing and results of clinical trials of edasalonexent and any of our other product candidates;
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commencement or termination of collaborations for our development programs;
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failure or discontinuation of any of our development programs;
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the success of existing or new competitive products or technologies;
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results of clinical trials of product candidates of our competitors;
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regulatory or legal developments in the United States and other countries;
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developments or disputes concerning patent applications, issued patents or other proprietary rights;
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the recruitment or departure of key personnel;
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the level of expenses related to any of our product candidates or clinical development programs;
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the results of our efforts to develop additional product candidates or products;
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actual or anticipated changes in estimates as to financial results, development timelines or recommendations by securities analysts;
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announcement or expectation of additional financing efforts;
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sales of our common stock by us, our insiders or other stockholders;
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variations in our financial results or those of companies that are perceived to be similar to us;
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changes in estimates or recommendations by securities analysts, if any, that cover our stock;
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changes in the structure of healthcare payment systems;
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market conditions in the pharmaceutical and biotechnology sectors;
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general economic, industry and market conditions; and
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the other factors described in this "Risk Factors" section.
Additionally,
in the past, securities class action litigation has often been brought against a company following a decline in the market price of its securities. This risk is especially
relevant for us because smaller pharmaceutical and biotechnology companies have experienced significant stock price volatility in recent years. If we face such litigation, it could result in
substantial costs and a diversion of management's attention and resources, which could harm our business.
We are an "emerging growth company," and the reduced disclosure requirements applicable to emerging growth
companies may make our common stock less attractive to investors.
We are an "emerging growth company," as defined in the Jumpstart Our Business Startups Act of 2012, or the JOBS Act, and may remain an emerging
growth company for up to five years. For so long as we remain an emerging growth company, we are permitted and plan to rely on exemptions from certain disclosure requirements that are applicable to
other public companies that are not emerging growth companies. These exemptions include not being required to comply with the auditor attestation requirements of Section 404 of the Sarbanes-Oxley Act
of 2002, or SOX Section 404, not being required to comply with any requirement that may be adopted by the Public Company Accounting Oversight Board regarding mandatory audit firm rotation or a
supplement to the auditor's report providing additional information about the audit and the financial statements, reduced disclosure obligations regarding executive compensation and exemptions from
the requirements of holding a nonbinding advisory vote on executive compensation and stockholder approval of any golden parachute payments not previously approved. Investors may find our common stock
less attractive as a result of our reliance on these exemptions. If some investors find our common stock less attractive as a result, there may be a less active trading market for our common stock and
our stock price may be more volatile.
We have incurred and will continue to incur increased costs as a result of operating as a public company, and
our management will be required to devote substantial time to new compliance initiatives and corporate governance practices.
As a public company, and particularly after we are no longer an "emerging growth company," we have incurred and will continue to incur
significant legal, accounting and other expenses that we did not incur as a private company. The Sarbanes-Oxley Act of 2002, the Dodd-Frank Wall Street Reform and Consumer Protection Act, the listing
requirements of The NASDAQ Global Market and other applicable securities rules and regulations impose various requirements on public companies, including establishment and maintenance of effective
disclosure and financial controls and corporate governance practices. We expect that we will need to hire additional accounting, finance and other personnel in connection with our efforts to comply
with the requirements of being a public company and our management and other personnel will need to devote a substantial amount of time towards maintaining compliance with these requirements. These
requirements will increase our legal and financial compliance costs and will make some activities more time-consuming and costly. We are
currently evaluating these rules and regulations, and cannot predict or estimate the amount of additional costs we may incur or the timing of such costs. These rules and regulations are often subject
to varying interpretations, in many cases due to their lack of specificity, and, as a result, their application in
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practice
may evolve over time as new guidance is provided by regulatory and governing bodies. This could result in continuing uncertainty regarding compliance matters and higher costs necessitated by
ongoing revisions to disclosure and governance practices.
Pursuant
to SOX Section 404 we are required to furnish reports by our management on our internal control over financial reporting with our Annual Reports on Form 10-K with the SEC.
However, while we remain an emerging growth company, we will not be required to include attestation reports on internal control over financial reporting issued by our independent registered public
accounting firm. To achieve compliance with SOX Section 404 within the prescribed period, we will be engaged in a process to document and evaluate our internal control over financial reporting, which
is both costly and challenging. In this regard, we will need to continue to dedicate internal resources, engage outside consultants and adopt a detailed work plan to assess and document the adequacy
of internal control over financial reporting, continue steps to improve control processes as appropriate, validate through testing that controls are functioning as documented and implement a
continuous reporting and improvement process for internal control over financial reporting. Despite our efforts, there is a risk that neither we nor our independent registered public accounting firm
will be able to conclude, within the prescribed timeframe or at all, that our internal control over financial reporting is effective as required by SOX Section 404. If we identify one or more material
weaknesses, it could result in an adverse reaction in the financial markets due to a loss of confidence in the reliability of our financial statements.
A significant portion of our total outstanding shares may be sold into the market in the near future, which
could cause the market price of our common stock to decline significantly, even if our business is doing well.
Sales of a substantial number of shares of our common stock in the public market could occur at any time. These sales, or the perception in the
market that the holders of a large number of shares of common stock intend to sell shares, could reduce the market price of our common stock. As of December 31, 2016, we had outstanding 18,817,572
shares of common stock. The holders of an aggregate of 6,474,446 of these outstanding shares of common stock, along with the holders of warrants to purchase 24,556 shares of common stock, have rights,
subject to conditions, to require us to file registration statements covering their shares or to include their shares in registration statements that we may file for ourselves or other stockholders.
Following registration, such shares could be freely sold in the public market, subject to volume limitations applicable to affiliates.
We
have filed registration statements registering a significant portion of the shares of common stock that we may issue under our equity compensation plans. As of December 31, 2016, we
had outstanding options to purchase an aggregate of approximately 2,270,169 shares of our common stock, of which options to purchase approximately 851,769 shares were vested. These shares can be
freely sold in the public market upon issuance and once vested, subject to volume limitations applicable to affiliates.
We do not anticipate paying any cash dividends on our capital stock in the foreseeable future, accordingly,
stockholders must rely on capital appreciation, if any, for any return on their investment.
We have never declared nor paid cash dividends on our capital stock. We currently plan to retain all of our future earnings, if any, to finance
the operation, development and growth of our business. Furthermore, the terms of our credit facility with MidCap, Flexpoint and Square 1 preclude us from paying dividends, and any future debt
agreements may also preclude us from paying dividends. As a result, capital appreciation, if any, of our common stock will be your sole source of gain for the foreseeable future.
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Our executive officers, directors and principal stockholders, if they choose to act together, have the
ability to control all matters submitted to stockholders for approval.
Our executive officers and directors, combined with our stockholders who own more than 5% of our outstanding common stock and their affiliates,
in the aggregate, beneficially owned shares representing approximately 63.8% of our capital stock as of December 31, 2016. As a result, if these stockholders were to choose to act together, they would
be able to control all matters submitted to our stockholders for approval, as well as our management and affairs. For example, these persons, if they choose to act together, would control the election
of directors and approval of any merger, consolidation or sale of all or substantially all of our assets. This concentration of ownership control may:
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delay, defer or prevent a change in control;
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entrench our management or the board of directors; or
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impede a merger, consolidation, takeover or other business combination involving us that other stockholders may desire.
Provisions in our corporate charter documents and under Delaware law could make an acquisition of us, which
may be beneficial to our stockholders, more difficult and may prevent attempts by our stockholders to replace or remove our current management.
Provisions in our corporate charter and our bylaws may discourage, delay or prevent a merger, acquisition or other change in control of us that
stockholders may consider favorable, including transactions in which you might otherwise receive a premium for your shares. These provisions could also limit the price that investors might be willing
to pay in the future for shares of our common stock, thereby depressing the market price of our common stock. In addition, because our board of directors is responsible for appointing the members of
our management team, these provisions may frustrate or prevent any attempts by our stockholders to replace or remove our current management by making it more difficult for stockholders to replace
members of our board of directors. Among other things, these provisions:
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establish a classified board of directors such that all members of the board are not elected at one time;
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allow the authorized number of our directors to be changed only by resolution of our board of directors;
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limit the manner in which stockholders can remove directors from the board;
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establish advance notice requirements for nominations for election to the board of directors or for proposing matters that can be acted on at
stockholder meetings;
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require that stockholder actions must be effected at a duly called stockholder meeting and prohibit actions by our stockholders by written
consent;
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limit who may call a special meeting of stockholder meetings;
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authorize our board of directors to issue preferred stock without stockholder approval, which could be used to institute a "poison pill" that
would work to dilute the stock ownership of a potential hostile acquirer, effectively preventing acquisitions that have not been approved by our board of directors; and
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require the approval of the holders of at least 75% of the votes that all our stockholders would be entitled to cast to amend or repeal certain
provisions of our charter or bylaws.
Moreover,
because we are incorporated in Delaware, we are governed by the provisions of Section 203 of the General Corporation Law of the State of Delaware, which prohibits a
person who
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owns
in excess of 15% of our outstanding voting stock from merging or combining with us for a period of three years after the date of the transaction in which the person acquired in excess of 15% of
our outstanding voting stock, unless the merger or combination is approved in a prescribed manner. This could discourage, delay or prevent someone from acquiring us or merging with us, whether or not
it is desired by, or beneficial to, our stockholders.
Our certificate of incorporation designates the state courts in the State of Delaware or, if no state court
located within the State of Delaware has jurisdiction, the federal court for the District of Delaware, as the sole and exclusive forum for certain types of actions and proceedings that may be
initiated by our stockholders, which could discourage lawsuits against the company and our directors and officers.
Our certificate of incorporation provides that, unless we consent in writing to the selection of an alternative forum, the Court of Chancery of
the State of Delaware (or, if the Court of Chancery does not have jurisdiction, the federal district court for the District of Delaware) will be the sole and exclusive forum for any derivative action
or proceeding brought on our behalf, any action asserting a claim of breach of a fiduciary duty owed by any of our directors, officers or employees to our company or our stockholders, any action
asserting a claim against us arising pursuant to any provision of the General Corporation Law of the State of Delaware or our certificate of incorporation or bylaws, or any action asserting a claim
against us governed by the internal affairs doctrine. This exclusive forum provision may limit the ability of our stockholders to bring a claim in a judicial forum that such stockholders find
favorable for disputes with us or our directors or officers, which may discourage such lawsuits against us and our directors and officers.
If securities or industry analysts do not publish research or publish inaccurate or unfavorable research
about our business, our share price and trading volume could decline.
The trading market for our common stock will likely depend, in part, on the research and reports that securities or industry analysts publish
about us or our business. We do not have any control over these analysts. There can be no assurance that analysts will cover us, or provide favorable coverage. If one or more analysts downgrade our
stock or change their opinion of our stock, our share price would likely decline. In addition, if one or more analysts cease coverage of our company or fail to regularly publish reports on us, we
could lose visibility in the financial markets, which could cause our share price or trading volume to decline.
Catabasis Pharmaceuticals, Inc.
Consolidated Statements Comprehensive Loss
(in thousands)
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Year Ended December 31,
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2016
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2015
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2014
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Net Loss
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$
|
(36,060
|
)
|
$
|
(32,630
|
)
|
$
|
(21,884
|
)
|
Other comprehensive loss:
|
|
|
|
|
|
|
|
|
|
|
Unrealized loss on available-for-sale securities
|
|
|
(4
|
)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Total other comprehensive loss:
|
|
|
(4
|
)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Comprehensive loss
|
|
$
|
(36,064
|
)
|
$
|
(32,630
|
)
|
$
|
(21,884
|
)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
The accompanying notes are an integral part of these consolidated financial statements
F-4
Table of Contents
Catabasis Pharmaceuticals, Inc.
Consolidated Statements of Convertible Preferred Stock and Stockholders' Equity (Deficit)
(in thousands, except share data)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Series A
Convertible
Preferred Stock
|
|
Series B
Convertible
Preferred Stock
|
|
|
|
Common Stock
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Accumulated
Other
Comprehensive
Loss
|
|
|
|
|
|
|
|
Number of
Shares
|
|
|
|
Additional
Paid-in
Capital
|
|
Accumulated
Deficit
|
|
Total
Stockholders'
Equity (Deficit)
|
|
|
|
Shares
|
|
Amount
|
|
Shares
|
|
Amount
|
|
|
|
Par Value
|
|
|
|
|
|
Balance at December 31, 2013
|
|
|
68,837,703
|
|
$
|
47,898
|
|
|
34,129,571
|
|
$
|
32,248
|
|
|
|
|
393,346
|
|
$
|
|
|
$
|
1,312
|
|
$
|
(53,496
|
)
|
$
|
|
|
$
|
(52,184
|
)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Proceeds from exercises of common stock options
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
99,854
|
|
|
1
|
|
|
117
|
|
|
|
|
|
|
|
|
118
|
|
Stock-based compensation expense
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
897
|
|
|
|
|
|
|
|
|
897
|
|
Net loss
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
(21,884
|
)
|
|
|
|
|
(21,884
|
)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Balance at December 31, 2014
|
|
|
68,837,703
|
|
|
47,898
|
|
|
34,129,571
|
|
|
32,248
|
|
|
|
|
493,200
|
|
|
1
|
|
|
2,326
|
|
|
(75,380
|
)
|
|
|
|
|
(73,053
|
)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Issuance of common stock from initial public offering, net of issuance costs of $7.3 million
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
5,750,000
|
|
|
5
|
|
|
61,739
|
|
|
|
|
|
|
|
|
61,744
|
|
Issuance of series B convertible preferred stock, net of issuance cost of $0.1 million
|
|
|
|
|
|
|
|
|
13,062,965
|
|
|
12,331
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Conversion of convertible preferred stock into common stock
|
|
|
(68,837,703
|
)
|
|
(47,898
|
)
|
|
(47,192,536
|
)
|
|
(44,579
|
)
|
|
|
|
9,029,549
|
|
|
9
|
|
|
92,468
|
|
|
|
|
|
|
|
|
92,477
|
|
Conversion of series B preferred stock warrants into warrants for the purchase of common stock
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
206
|
|
|
|
|
|
|
|
|
206
|
|
Proceeds from exercises of common stock options
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
40,548
|
|
|
|
|
|
91
|
|
|
|
|
|
|
|
|
91
|
|
Stock-based compensation expense
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
1,658
|
|
|
|
|
|
|
|
|
1,658
|
|
Net loss
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
(32,630
|
)
|
|
|
|
|
(32,630
|
)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Balance at December 31, 2015
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
15,313,297
|
|
|
15
|
|
|
158,488
|
|
|
(108,010
|
)
|
|
|
|
|
50,493
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Issuance of common stock for registered direct and at-the-market offerings, net of issuance costs of $1.1 million
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
3,243,015
|
|
|
3
|
|
|
11,991
|
|
|
|
|
|
|
|
|
11,994
|
|
Proceeds from exercises of common stock options and warrants
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
261,260
|
|
|
1
|
|
|
502
|
|
|
|
|
|
|
|
|
503
|
|
Stock-based compensation expense
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
2,160
|
|
|
|
|
|
|
|
|
2,160
|
|
Unrealized losses on short-term investments
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
(4
|
)
|
|
(4
|
)
|
Net loss
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
(36,060
|
)
|
|
|
|
|
(36,060
|
)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Balance at December 31, 2016
|
|
|
|
|
$
|
|
|
|
|
|
$
|
|
|
|
|
|
18,817,572
|
|
$
|
19
|
|
$
|
173,141
|
|
$
|
(144,070
|
)
|
$
|
(4
|
)
|
$
|
29,086
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
The
accompanying notes are an integral part of these consolidated financial statements
F-5
Table of Contents
Catabasis Pharmaceuticals, Inc.
Consolidated Statements of Cash Flows
(in thousands)
|
|
|
|
|
|
|
|
|
|
|
|
|
Year Ended December 31,
|
|
|
|
2016
|
|
2015
|
|
2014
|
|
Operating activities
|
|
|
|
|
|
|
|
|
|
|
Net loss
|
|
$
|
(36,060
|
)
|
$
|
(32,630
|
)
|
$
|
(21,884
|
)
|
Reconciliation of net loss to net cash used in operating activities:
|
|
|
|
|
|
|
|
|
|
|
Depreciation and amortization
|
|
|
395
|
|
|
202
|
|
|
248
|
|
Stock-based compensation expense
|
|
|
2,160
|
|
|
1,658
|
|
|
897
|
|
Accretion of discount/premium on investment securities
|
|
|
148
|
|
|
|
|
|
|
|
Non-cash interest expense
|
|
|
277
|
|
|
293
|
|
|
74
|
|
Gain on the sale of fixed assets
|
|
|
(52
|
)
|
|
|
|
|
|
|
Changes in assets and liabilities:
|
|
|
|
|
|
|
|
|
|
|
Prepaid expenses and other current assets
|
|
|
(229
|
)
|
|
(450
|
)
|
|
(208
|
)
|
Other assets
|
|
|
|
|
|
2
|
|
|
|
|
Accounts payable
|
|
|
77
|
|
|
196
|
|
|
481
|
|
Accrued expenses
|
|
|
418
|
|
|
954
|
|
|
8
|
|
Deferred rent
|
|
|
8
|
|
|
(18
|
)
|
|
(28
|
)
|
|
|
|
|
|
|
|
|
|
|
|
Net cash used in operating activities
|
|
|
(32,858
|
)
|
|
(29,793
|
)
|
|
(20,412
|
)
|
|
|
|
|
|
|
|
|
|
|
|
Investing activities
|
|
|
|
|
|
|
|
|
|
|
Purchases of available-for-sale securities
|
|
|
(45,539
|
)
|
|
|
|
|
(4,976
|
)
|
Sales and maturities of available-for-sale securities
|
|
|
30,456
|
|
|
|
|
|
4,976
|
|
Purchases of property and equipment
|
|
|
(459
|
)
|
|
(421
|
)
|
|
(228
|
)
|
Sale of property and equipment
|
|
|
52
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Net cash used in investing activities
|
|
|
(15,490
|
)
|
|
(421
|
)
|
|
(228
|
)
|
|
|
|
|
|
|
|
|
|
|
|
Financing activities
|
|
|
|
|
|
|
|
|
|
|
Proceeds from initial public offering, net of issuance costs
|
|
|
|
|
|
61,744
|
|
|
|
|
Proceeds from issuance of preferred stock, net of issuance costs
|
|
|
|
|
|
12,331
|
|
|
|
|
Proceeds from registered direct offering, net of issuance costs
|
|
|
10,603
|
|
|
|
|
|
|
|
Proceeds from at-the-market offering, net of issuance costs
|
|
|
1,391
|
|
|
|
|
|
|
|
Proceeds from exercise of common stock options and warrants
|
|
|
503
|
|
|
91
|
|
|
118
|
|
Proceeds from borrowing
|
|
|
|
|
|
5,000
|
|
|
5,000
|
|
Payments on borrowing
|
|
|
(3,333
|
)
|
|
(833
|
)
|
|
|
|
Debt issuance costs
|
|
|
|
|
|
(7
|
)
|
|
(284
|
)
|
|
|
|
|
|
|
|
|
|
|
|
Net cash provided by financing activities
|
|
|
9,164
|
|
|
78,326
|
|
|
4,834
|
|
|
|
|
|
|
|
|
|
|
|
|
Net (decrease) increase in cash and cash equivalents
|
|
|
(39,184
|
)
|
|
48,112
|
|
|
(15,806
|
)
|
Cash and cash equivalents, beginning of period
|
|
|
62,780
|
|
|
14,668
|
|
|
30,474
|
|
|
|
|
|
|
|
|
|
|
|
|
Cash and cash equivalents, end of period
|
|
$
|
23,596
|
|
$
|
62,780
|
|
$
|
14,668
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Supplemental disclosure of cash flow information
|
|
|
|
|
|
|
|
|
|
|
Cash paid for interest
|
|
$
|
582
|
|
$
|
684
|
|
$
|
100
|
|
|
|
|
|
|
|
|
|
|
|
|
Non-cash financing activities
|
|
|
|
|
|
|
|
|
|
|
Warrants for the purchase of series B preferred stock issued in conjunction with credit facility
|
|
$
|
|
|
$
|
107
|
|
$
|
110
|
|
|
|
|
|
|
|
|
|
|
|
|
Initial public offering costs in accounts payable and accrued liabilities
|
|
$
|
|
|
$
|
(492
|
)
|
$
|
492
|
|
|
|
|
|
|
|
|
|
|
|
|
Reclassification of deferred IPO costs from non-current assets to additional paid-in capital
|
|
$
|
|
|
$
|
1,787
|
|
$
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Reclassification of warrant liability to additional paid-in capital
|
|
$
|
|
|
$
|
206
|
|
$
|
|
|
|
|
|
|
|
|
|
|
|
|
|
The accompanying notes are an integral part of these consolidated financial statements.
F-6
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements
1. Organization and Operations
The Company
Catabasis Pharmaceuticals, Inc. (the "Company") is a clinical-stage biopharmaceutical company focused on the discovery, development and
commercialization of novel therapeutics based on the Company's proprietary Safely Metabolized And Rationally Targeted, or SMART, linker drug discovery platform. The Company's SMART linker technology
platform enables the Company to engineer product candidates that can simultaneously modulate multiple targets in a disease. The Company's proprietary product candidates impact pathways that are
central to diseases where efficacy may be optimized by a multiple target approach. The Company's primary focus is on treatments for rare diseases. The Company has applied its SMART linker drug
discovery platform to build an internal pipeline of product candidates for rare diseases and plans to pursue partnerships to develop additional product candidates. The Company was incorporated in the
State of Delaware on June 26, 2008.
Liquidity
In June 2015, the Company completed its initial public offering (the "IPO"). All of the shares issued and sold in the IPO were registered
pursuant to a registration statement on Form S-1, as amended. An aggregate of 5,750,000 shares of common stock ("Common Stock") registered pursuant to the registration statement were sold at a price
to the public of $12.00 per share (including 750,000 shares of Common Stock sold pursuant to the exercise of an overallotment option granted to the Company's underwriters in connection with the IPO).
Net proceeds of the IPO were $61.7 million, after deducting underwriting discounts, commissions and offering-related expenses payable by the Company of approximately $7.3 million. In connection with
the IPO, all shares of the Company's convertible Preferred Stock ("Preferred Stock") were automatically converted into an aggregate of 9,029,549 shares of its Common Stock and its outstanding warrants
to purchase 315,688 shares of Preferred Stock were automatically converted into warrants to purchase 24,566 shares of Common Stock.
In
August 2016, the Company entered into a sales agreement with Cowen and Company LLC ("Cowen"), pursuant to which the Company could issue and sell shares of Common Stock for an
aggregate maximum offering amount of $10.0 million under an at-the-market ("ATM") offering program. Cowen is not required to sell any specific amount, but acts as the Company's sales agent using
commercially reasonable efforts that are consistent with Cowen's normal trading and sales practices. Shares sold pursuant to the sales agreement have been sold pursuant to a shelf registration
statement, which became effective on July 19, 2016 (the "Shelf Registration Statement"). The Company pays Cowen 3% of the gross proceeds from any Common Stock sold through the sales agreement.
During
the year ended December 31, 2016, the Company sold an aggregate of 368,015 shares of Common Stock pursuant to the ATM offering program, at an average price of $4.35 per
share, for gross proceeds of $1.6 million, resulting in net proceeds of $1.4 million after deducting sales commissions and offering expenses. As of December 31, 2016, $8.4 million of common
stock remained available under the ATM offering program.
In
September 2016, the Company closed an underwritten registered direct offering, in which it sold 2,875,000 shares of Common Stock (including 375,000 shares of Common Stock sold
pursuant to the exercise of an option by the underwriter to purchase additional shares) at an offering price of $4.00 per share. The shares sold in the offering were sold pursuant to the Shelf
Registration Statement. The Company received aggregate gross proceeds from the offering of $11.5 million, resulting in net
F-7
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
1. Organization and Operations (Continued)
proceeds
of $10.6 million after deducting underwriting discounts and commissions and offering expenses.
As
of December 31, 2016, the Company had an accumulated deficit of $144.1 million. The Company has been primarily involved with research and development activities and has
incurred operating losses and negative cash flows from operations since its inception. The Company is subject to a number of risks similar to other life science companies, including, but not limited
to, successful discovery and development of its drug candidates, raising additional capital, development by its competitors of new technological innovations, protection of proprietary technology and
regulatory approval and market acceptance of the Company's products. The Company anticipates that it will continue to incur significant operating losses for the next several years as it continues to
develop its product candidates. The Company adopted Accounting Standards Update ("ASU") No. 2014-15,
Presentation of Financial StatementsGoing Concern: Disclosure
of Uncertainties about an Entity's Ability to Continue as a Going Concern
("ASU 2014-15") in connection with the issuance if its consolidated financial statements for the year
ended December 31, 2016. The Company's current operating plan provides for cash to fund operations through March 31, 2018, assuming no unscheduled repayment of indebtedness prior to such date.
As the lender has the ability to call the debt prior to the maturity date, that could affect the Company's ability to continue as a going concern for a period of one year from the date of issuance of
the financial statements. The Company believes that the condition is mitigated by management's plans which include the ability to reduce or delay expenditures including expenditures for employee
incentive compensation and direct program expenses.
The
Company will require substantial additional capital to fund operations. The Company has not generated any product revenues and has financed its operations primarily through public
offerings and private placements of its equity securities. There can be no assurance that the Company will be able to obtain additional debt or equity financing or generate product revenue or revenues
from collaborative partners, on terms acceptable to the Company, on a timely basis or at all. The failure of the Company to obtain sufficient funds on acceptable terms when needed could have a
material adverse effect on the Company's business, results of operations, and financial condition.
2. Summary of Significant Accounting Policies
Basis of Presentation and Principles of Consolidation
The accompanying consolidated financial statements include the accounts of the Company and its wholly-owned subsidiary, Catabasis Securities
Corporation. All intercompany balances and transactions have been eliminated in consolidation. These consolidated financial statements have been prepared in accordance with United States generally
accepted accounting principles ("U.S. GAAP") and include all adjustments necessary for the fair presentation of the Company's financial position for the periods presented.
Use of Estimates
The preparation of the Company's consolidated financial statements in conformity with U.S. GAAP requires management to make estimates and
assumptions that affect the amounts reported in the consolidated financial statements and accompanying notes. Actual results could differ from such estimates.
F-8
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
2. Summary of Significant Accounting Policies (Continued)
Prior
to completion of its IPO, the Company utilized significant estimates and assumptions in determining the fair value of its Common Stock. The board of directors determined the
estimated fair value of the Common Stock based on a number of objective and subjective factors. Such factors included the external market conditions affecting the biotechnology industry sector, the
prices at which the Company sold shares of Preferred Stock, the achievement of research and development milestones, the superior rights and preferences of securities senior to the Common Stock at the
time and the likelihood of achieving a liquidity event, such as an initial public offering or sale of the Company.
The
Company utilized various valuation methodologies in accordance with the framework of the American Institute of Certified Public Accountants ("AICPA"), Audit and Accounting Practice
Aid Series: Valuation of Privately Held Company Equity Securities Issued as Compensation ("AICPA Practice Aid"), to estimate the fair value of its Common Stock. The methodologies included the Option
Pricing Method utilizing the Back-solve Method (a form of the market approach defined in the AICPA Practice Aid) and the Probability-Weighted Expected Return Method based upon the probability of
occurrence of certain future liquidity events such as an initial public offering or sale of the Company. Each valuation methodology included estimates and assumptions that required the Company's
judgment. Significant changes to the key assumptions used in the valuations could result in different fair values of Common Stock at each valuation date.
The
Company utilizes certain estimates to record expenses relating to research and development contracts. These contract estimates, which are primarily related to the length of service
of each contract, are determined by the Company based on input from internal project management, as well as from third-party service providers.
Off-Balance Sheet Risk and Concentrations of Credit Risk
The Company has no off-balance sheet risk, such as foreign exchange contracts, option contracts or other foreign hedging arrangements. Financial
instruments that subject the Company to credit risk primarily consist of cash and cash equivalents and restricted cash. The primary objectives for the Company's investment portfolio are the
preservation of capital and the maintenance of liquidity. The Company's investment policy includes guidelines on the quality of the institutions and financial instruments and defines allowable
investments that the Company believes minimizes the exposure to concentration of credit risk.
Cash and Cash Equivalents
The Company considers highly liquid investments with a maturity of three months or less when purchased to be cash equivalents. Cash equivalents,
which consist primarily of money market funds backed by U.S. government securities, are stated at fair value. Cash and cash equivalents consist of the following (in thousands):
|
|
|
|
|
|
|
|
|
|
December 31,
|
|
|
|
2016
|
|
2015
|
|
Cash
|
|
$
|
1,173
|
|
$
|
776
|
|
Money market fund
|
|
|
22,423
|
|
|
62,004
|
|
|
|
|
|
|
|
|
|
Total
|
|
$
|
23,596
|
|
$
|
62,780
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
F-9
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
2. Summary of Significant Accounting Policies (Continued)
Available-for-Sale Investments
The Company classifies all short-term investments with a remaining maturity of greater than three months at the time of purchase as
available-for-sale. Available-for-sale securities are recorded at fair value, with the unrealized gains and losses reported in other comprehensive loss. The amortized cost of debt securities is
adjusted for the amortization of premiums and accretion of discounts to maturity. Such amortization is included in interest and investment income. Realized gains and losses, interest, dividends and
declines in value judged to be other-than-temporary are included in interest and investment income.
The
cost of securities sold is based on the specific identification method for purposes of recording realized gains and losses. To determine whether an other-than-temporary impairment
exists, the Company considers whether it has the ability and intent to hold the investment until a market price recovery, and whether evidence indicating the recoverability of the cost of the
investment outweighs evidence to the contrary.
Fair Value of Financial Instruments
The fair value hierarchy prioritizes the inputs to valuation techniques used to measure fair value into three broad levels as follows: Level 1
inputs are quoted prices (unadjusted) in active markets for identical assets or liabilities; Level 2 inputs are inputs other than quoted prices included within Level 1 that are observable for the
asset or liability, either directly or indirectly; and Level 3 inputs are unobservable inputs that reflect the Company's own assumptions about the assumptions market participants would use in pricing
the asset or liability. Financial assets and liabilities are classified in their entirety based on the lowest level of input that is significant to the fair value measurement.
The
carrying amounts reflected in the balance sheets for cash equivalents, restricted cash, prepaid expenses and other current assets, accounts payable and accrued expenses approximate
their fair values at December 31, 2016 and 2015, due to their short-term nature. There have been no changes to the
valuation methods during the years ended December 31, 2016 and 2015. The Company evaluates transfers between levels at the end of each reporting period. There were no transfers of assets or
liabilities between levels during the year ended December 31, 2016 and 2015. At December 31, 2016, the carrying value of the Company's debt approximated fair value, which was determined
using Level 3 inputs, including a quoted interest rate.
The
Company's investment portfolio includes fixed income securities that do not always trade on a daily basis. As a result, the pricing services used by the Company apply other available
information as applicable through processes such as benchmark yields, benchmarking of like securities, sector groupings and matrix pricing to prepare valuations. In addition, model processes are used
to assess interest rate impact and develop prepayment scenarios. These models take into consideration relevant credit information, perceived market movements, sector news and economic events. The
inputs into these models may include benchmark yields, reported trades, broker-dealer quotes, issuer spreads and other relevant data. The Company validates the prices provided by its third party
pricing services by obtaining market values from other pricing sources and analyzing pricing data in certain instances. The Company determines the fair value of available-for-sale securities (Note 3)
using Level 2 inputs.
F-10
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
2. Summary of Significant Accounting Policies (Continued)
Deferred Financing Costs
Deferred financing costs include costs directly attributable to the Company's offerings of its equity securities and its debt financings. Costs
attributable to equity offerings are charged against the proceeds of the offering once the offering is completed. Costs attributable to debt financings are deferred and amortized over the term of the
debt using the effective interest rate method.
On
April 7, 2015, the Financial Accounting Standards Board issued ASU No. 2015-03,
Simplifying the Presentation of Debt Issuance
Costs
("ASU 2015-03"). ASU 2015-03 requires debt issuance costs to be presented in an entity's balance sheet as a direct deduction from the associated debt liability. The
standard is retrospectively effective for annual reporting periods beginning after December 15, 2015.
The
Company adopted the standard in the three months ended March 31, 2016, which resulted in a balance sheet reclassification of issuance costs in connection with its notes
payable of approximately $32 thousand recorded in prepaid expenses and other current assets and approximately $22 thousand recorded in other assets to a reduction in current portion of
notes payable, net of discount and in notes
payable, net of current portion and discount, respectively. The Company's adoption of this standard did not have any impact on its results of operations or cash flows for the twelve months ended
December 31, 2016.
Property and Equipment
Property and equipment consist of laboratory equipment, computer equipment, leasehold improvements and furniture and fixtures. Property and
equipment is stated at cost and depreciated using the straight-line method over the estimated useful lives of the respective assets. Costs of major additions and betterments are capitalized;
maintenance and repairs, which do not improve or extend the life of the respective assets, are charged to expense as incurred. Upon retirement or sale, the cost of the disposed asset and the related
accumulated depreciation are removed from the accounts and the resulting gain or loss is recognized.
Impairment of Long-Lived Assets
The Company continually evaluates whether events or circumstances have occurred that indicate that the estimated remaining useful life of its
long-lived assets may warrant revision or that the carrying value of these assets may be impaired. The Company has not recognized any significant impairment charges from inception through
December 31, 2016.
Research and Development Expenses
Research and development costs are expensed as incurred. Research and development costs include salaries and personnel-related costs,
stock-based compensation, consulting fees, fees paid for contract research services, the costs of laboratory equipment and facilities and other external costs. Nonrefundable advance payments for goods
or services to be received in the future for use in research and development activities are deferred. The deferred amounts are expensed as the related goods are delivered or the services are
performed.
F-11
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
2. Summary of Significant Accounting Policies (Continued)
Stock-Based Compensation
The Company accounts for its stock-based compensation awards in accordance with Accounting Standards Codification ("ASC") Topic 718,
CompensationStock
Compensation (
"ASC 718"). ASC 718 requires all share-based payments to employees, including grants of employee stock
options, to be recognized in the statements of operations based on their grant date fair values. For stock options granted to employees and to members of the board of directors for their services on
the board of directors, the Company estimates the grant date fair value of each option award using the Black-Scholes option-pricing model. The use of the Black-Scholes option-pricing model requires
management to make assumptions with respect to the expected term of the option, the expected volatility of the Common Stock consistent with the expected term of the option, risk-free interest rates
and expected dividend yields of the Common Stock.
For
awards subject to service-based vesting conditions, the Company recognizes stock-based compensation expense, net of estimated forfeitures, equal to the grant date fair value of stock
options on a straight-line basis over the requisite service period.
The
Company expenses restricted stock awards based on the fair value of the award on a straight-line basis over the associated service period of the award.
Share-based
payments issued to non-employees are recorded at their fair values, and are periodically revalued as the equity instruments vest and are recognized as expense over the
related service period in accordance with the provisions of ASC Topic 505,
Equity
. For equity instruments granted to non-employees, the Company
recognizes stock-based compensation expense on a straight-line basis.
During
the years ended December 31, 2016, 2015 and 2014, the Company recorded stock-based compensation expense for employee and non-employee stock options and restricted stock,
which was allocated as follows in the statements of operations (in thousands):
|
|
|
|
|
|
|
|
|
|
|
|
|
Year Ended December 31,
|
|
|
|
2016
|
|
2015
|
|
2014
|
|
Research and development
|
|
$
|
723
|
|
$
|
681
|
|
$
|
434
|
|
General and administrative
|
|
|
1,437
|
|
|
977
|
|
|
463
|
|
|
|
|
|
|
|
|
|
|
|
|
Total
|
|
$
|
2,160
|
|
$
|
1,658
|
|
$
|
897
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
No
related tax benefits were recognized for the years ended December 31, 2016, 2015 and 2014.
Grant Awards
In the years ended December 31, 2016, 2015 and 2014, the Company received $376,000, $100,000 and $0, respectively, in grants from the
Muscular Dystrophy Association, Friedreich's Ataxia Research Alliance and Parent Project for Muscular Dystrophy. The awards were recorded as a reduction to research and development expenses as the
related expenses were incurred in the Company's statements of operations.
F-12
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
2. Summary of Significant Accounting Policies (Continued)
Net Loss Per Share
Basic net loss per share is calculated by dividing net loss by the weighted average shares outstanding during the period, without consideration
for Common Stock equivalents. Diluted net loss per share is calculated by adjusting weighted average shares outstanding for the dilutive effect of Common Stock equivalents outstanding for the period,
determined using the treasury-stock method. For purposes of the dilutive net loss per share calculation, Preferred Stock, stock options, warrants to purchase Common Stock and warrants to purchase
Preferred Stock are considered to be Common Stock equivalents but are excluded from the calculation of diluted net loss per share, as their effect would be anti-dilutive; therefore, basic and diluted
net loss per share were the same for all periods presented.
The
following Common Stock equivalents were excluded from the calculation of diluted net loss per share for the periods indicated because including them would have had an anti-dilutive
effect:
|
|
|
|
|
|
|
|
|
|
|
|
|
Year Ended December 31,
|
|
|
|
2016
|
|
2015
|
|
2014
|
|
Convertible preferred stock
|
|
|
|
|
|
|
|
|
8,012,988
|
|
Stock options
|
|
|
2,270,169
|
|
|
1,723,554
|
|
|
1,226,140
|
|
Common stock warrants
|
|
|
24,566
|
|
|
59,405
|
|
|
34,839
|
|
Preferred stock warrants
|
|
|
|
|
|
|
|
|
12,283
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
2,294,735
|
|
|
1,782,959
|
|
|
9,286,250
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Income Taxes
The Company provides deferred tax assets and liabilities for the expected future tax consequences of temporary differences between the Company's
financial statement carrying amounts and the tax basis of assets and liabilities using enacted tax rates expected to be in effect in the years in which the differences are expected to reverse. A
valuation allowance is provided to reduce the deferred tax assets to the amount that will more likely than not be realized.
The
Company accounts for uncertain tax positions in accordance with the provisions of ASC Topic 740
, ExpensesIncome
Taxes
. When uncertain tax positions exist, the Company recognizes the tax benefit of tax positions to the extent that the benefit will more likely than not be realized. The
determination as to whether the tax benefit will more likely than not be realized is based upon the technical merits of the tax position as well as consideration of the available facts and
circumstances. As of December 31, 2016, 2015 and 2014, the Company did not have any significant uncertain tax positions.
Segment Information
Operating segments are identified as components of an enterprise for which separate discrete financial information is available for evaluation
by the chief operating decision maker, or decision making group, in making decisions on how to allocate resources and assess performance. The Company views its operations and manages its business in
one operating segment. The Company operates in one geographic segment.
F-13
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
2. Summary of Significant Accounting Policies (Continued)
Comprehensive Loss
Comprehensive loss is defined as the change in equity of a business enterprise during a period from transactions and other events and
circumstances from non-owner sources. For the year ended December 31, 2016, amounts in accumulated other comprehensive loss were comprised of unrealized gains and losses on available-for-sale
securities. For the years ended December 31, 2015 and 2014, comprehensive loss was equal to net loss.
Recent Accounting Pronouncements
From time to time, new accounting pronouncements are issued by the Financial Accounting Standards Board ("FASB") or other standard setting
bodies and adopted by the Company as of the specified effective date. Unless otherwise discussed, the Company believes that the impact of recently issued standards that are not yet effective will not
have a material impact on its financial position or results of operations upon adoption.
In
August 2014, the FASB issued ASU No. 2014-15,
Presentation of Financial StatementsGoing Concern: Disclosure of Uncertainties about an Entity's
Ability to Continue as a Going Concern
. ASU 2014-15 is intended to define management's responsibility to evaluate whether there is substantial doubt about an
organization's ability to continue as a going concern and to provide related footnote disclosures, if required. ASU 2014-15 is effective for annual reporting periods ending after December 15,
2016, and applies to annual and interim periods thereafter. The Company adopted this standard on December 31, 2016 (Note 1).
In
May 2014, the FASB issued ASU 2014-09,
Revenue from Contracts with Customers
(Topic 606), ("ASU 2014-09"). The standard will replace
existing revenue recognition standards and significantly expand the disclosure requirements for revenue arrangements. It may be adopted either retrospectively or on a modified retrospective basis to
new contracts and existing contracts with remaining performance obligations as of the effective date. The standard will become effective for us on January 1, 2018. At this time, the Company has
not decided on which method it will use to adopt the new standard, nor has it determined the effects of the new guidelines on its results of operations and financial position as the Company does not
currently have any arrangements that would be impacted by the new standard. As a result, the Company is continuing to evaluate the method of adoption and the impact of this standard on its
consolidated financial statements.
In
February 2016, the FASB issued ASU 2016-02,
Leases
. This standard amends the existing guidance to require lessees to present most
leases on their balance sheets but recognize corresponding expenses on their statements of operations. It is effective for annual reporting periods beginning after December 15, 2018, but early
adoption is permitted. The Company is currently evaluating the impact that this standard will have on its consolidated financial statements.
In
March 2016, the FASB issued ASU 2016-09,
Improvements to Employee Share-Based Payment Accounting
. This standard amends the existing
guidance in an attempt to simplify several aspects of accounting for employee share-based payment transactions. It is effective for annual reporting periods beginning after December 15, 2016, but
early adoption is permitted. The Company adopted the ASU on January 1, 2017 and adopted an accounting policy to record forfeitures as they occur. The Company does not expect this standard will
have a material effect on its consolidated financial statements.
F-14
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
3. Financial Instruments
The following tables present information about the Company's financial assets and liabilities that have been measured at fair value, and indicates the fair value hierarchy of the
valuation inputs utilized to determine such fair value. Below is a summary of assets and liabilities measured at fair value on a recurring basis (in thousands):
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
As of December 31, 2016
|
|
|
|
Quoted Prices
in Active
Markets
(Level 1)
|
|
Significant
Observable
Inputs
(Level 2)
|
|
Significant
Unobservable
Inputs
(Level 3)
|
|
Total
|
|
Assets:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Cash and cash equivalents:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Money market funds
|
|
$
|
22,423
|
|
$
|
|
|
$
|
|
|
$
|
22,423
|
|
Available-for-sale securities:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Corporate debt securities
|
|
|
|
|
|
13,930
|
|
|
|
|
|
13,930
|
|
U.S. government-sponsored securities
|
|
|
|
|
|
1,001
|
|
|
|
|
|
1,001
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Total assets
|
|
$
|
22,423
|
|
$
|
14,931
|
|
$
|
|
|
$
|
37,354
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
As of December 31, 2015
|
|
|
|
Quoted Prices
in Active
Markets
(Level 1)
|
|
Significant
Observable
Inputs
(Level 2)
|
|
Significant
Unobservable
Inputs
(Level 3)
|
|
Total
|
|
Assets:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Money market funds
|
|
$
|
62,004
|
|
$
|
|
|
$
|
|
|
$
|
62,004
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Total assets
|
|
$
|
62,004
|
|
$
|
|
|
$
|
|
|
$
|
62,004
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
As
of December 31, 2016 and December 31, 2015, the Company's cash equivalents consisted principally of money market funds, which approximated their fair value due to their short-term
nature.
4. Available-for-Sale Securities
As of December 31, 2015, the Company held no available-for-sale securities. The following table summarizes the available-for-sale securities held at December 31, 2016 (in thousands):
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Amortized Cost
|
|
Gross Unrealized
Gains
|
|
Gross Unrealized
Losses
|
|
Fair Value
|
|
December 31, 2016
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Corporate debt securities
|
|
$
|
13,934
|
|
$
|
|
|
$
|
|
(4)
|
$
|
13,930
|
|
U.S. government-sponsored securities
|
|
|
1,001
|
|
|
|
|
|
|
|
|
1,001
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Total
|
|
$
|
14,935
|
|
$
|
|
|
$
|
|
(4)
|
$
|
14,931
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
The
contractual maturities of all available-for-sale securities held at December 31, 2016 were one year or less. There were fifteen available-for-sale securities in an unrealized loss
position at December 31, 2016, none of which had been in an unrealized loss position for more than 12 months. The aggregate fair value of these securities at December 31, 2016 was approximately
$13.0 million. The
F-15
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
4. Available-for-Sale Securities (Continued)
Company
reviews its investments for other-than-temporary impairment whenever the fair value of an investment is less than amortized cost and evidence indicates that an investment's carrying amount is
not recoverable within a reasonable period of time. To determine whether an impairment is
other-than-temporary, the Company considers whether it has the ability and intent to hold the investment until a market price recovery and considers whether evidence indicating the cost of the
investment is recoverable outweighs evidence to the contrary. The Company does not intend to sell the investments that were in unrealized loss positions at December 31, 2016, and it is not more likely
than not that the Company will be required to sell the investments before recovery of their amortized cost bases, which may be at maturity. The Company did not hold any securities with
other-than-temporary impairment at December 31, 2016.
Unrealized
holding gains or losses for the period that have been included in accumulated other comprehensive income, as well as gains and losses reclassified out of accumulated other
comprehensive income into other income, net, were not material to the Company's consolidated results of operations. During the years ended December 31, 2016 and 2015 the Company received $7.8 million
and $0 million in proceeds from sales of available-for-sale securities, respectively, the gains on which were not material to the Company's consolidated results of operations.
5. Restricted Cash
At December 31, 2016 and 2015, the Company had an outstanding letter of credit for $0.1 million as a security deposit for its operating lease agreement for office space (Note 9). The
Company is required to maintain this deposit for the duration of the lease agreement.
6. Property and Equipment
Property and equipment and related accumulated depreciation were as follows (in thousands):
|
|
|
|
|
|
|
|
|
|
|
|
|
|
December 31,
|
|
|
|
Estimated Useful Life (Years)
|
|
2016
|
|
2015
|
|
Lab equipment
|
|
3
|
|
$
|
1,565
|
|
$
|
1,350
|
|
Computer equipment
|
|
3
|
|
|
166
|
|
|
166
|
|
Furniture and fixtures
|
|
5
|
|
|
77
|
|
|
77
|
|
Leasehold improvements
|
|
Lesser of useful life or remaining lease term
|
|
|
259
|
|
|
261
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
2,067
|
|
|
1,854
|
|
Less accumulated depreciation and amortization
|
|
|
|
|
(1,499
|
)
|
|
(1,350
|
)
|
|
|
|
|
|
|
|
|
|
|
Total property and equipment, net
|
|
|
|
$
|
568
|
|
$
|
504
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Depreciation
and amortization expense was $0.4 million, $0.2 million and $0.2 million for the years ended December 31, 2016, 2015 and 2014, respectively.
F-16
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
7. Accrued Expenses
Accrued expenses consisted of the following (in thousands):
|
|
|
|
|
|
|
|
|
|
December 31,
|
|
|
|
2016
|
|
2015
|
|
Accrued compensation
|
|
$
|
1,252
|
|
$
|
1,181
|
|
Accrued contracted research costs
|
|
|
1,850
|
|
|
1,261
|
|
Accrued professional fees
|
|
|
215
|
|
|
181
|
|
Accrued other
|
|
|
360
|
|
|
655
|
|
|
|
|
|
|
|
|
|
Total
|
|
$
|
3,677
|
|
$
|
3,278
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
8. Notes Payable
On August 27, 2014, the Company entered into a credit facility with MidCap Financial Trust, Flexpoint MCLS Holdings, LLC and Square 1 Bank, which was subsequently amended in March and
December 2015 (as amended, the "Credit Facility"). The Credit Facility provided for initial borrowings of $5.0 million under a term loan ("Term Loan A") and additional borrowings of up to $20.0
million under other term loans, for a maximum of $25.0 million. On August 27, 2014, the Company received proceeds of $5.0 million from the issuance of promissory notes under Term Loan A. On March 31,
2015, the Company received proceeds of $5.0 million from the issuance of promissory notes under another term loan ("Term Loan B"). The remaining amounts available for borrowing under this arrangement
expired unused as of July 31, 2015, leaving total borrowings under the Credit Facility at $10.0 million. All amounts outstanding under the Credit Facility are due on October 1, 2018 and are
collateralized by substantially all of the Company's personal property, other than its intellectual property.
Interest-only
payments were due monthly on amounts outstanding under the Credit Facility until September 1, 2015 and, thereafter, interest and principal payments are due in 36 equal
monthly installments from October 1, 2015 through September 1, 2018. Amounts due under the Credit Facility bear interest at an annual rate of 7.49%. In addition, a final payment equal to 3.48% of any
amounts drawn under the Credit Facility is due upon the earlier of the maturity date, acceleration of the term loans or prepayment of all or part of the term loans. The final payment is being accrued
as additional interest expense using the effective-interest method from the date of issuance through the maturity date, and is recorded within other long-term liabilities. In the event of prepayment,
the Company is obligated to pay 1% to 3% of the amount of the outstanding principal depending upon the timing of the prepayment. The effective interest rate as of December 31, 2016 was 11.2%.
In
conjunction with Term Loan A, the Company issued warrants (the "2014 Warrants") to purchase 157,844 shares of Series B Convertible Preferred Stock at an exercise price of $0.9503 per
share to the lenders. In conjunction with Term Loan B, the Company issued warrants (the "2015 Warrants") to purchase an additional 157,844 shares of Series B Convertible Preferred Stock at an exercise
price of $0.9503 per share to the lenders. Upon the closing of the Company's IPO on June 30, 2015, the 2014 Warrants and 2015 Warrants were automatically converted into warrants to purchase an
aggregate of 24,566 shares of Common Stock at an exercise price of $12.2114 per share. The 2014 Warrants and 2015 Warrants were exercisable immediately and have seven-year lives. The 2014 Warrants and
2015 Warrants were initially valued at $0.1 million and $0.1 million, respectively, using the Black-Scholes option-pricing model. The Company recorded debt discounts of $0.1 million and $0.1
F-17
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
8. Notes Payable (Continued)
million
upon issuance of the 2014 Warrants and 2015 Warrants, respectively, which are being accreted as interest expense using the effective-interest method over the remaining term of the loan.
There
are no financial covenants associated with the Credit Facility; however, there are negative covenants restricting the Company's activities, including limitations on asset
dispositions, mergers or acquisitions; encumbering or granting a security interest in its intellectual property; incurring indebtedness or liens; paying dividends; making certain investments; and
entering into certain other business transactions.
Upon
the occurrence and continuation of an event of default, the lenders have the right to exercise certain remedies against the Company and the collateral securing the loans under the
Credit Facility, including cash. Events of default include, among other things, failure to pay amounts due under the Credit Facility, insolvency, the occurrence of a material adverse event, which
includes a material adverse change in the business, operations or conditions (financial or otherwise) of the Company or a material impairment of the prospect of repayment of any portion of the
obligations, the occurrence of any default under certain other indebtedness and a final judgment against the Company in an amount greater than $250,000. The occurrence of a material adverse event
could result in acceleration of the payment of the debt. At December 31, 2016 and 2015, the Company concluded that the likelihood of the acceleration of the debt was remote, as a material adverse
event had not occurred and was unlikely to occur and therefore the debt was classified in current and long-term liabilities based on scheduled principal payments. Following the occurrence and during
the continuance of an event of default, borrowings under the Credit Facility shall bear interest at a rate per annum, which is five hundred basis points, or 5.00%, above the rate that is otherwise
applicable.
The
Company assessed all terms and features of the Credit Facility in order to identify any potential embedded features that would require bifurcation or any beneficial conversion
features. As part of this analysis, the Company assessed the economic characteristics and risks of the Credit Facility, including put and call features. The Company determined that all features of the
Credit Facility were clearly and
closely associated with a debt host and did not require bifurcation as a derivative liability, or the fair value of the feature was immaterial to the Company's financial statements. The Company
reassesses the features on a quarterly basis to determine if they require separate accounting.
Estimated
future principal payments at December 31, 2016 are as follows (in thousands):
|
|
|
|
|
Year Ending December 31,
|
|
Amount
|
|
2017
|
|
|
3,333
|
|
2018
|
|
|
2,500
|
|
|
|
|
|
|
Total
|
|
$
|
5,833
|
|
Less: discount for warrants and costs paid to lender
|
|
|
(111
|
)
|
Less: current portion
|
|
|
(3,243
|
)
|
|
|
|
|
|
Note payable, net of current portion and discount
|
|
$
|
2,479
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
During
the years ended December 31, 2016, 2015 and 2014, the Company recognized $0.8 million, $1.0 million and $0.2 million, respectively, of interest expense related to the Credit
Facility.
F-18
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
9. Commitments
In November 2010, the Company entered into a five-year, non-cancelable operating lease for office and laboratory space that provided for a five-year extension upon the completion of the
lease term. In December 2011, the Company signed a lease amendment (the "2011 Lease Amendment") that expanded the leased premises beginning in the second quarter of 2012. The 2011 Lease Amendment also
extended the term of the existing lease through June 30, 2017. The 2011 Lease Amendment includes a free rent period for the expansion premises and escalating rent payments. In July 2015, the Company
signed another lease amendment (the "2015 Lease Amendment") that expanded the leased premises beginning in the third quarter of 2015. The 2015 Lease Amendment includes escalating rent payments and is
effective through June 30, 2017. In November 2016, the Company signed a third lease amendment (the "2016 Lease Amendment"). The 2016 Lease Amendment includes escalating rent payments and is effective
through June 30, 2018. The Company is recognizing rent expense on a straight-line basis over the lease term.
Future
minimum payments required under the non-cancelable operating lease as of December 31, 2016 are summarized as follows (in thousands):
|
|
|
|
|
Period Ending December 31,
|
|
Amount
|
|
2017
|
|
$
|
1,288
|
|
2018
|
|
|
680
|
|
|
|
|
|
|
Total minimum lease payments
|
|
$
|
1,968
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Rent
expense for the years ended December 31, 2016, 2015 and 2014 was $0.9 million, $0.8 million and $0.7 million, respectively.
10. Convertible Preferred Stock
On March 13, 2015, the Company's board of directors authorized the Company to increase the authorized number of shares of Series B Preferred Stock to 56,026,590 in connection with an
anticipated Series B Preferred Stock financing. The Company subsequently issued 13,062,965 shares of Series B Preferred Stock at $0.9503 per share, and received net proceeds of $12.3 million.
Prior
to the IPO, the holders of the Company's convertible Preferred Stock had certain voting, dividend rights, as well as liquidation preferences and conversion privileges. All rights,
preferences, and privileges associated with the convertible Preferred Stock were terminated at the time of the Company's IPO in conjunction with the conversion of all outstanding shares of convertible
Preferred Stock into shares of Common Stock.
Upon
the closing of the Company's IPO on June 30, 2015, all outstanding shares of the Company's Preferred Stock were automatically converted into 9,029,549 shares of Common Stock. As of
December 31, 2016, the Company had 5,000,000 shares of Preferred Stock authorized for issuance, $0.001 par value per share, with none issued or outstanding.
Preferred
stock may be issued from time to time in one or more series, each series to have such terms as stated or expressed in the resolutions providing for the issue of such series
adopted by the board of directors of the Company. Preferred Stock which may be redeemed, purchased or acquired by the Company may be reissued except as otherwise provided by law.
F-19
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
11. Common Stock
As of December 31, 2016, the Company had 150,000,000 shares of Common Stock authorized for issuance, $0.001 par value per share, with 18,817,572 shares issued and outstanding. The
voting, dividend and liquidation rights of holders of Common Stock are subject to and qualified by the rights, powers and preferences of the holders of any outstanding Preferred Stock. The Company's
Common Stock has the following characteristics:
Voting
The holders of Common Stock are entitled to one vote for each share of Common Stock held at all meetings of stockholders and written actions in
lieu of meetings.
Dividends
The holders of Common Stock are entitled to receive dividends, if and when declared by the board of directors. Cash dividends may not be
declared or paid to holders of Common Stock until paid on each series of outstanding Preferred Stock in accordance with their respective terms. No dividends have been declared or paid from the
Company's inception through December 31, 2016.
Liquidation
In the event of any voluntary or involuntary liquidation, dissolution or winding up of the Company, the holders of Common Stock are entitled to
share ratably in the Company's assets available for distribution to stockholders, subject to any preferential or other rights of any then-outstanding Preferred Stock.
Reserved for Future Issuance
The Company has reserved for future issuance the following shares of Common Stock:
|
|
|
|
|
|
|
|
|
|
As of December 31,
|
|
|
|
2016
|
|
2015
|
|
Warrants for the purchase of Common Stock
|
|
|
24,566
|
|
|
59,405
|
|
Options to purchase Common Stock
|
|
|
2,939,968
|
|
|
2,557,456
|
|
Employee Stock Purchase Plan
|
|
|
335,484
|
|
|
182,352
|
|
|
|
|
|
|
|
|
|
Total
|
|
|
3,300,018
|
|
|
2,799,213
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
12. Stock Incentive Plans
Prior to the Company's IPO, the Company granted awards to eligible participants under its 2008 Equity Incentive Plan ("2008 Plan"). In May 2015, the Company's board of directors adopted,
and in June 2015, the Company's stockholders approved, the 2015 Stock Incentive Plan ("2015 Plan"), which became effective immediately prior to the effectiveness of the Company's IPO. Subsequent to
the Company's IPO, option grants are awarded to eligible participants only under the 2015 Plan.
The
2015 Plan provides for the grant of incentive stock options, non-statutory stock options, restricted stock awards, restricted stock units, stock appreciation rights and other
stock-based awards. The Company's employees, officers, directors and consultants and advisors are eligible to receive
F-20
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
12. Stock Incentive Plans (Continued)
awards
under the 2015 Plan. The maximum number of shares of Common Stock that may be delivered in satisfaction of awards under the 2015 Plan is 1,068,287 shares, plus (1) 25,942 shares that were
available for grant under the 2008 Plan immediately prior to the closing of the IPO, (2) the number of shares of Common Stock subject to outstanding awards under the 2008 Plan upon closing of the IPO
that expire, terminate or are otherwise surrendered, cancelled, forfeited or repurchased by the Company at their original issuance price pursuant to a contractual repurchase right and (3) an annual
increase, to be added the first day of each fiscal year, beginning with the fiscal year ending December 31, 2016 and continuing until, and including, the fiscal year ending December 31,
2025, equal to the lowest of 1,297,334 shares of Common Stock, 4% of the number of shares of Common Stock outstanding on the first day of the fiscal year and an amount determined by the Company's
board of directors. The January 1, 2017 and 2016 increases to the 2015 Plan added 752,700 and 612,531 authorized shares, respectively.
As
of December 31, 2016, the Company had reserved 1,000,606 shares of Common Stock under the 2008 Plan, of which none remained available for future issuance. As of December 31, 2016, the
Company had reserved 1,939,362 shares of Common Stock under the 2015 Plan, of which 669,799 shares remained available for future issuance. Under the 2015 Plan, stock options may not be granted with
exercise prices at less than fair value on the date of the grant.
Terms
of stock option agreements, including vesting requirements, are determined by the Company's board of directors, subject to the provisions of the applicable stock incentive plan.
Options and restricted stock awards granted by the Company generally vest ratably over four years, with a one-year cliff, and options are exercisable from the date of grant for a period of ten years.
Restricted stock issuances and early exercises of stock options are subject to a Company right of repurchase at the original issuance price, which right lapses over the vesting period of the stock.
For options and restricted stock awards granted through December 31, 2016, the exercise price or purchase price, as applicable, equaled the estimated fair value of the Common Stock as determined by
the Company's board of directors on the date of grant.
A
summary of the Company's stock option activity and related information for employees and nonemployees follows:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Shares
|
|
Weighted-
Average
Exercise Price
|
|
Weighted
Average
Remaining
Contractual
Term
(years)
|
|
Aggregate
Intrinsic Value
(in thousands)
|
|
Outstanding at December 31, 2015
|
|
|
1,723,554
|
|
$
|
6.66
|
|
|
7.92
|
|
$
|
4,267
|
|
Granted
|
|
|
1,068,845
|
|
$
|
4.49
|
|
|
|
|
|
|
|
Exercised
|
|
|
(230,019
|
)
|
$
|
2.00
|
|
|
|
|
|
|
|
Cancelled or forfeited
|
|
|
(292,211
|
)
|
$
|
6.60
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Outstanding at December 31, 2016
|
|
|
2,270,169
|
|
$
|
6.11
|
|
|
8.14
|
|
$
|
613
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Exercisable at December 31, 2016
|
|
|
851,769
|
|
$
|
5.79
|
|
|
6.64
|
|
$
|
607
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Vested or expected to vest at December 31, 2016
|
|
|
2,177,976
|
|
$
|
6.12
|
|
|
8.09
|
|
$
|
613
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
F-21
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
12. Stock Incentive Plans (Continued)
The
total intrinsic value of options exercised for the years ended December 31, 2016, 2015 and 2014 was $0.5 million, $0.3 million and $0.6 million, respectively. The total fair value of
employee options vested for the years ended December 31, 2016, 2015 and 2014 was $2.3 million, $1.4 million and $0.5 million, respectively.
At
December 31, 2016, the total unrecognized compensation expense related to unvested stock option awards, including estimated forfeitures, was $4.9 million. The Company expects to
recognize that cost over a weighted-average period of approximately 2.5 years.
Stock-Based Compensation Expense
The fair value of stock options granted to employees and non-employees was estimated using the Black-Scholes option-pricing model based on the
following assumptions:
|
|
|
|
|
|
|
|
|
|
|
|
|
Year Ended December 31,
|
|
|
|
2016
|
|
2015
|
|
2014
|
|
Weighted average expected volatility
|
|
|
72.0 - 73.9
|
%
|
|
73.6 - 86.8
|
%
|
|
75.2 - 83.4
|
%
|
Expected term (in years)
|
|
|
6.25
|
|
|
6.17 - 10.00
|
|
|
6.25 - 10.00
|
|
Risk free interest rate
|
|
|
1.24 - 2.00
|
%
|
|
0.92 - 2.45
|
%
|
|
1.71 - 3.01
|
%
|
Expected dividend yield
|
|
|
0
|
%
|
|
0
|
%
|
|
0
|
%
|
Volatility
Due to the lack of company-specific historical and implied volatility data of its Common Stock, the Company does not have relevant historical
data to support its expected volatility. As such, the Company has used a weighted average of expected volatility based on the volatilities of a representative group of publicly traded
biopharmaceutical companies. For purposes of identifying representative companies, the Company considered characteristics such as number of product candidates in early stages of product development,
area of therapeutic focus, length of trading history, similar vesting provisions and a similar percentage of stock options that were in-the-money. The expected volatility was determined using a
weighted average of the historical volatilities of the representative group of companies for a period equal to the expected term of the option grant. The Company intends to continue to consistently
apply this process using the same representative companies until a sufficient amount of historical information regarding the volatility of the Company's own share price becomes available or until
circumstances change, such that the identified entities are no longer representative companies. In the latter case, more suitable, similar entities whose share prices are publicly available would be
utilized in the calculation.
Expected Term
The Company uses the "simplified method" to estimate the expected term of stock option grants. Under this approach, the weighted-average
expected life is presumed to be the average of the contractual term (ten years) and the vesting term (generally four years) of the Company's stock options, taking into consideration multiple vesting
tranches. The Company utilizes this method due to lack of historical exercise data and the plain-vanilla nature of the Company's share-based awards.
F-22
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
12. Stock Incentive Plans (Continued)
Risk-Free Rate
The risk-free rate was based on the yield curve of U.S. Treasury securities with periods commensurate with the expected term of the options
being valued.
Forfeitures
The Company is also required to estimate forfeitures at the time of grant, and revise those estimates in subsequent periods if actual
forfeitures differ from its estimates. The Company uses historical data to estimate pre-vesting option forfeitures and record stock-based compensation expense only for those awards that are expected
to vest. To the extent that actual forfeitures differ from the Company's estimates, the difference is recorded as a cumulative adjustment in the period the estimates are revised.
Employee Stock Purchase Plan
In June 2015, the Company's board of directors adopted and the Company's stockholders approved the 2015 Employee Stock Purchase Plan (the "2015
ESPP") which became effective upon closing of the IPO. The 2015 ESPP initially authorized the issuance of up to a total of 182,352 shares of Common Stock to participating eligible employees. The
number of authorized shares increases each January 1, commencing on January 1, 2016 and ending on December 31, 2026, by an amount equal to the lesser of one percent of the Company's outstanding shares
as of the first day of the applicable year, 364,705 shares and any lower amount determined by the Company's board of directors. The January 1, 2017 and 2016 increases to the 2015 ESPP added 188,175
and 153,132 authorized shares, respectively. As of December 31, 2016, there had been no shares issued under the 2015 ESPP.
13. Income Taxes
For the years ended December 31, 2016, 2015 and 2014, the Company did not record a provision for federal or state income taxes as it has incurred cumulative net operating losses since
inception.
A
reconciliation of the U.S. statutory income tax rate to the Company's effective tax rate is as follows for the years ended December 31, 2016, 2015 and 2014:
|
|
|
|
|
|
|
|
|
|
|
|
|
Year Ended December 31,
|
|
|
|
2016
|
|
2015
|
|
2014
|
|
Federal income tax (benefit) at statutory rate
|
|
|
34.00
|
%
|
|
34.00
|
%
|
|
34.00
|
%
|
Permanent differences
|
|
|
(0.85
|
)
|
|
(0.86
|
)
|
|
(1.29
|
)
|
Federal research and development credits and adjustments
|
|
|
2.43
|
|
|
2.64
|
|
|
2.70
|
|
State income tax, net of federal benefit
|
|
|
5.70
|
|
|
5.77
|
|
|
6.03
|
|
Other
|
|
|
(0.40
|
)
|
|
0.28
|
|
|
(0.15
|
)
|
Change in valuation allowance
|
|
|
(40.88
|
)
|
|
(41.82
|
)
|
|
(41.29
|
)
|
|
|
|
|
|
|
|
|
|
|
|
Effective income tax rate
|
|
|
|
%
|
|
|
%
|
|
|
%
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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F-23
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
13. Income Taxes (Continued)
The
Company's deferred tax assets consisted of the following (in thousands):
|
|
|
|
|
|
|
|
|
|
Year Ended
December 31,
|
|
|
|
2016
|
|
2015
|
|
Deferred tax assets
|
|
|
|
|
|
|
|
Net operating loss carryforwards
|
|
$
|
48,682
|
|
$
|
35,042
|
|
Tax credit carryforwards
|
|
|
4,833
|
|
|
3,762
|
|
Capitalized research and development
|
|
|
3,394
|
|
|
4,087
|
|
Capitalized legal expenses
|
|
|
1,597
|
|
|
1,464
|
|
Other differences
|
|
|
1,335
|
|
|
815
|
|
|
|
|
|
|
|
|
|
Total deferred tax assets
|
|
|
59,841
|
|
|
45,170
|
|
Valuation allowance
|
|
|
(59,841
|
)
|
|
(45,170
|
)
|
|
|
|
|
|
|
|
|
Net deferred tax assets
|
|
$
|
|
|
$
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
The
Company recorded increases to the valuation allowance of $14.7 million, $13.6 million and $9.0 million during the years ended December 31, 2016, 2015 and 2014, respectively, due
primarily to an increase in the net operating loss carryforwards and tax credits.
In
assessing the realizability of deferred tax assets, the Company considers whether it is more likely than not that some portion or all of the deferred tax assets will not be realized.
The ultimate realization of deferred tax assets is dependent upon the generation of future taxable income during the periods in which the temporary differences representing net future deductible
amounts become deductible. Due to the Company's history of losses and expectation of future losses, the deferred tax assets were fully offset by a valuation allowance at December 31, 2016 and 2015.
As
of December 31, 2016, the Company had approximately $124.7 million of federal and $123.1 million of state net operating loss carryforwards to offset future taxable income, if any.
Such net operating loss carryforwards expire at varying times through the year 2036, if not utilized. Included in the federal and state net operating losses are deductions attributable to excess tax
benefits from the disqualifying disposition of incentive stock options and the exercise of non-qualified stock options of $0.5 million. The Company will record these off-balance sheet net operating
losses and the related valuation allowance to retained earnings upon the adoption of ASU 2016-09 in 2017. Company also had approximately $3.9 million of federal and $1.5 million of state tax credit
carryforwards available to reduce future tax liabilities as of December 31, 2016, which will expire at varying times through the year 2036.
The
Internal Revenue Code of 1986, as amended (the "Code"), provides for a limitation of the annual use of net operating losses and other tax attributes (such as research and development
tax credit carryforwards) following certain ownership changes (as defined by the Code) that could limit the Company's ability to utilize these carryforwards. At this time, the Company has not
completed a study to assess whether an ownership change under Section 382 of the Code has occurred, or whether there have been multiple ownership changes since the Company's formation, due to the
costs and complexities associated with such a study. The Company may have experienced various ownership changes, as defined by the Code, as a result of past financing transactions. Accordingly, the
Company's ability to utilize the aforementioned carryforwards may be limited. Additionally, U.S. tax laws limit the
F-24
Table of Contents
Catabasis Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements (Continued)
13. Income Taxes (Continued)
time
during which these carryforwards may be applied against future taxes. Therefore, the Company may not be able to take full advantage of these carryforwards for federal or state income tax
purposes.
As
of December 31, 2016 and 2015, the Company did not have any significant unrecognized tax benefits.
As
of December 31, 2016, the Company had not accrued interest or penalties related to uncertain tax positions. The Company's tax returns for the years ended December 31, 2008
through December 31, 2016 are still subject to examination by major tax jurisdictions. The Company will recognize interest and penalties, if any, related to uncertain tax positions in income
tax expense.
14. Defined Contribution Benefit Plan
The Company sponsors a 401(k) retirement plan, in which substantially all of its full-time employees are eligible to participate. Participants may contribute a percentage of their annual
compensation to this plan, subject to statutory limitations. The Company did not provide any contributions to this plan during the years ended December 31, 2016, 2015 or 2014.
15. Quarterly Financial Information (unaudited, in thousands, except share and per share data)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Three Months Ended
|
|
|
|
March 31,
2016
|
|
June 30,
2016
|
|
September 30,
2016
|
|
December 31,
2016
|
|
Operating expenses
|
|
$
|
9,206
|
|
$
|
9,396
|
|
$
|
8,283
|
|
$
|
8,673
|
|
Net loss
|
|
|
(9,418
|
)
|
|
(9,445
|
)
|
|
(8,419
|
)
|
|
(8,778
|
)
|
Net loss per share:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Basic and Diluted
|
|
$
|
(0.61
|
)
|
$
|
(0.61
|
)
|
$
|
(0.54
|
)
|
$
|
(0.47
|
)
|
Weighted-average common shares outstanding used in net loss per share:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Basic and Diluted
|
|
|
15,335,516
|
|
|
15,373,964
|
|
|
15,512,608
|
|
|
18,699,480
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Three Months Ended
|
|
|
|
March 31,
2015
|
|
June 30,
2015
|
|
September 30,
2015
|
|
December 31,
2015
|
|
Operating expenses
|
|
$
|
6,360
|
|
$
|
7,765
|
|
$
|
8,201
|
|
$
|
9,333
|
|
Net loss
|
|
|
(6,500
|
)
|
|
(8,039
|
)
|
|
(8,485
|
)
|
|
(9,606
|
)
|
Net loss per share:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Basic and Diluted
|
|
$
|
(13.14
|
)
|
$
|
(8.07
|
)
|
$
|
(0.55
|
)
|
$
|
(0.63
|
)
|
Weighted-average common shares outstanding used in net loss per share:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Basic and Diluted
|
|
|
494,590
|
|
|
996,592
|
|
|
15,297,794
|
|
|
15,298,810
|
|
F-25
Table of Contents
SIGNATURES
Pursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, the registrant has duly caused this report to be
signed on its behalf by the undersigned, thereunto duly authorized.
|
|
|
|
|
|
|
Catabasis Pharmaceuticals, Inc.
|
Date: March 16, 2017
|
|
By:
|
|
/s/ JILL C. MILNE
Jill C. Milne
President and Chief Executive Officer
|
Pursuant
to the requirements of the Securities Exchange Act of 1934, this report has been signed by the following persons on behalf of the registrant in the capacities and on the dates
indicated.
|
|
|
|
|
Signature
|
|
Title
|
|
Date
|
|
|
|
|
|
/s/ JILL C. MILNE
Jill C. Milne
|
|
President and Chief Executive Officer and Director (Principal Executive Officer)
|
|
March 16, 2017
|
/s/ DEIRDRE CUNNANE
Deirdre Cunnane
|
|
Senior Vice President, General Counsel and Treasurer (Principal Financial Officer)
|
|
March 16, 2017
|
/s/ NOAH CLAUSER
Noah Clauser
|
|
Senior Director of Finance and Controller (Principal Accounting Officer)
|
|
March 16, 2017
|
/s/ MICHAEL ROSS
Michael Ross
|
|
Director
|
|
March 16, 2017
|
/s/ NICHOLAS GALAKATOS
Nicholas Galakatos
|
|
Director
|
|
March 16, 2017
|
/s/ JEAN GEORGE
Jean George
|
|
Director
|
|
March 16, 2017
|
/s/ KENNETH BATE
Kenneth Bate
|
|
Director
|
|
March 16, 2017
|
/s/ BURT ADELMAN
Burt Adelman
|
|
Director
|
|
March 16, 2017
|
/s/ MICHAEL KISHBAUCH
Michael Kishbauch
|
|
Director
|
|
March 16, 2017
|
Table of Contents
EXHIBIT INDEX
|
|
|
|
Exhibit
Number
|
|
Description of Exhibit
|
|
3.1
|
|
Restated Certificate of Incorporation of the Registrant (incorporated by reference to Exhibit 3.1 to the Registrant's Current Report on Form 8-K (File No. 001-37467) filed with the Securities and Exchange Commission on
July 1, 2015)
|
|
|
|
|
|
3.2
|
|
Amended and Restated Bylaws of the Registrant (incorporated by reference to Exhibit 3.2 to the Registrant's Current Report on Form 8-K (File No. 001-37467) filed with the Securities and Exchange Commission on July 1,
2015)
|
|
|
|
|
|
4.1
|
|
Specimen stock certificate evidencing the shares of common stock (incorporated by reference to Exhibit 4.1 to the Registrant's Registration Statement on Form S-1 (File No. 333-204144) filed with the Securities and
Exchange Commission on June 11, 2015)
|
|
|
|
|
|
10.1
|
|
Warrant to purchase shares of Series B Preferred Stock issued on August 27, 2014 by the Registrant to Square 1 Bank (incorporated by reference to Exhibit 10.2 to the Registrant's Registration Statement on Form S-1 (File
No. 333-204144) filed with the Securities and Exchange Commission on May 13, 2015)
|
|
|
|
|
|
10.2
|
|
Warrant to purchase shares of Series B Preferred Stock issued on August 27, 2014 by the Registrant to Midcap Financial SBIC, L.P. (incorporated by reference to Exhibit 10.3 to the Registrant's Registration Statement
on Form S-1 (File No. 333-204144) filed with the Securities and Exchange Commission on May 13, 2015)
|
|
|
|
|
|
10.3
|
*
|
Amended and Restated 2008 Equity Incentive Plan, as amended (incorporated by reference to Exhibit 10.4 to the Registrant's Registration Statement on Form S-1 (File No. 333-204144) filed with the Securities and Exchange
Commission on May 13, 2015)
|
|
|
|
|
|
10.4
|
*
|
Form of Incentive Stock Option Agreement under Amended and Restated 2008 Equity Incentive Plan (incorporated by reference to Exhibit 10.5 to the Registrant's Registration Statement on Form S-1 (File No. 333-204144) filed
with the Securities and Exchange Commission on May 13, 2015)
|
|
|
|
|
|
10.5
|
*
|
Form of Nonstatutory Stock Option Agreement under Amended and Restated 2008 Equity Incentive Plan (incorporated by reference to Exhibit 10.6 to the Registrant's Registration Statement on Form S-1 (File No. 333-204144)
filed with the Securities and Exchange Commission on May 13, 2015)
|
|
|
|
|
|
10.6
|
*
|
2015 Stock Incentive Plan (incorporated by reference to Exhibit 10.7 to the Registrant's Registration Statement on Form S-1 (File No. 333-204144) filed with the Securities and Exchange Commission on June 11,
2015)
|
|
|
|
|
|
10.7
|
*
|
Form of Incentive Stock Option Agreement under 2015 Stock Incentive Plan (incorporated by reference to Exhibit 10.8 to the Registrant's Registration Statement on Form S-1 (File No. 333-204144) filed with the Securities
and Exchange Commission on June 3, 2015)
|
|
|
|
|
|
10.8
|
*
|
Form of Nonstatutory Stock Option Agreement under 2015 Stock Incentive Plan (incorporated by reference to Exhibit 10.9 to the Registrant's Registration Statement on Form S-1 (File No. 333-204144) filed with the Securities
and Exchange Commission on June 3, 2015)
|
|
|
|
|
|
10.9
|
*
|
2015 Employee Stock Purchase Plan (incorporated by reference to Exhibit 10.22 to the Registrant's Registration Statement on Form S-1 (File No. 333-204144) filed with the Securities and Exchange Commission on June 3,
2015)
|
|
|
|
|
Table of Contents
|
|
|
|
Exhibit
Number
|
|
Description of Exhibit
|
|
10.10
|
|
Second Amended and Restated Investors' Rights Agreement, dated as of March 17, 2015, among the Registrant and the other parties thereto, as amended June 10, 2015 (incorporated by reference to Exhibit 10.1 to the
Registrant's Registration Statement on Form S-1 (File No. 333-204144) filed with the Securities and Exchange Commission on June 11, 2015)
|
|
|
|
|
|
10.11
|
*
|
Amended and Restated Employment Agreement, dated as of April 7, 2010, by and between the Registrant and Jill C. Milne, as amended (incorporated by reference to Exhibit 10.10 to the Registrant's Registration Statement on
Form S-1 (File No. 333-204144) filed with the Securities and Exchange Commission on May 13, 2015)
|
|
|
|
|
|
10.12
|
*
|
Offer Letter, dated as of September 30, 2015, by and between the Registrant and Deirdre Cunnane (incorporated by reference to Exhibit 10.23 to the Registrant's Annual Report on Form 10-K (File No. 001-37467) filed with
the Securities and Exchange Commission on March 15, 2016)
|
|
|
|
|
|
10.13
|
*
|
Catabasis Pharmaceuticals, Inc. Executive Severance Benefits Plan effective April 15, 2016 (incorporated by reference to Exhibit 99.1 to the Registrant's Current Report on Form 8-K (File No. 001-37467) filed with the
Securities and Exchange Commission on April 19, 2016)
|
|
|
|
|
|
10.14
|
*
|
Form of Indemnification Agreement by and between the Registrant and each of its executive officers and directors (incorporated by reference to Exhibit 10.13 to the Registrant's Registration Statement on Form S-1 (File No.
333-204144) filed with the Securities and Exchange Commission on May 13, 2015)
|
|
|
|
|
|
10.15
|
|
Credit and Security Agreement, dated as of August 27, 2014, by and among the Registrant, Midcap Financial SBIC, L.P., Square 1 Bank and the other lenders identified therein, as amended on March 31, 2015 (incorporated by
reference to Exhibit 10.14 to the Registrant's Registration Statement on Form S-1 (File No. 333-204144) filed with the Securities and Exchange Commission on May 13, 2015)
|
|
|
|
|
|
10.16
|
|
Second Amendment to Credit and Security Agreement, dated as of December 22, 2015, by and among the Registrant, Midcap Financial SBIC, L.P., Square 1 Bank and the other lenders identified therein (incorporated by reference
to Exhibit 10.24 to the Registrant's Annual Report on Form 10-K (File No. 001-37467) filed with the Securities and Exchange Commission on March 15, 2016)
|
|
|
|
|
|
10.17
|
|
Indenture of Lease, dated as of December 17, 2010, by and between the Registrant and RB Kendall Fee, LLC, as amended (incorporated by reference to Exhibit 10.15 to the Registrant's Registration Statement on Form S-1 (File
No. 333-204144) filed with the Securities and Exchange Commission on May 13, 2015)
|
|
|
|
|
|
10.18
|
|
Second Amendment of Lease, dated as of July 16, 2015, by and between the Registrant and DWF IV One Kendall, LLC (incorporated by reference to Exhibit 10.1 to the Registrant's Quarterly Report on Form 10-Q (File No.
001-37467) filed with the Securities and Exchange Commission on November 11, 2015)
|
|
|
|
|
|
10.19
|
|
Third Amendment of Lease, dated as of November 3, 2016, by and between the Registrant and DWF IV One Kendall, LLC (incorporated by reference to Exhibit 99.1 to the Registrant's Current Report on Form 8-K (File No.
001-37467) filed with the Securities and Exchange Commission on November 7, 2016)
|
|
|
|
|
|
10.20
|
|
Form of Common Stock Warrant (incorporated by reference to Exhibit 10.17 to the Registrant's Registration Statement on Form S-1 (File No. 333-204144) filed with the Securities and Exchange Commission on May 13,
2015)
|
|
|
|
|