Item
1. BUSINESS
All
references in this report to “Corbus,” the “Company,” “we,” “us,” or “our”
mean Corbus Pharmaceuticals Holdings, Inc. and its subsidiaries unless we state otherwise or the context otherwise indicates.
Overview
We
are a Phase 3, clinical-stage pharmaceutical company focused on the development and commercialization of novel therapeutics to
treat chronic and serious inflammatory and fibrotic diseases with clear unmet medical needs by targeting the human endocannabinoid
system (ECS). We are developing a pipeline of cannabinoid drug candidates which are rationally designed, synthetic, small molecule
drugs which target the ECS to treat inflammatory and fibrotic diseases. Our focus on the ECS is backed by an ever-expanding body
of knowledge on the biology of the ECS and its role as being a master regulator of inflammation and fibrosis. Our lead investigational
drug candidate, lenabasum, is a novel, synthetic, oral, cannabinoid type 2 (CB2) agonist designed to resolve chronic inflammation,
limit fibrosis and support tissue repair. We are currently developing lenabasum to treat four life threatening diseases: systemic
sclerosis (SSc), dermatomyositis (DM), cystic fibrosis (CF) and systemic lupus erythematosus (SLE). In addition, we are developing
a pipeline of experimental drug candidates from our library of novel compounds targeting the ECS. Our pipeline also includes CRB-4001,
a 2nd generation, peripherally restricted cannabinoid receptor type 1 (CB1) inverse agonist designed to treat organ specific fibrotic
liver diseases, such as nonalcoholic steatohepatitis, or NASH.
Lenabasum
selectively binds to CB2 in the periphery, which is preferentially expressed on activated immune cells, fibroblasts and other
cell types, including muscle and bone cells. Lenabasum stimulates the production of Specialized Pro-Resolving Lipid Mediators
(SPMs) that act to resolve inflammation and halt fibrosis without immunosuppression by activating endogenous pathways. These pathways
are activated in healthy individuals during the course of normal immune responses but are dysfunctional in patients with chronic
inflammatory and fibrotic diseases. By its binding to CB2, lenabasum drives innate immune responses from the activation phase
into the resolution phase. CB2 plays a central role in modulating and resolving inflammation by, in effect, turning heightened
inflammation “off” and restoring homeostasis. This has been demonstrated in animal models lacking CB2 as well as humans
with genetic polymorphism in the CB2 gene, as these exhibit excessive inflammation and fibrosis in response to activators of the
innate immune system.
Lenabasum
is currently being evaluated in a Phase 3 SSc study that has completed the enrollment of 365 patients with top-line data expected
to be reported in the summer of 2020, a Phase 2b CF study that has completed the enrollment of 426 patients with topline data
expected in the summer of 2020, and a Phase 3 study in DM that is expected to enroll 150 patients. In addition, we are conducting
a Phase 2 SLE study funded by a grant through the National Institutes of Health, or NIH, that is expected to enroll 100 patients.
Open-label extension studies are ongoing in SSc and DM for patients who completed the Phase 2 studies and Phase 3 studies in these
indications. Lenabasum has generated positive clinical data in three consecutive Phase 2 studies in diffuse cutaneous SSc, CF
and skin-predominant DM. Lenabasum has demonstrated acceptable safety and tolerability profiles in clinical studies to date.
The
U.S. Food and Drug Administration, or FDA, has granted lenabasum Orphan Drug Designation
as well as Fast Track Status for SSc and CF, and Orphan Drug Designation for DM. The European Medicines Authority, or EMA, has
granted lenabasum Orphan Drug Designation for SSc, CF and DM.
Since
our inception, we have devoted substantially all of our efforts to business planning, research and development,
recruiting management and technical staff, acquiring operating assets and raising capital. Our research and development
activities have included conducting pre-clinical studies, developing manufacturing methods and the manufacturing of our drug lenabasum
for clinical trials and conducting clinical studies in patients. Two of the four clinical
programs for lenabasum are being supported by non-dilutive awards and grants. The NIH has funded the majority of the clinical
development costs for the DM Phase 2 clinical trial and is funding the SLE Phase 2
clinical trial. In cystic fibrosis, the Phase 2b clinical trial is being supported by the 2018 CFF Award of up to $25 million,
and the Phase 2 clinical trial was partially funded by a $5 million award from the Cystic Fibrosis Foundation Therapeutics, Inc.,
a non-profit drug discovery and development affiliate of the Cystic Fibrosis Foundation.
In
September 2018, we acquired an exclusive worldwide license to develop, manufacture and market drug candidates from more than 600
compounds, targeting the endocannabinoid system from Jenrin Discovery LLC, or Jenrin. The pipeline includes CRB-4001, our peripherally-restricted,
CB1 inverse agonist targeting liver, lung, heart and kidney fibrotic diseases. The current patent portfolio for CRB-4001 includes
multiple issued patents and pending patent applications. CRB-4001 was developed in collaboration with and with financial support
from the NIH. CRB-4001 was specifically designed to eliminate blood-brain barrier penetration and brain CB1 receptor occupancy
that mediate the neuropsychiatric issues associated with first-generation CB1 inverse agonists such as rimonabant. Potential indications
for CRB-4001 include NASH, primary biliary cholangitis, idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, myocardial
fibrosis after myocardial infarction, and acute interstitial nephritis, among others.
On
January 3, 2019, we entered into a strategic collaboration with Kaken Pharmaceutical Co., Ltd., or Kaken, for the development
and commercialization in Japan of our investigational drug lenabasum for the treatment of SSc and DM, two rare and serious autoimmune
diseases. Under the terms of the agreement, Kaken received an exclusive license to commercialize and market lenabasum in Japan
for SSc and DM. In March 2019, Kaken made an upfront payment to us of $27 million. We will be eligible to receive up to an additional
$173 million upon achievement of certain regulatory, development and sales milestones as well as double-digit royalties.
The
development status of Corbus pipeline is summarized below:
Figure
1: Clinical development pipeline
Clinical
Development-Lenabasum
Systemic
Sclerosis (SSc)
Ongoing
Phase 3 Study
In
December 2017, we initiated a Phase 3 double-blind placebo-controlled multi-center international clinical study (“RESOLVE-1)
in diffuse cutaneous SSc and we completed enrollment of 365 patients in May 2019. Topline data from this study are expected in
summer of 2020. The RESOLVE-1 is a multi-national, 52-week study with subjects being randomized 1:1:1 to receive lenabasum 5 mg
twice per day, lenabasum 20 mg twice per day or placebo twice per day.
The
primary efficacy outcome of the RESOLVE-1 study is the American College of Rheumatology Combined Response Index in diffuse cutaneous
Systemic Sclerosis (ACR CRISS). The ACR CRISS score is a composite measure of clinical improvement calculated from weighted changes
from baseline in five core outcome measures commonly used to evaluate treatment effect in trials for SSc: modified Rodnan Skin
core (mRSS), Health Assessment Questionnaire - Disability Index (HAQ-DI), forced vital capacity (FVC) percent predicted, and patient
and physician global assessments of health related to SSc The study is also evaluating multiple secondary endpoints, including
changes in mRSS, HAQ-DI, and FVC percent predicted. These same outcomes were evaluated in the Phase 2 study and are also outcomes
for the ongoing open-label Phase 2 and Phase 3 extension studies. The open-label extension
enables all the participants in the study to continue to receive lenabasum following the conclusion of the trial period.
Encouraging
Data from Ongoing Open-Label Extension Study
Thirty-six
subjects with diffuse cutaneous SSc received open-label dosing with lenabasum at 20 mg twice per day following 16 weeks participation
in the preceding double-blinded placebo-controlled part of the lenabasum Phase 2 study. Patients had a mean of about 20 weeks
off treatment from the end of lenabasum dosing during the placebo-controlled period before starting open-label dosing. Lenabasum
was administered in addition to standard-of-care treatments for SSc, including concomitant immunosuppressive drugs in 92% of subjects.
Efficacy
Outcomes
The
ACR CRISS score (ACR CRISS), the primary outcome for Phase 3 RESOLVE-1, increased steadily over time with lenabasum open-label
dosing and has maintained ≥ 0.95 from Month 12 through Month 25 in the OLE. Also the mRSS improved > 9.2 points during
the same time. Patient and physician global assessments of health, skin symptoms, itch, and patient-reported disability and function
showed either stabilization or continued improvement during the OLE from Month 12 through 24. No severe or serious adverse events
(AE) or study discontinuations related to lenabasum to date in the OLE.
Figure
2: ACR CRISS Results from Phase 2 Study
Figure
3: mRSS Results from Phase 2 Study
Safety
There
have been no severe or serious adverse events (AEs) or study discontinuations related to lenabasum to date and no clinically significant
laboratory abnormalities related to lenabasum in the Phase 2 study, and the safety and tolerability profile of lenabasum remains
favorable after months of dosing in the open label extension.
Cystic
Fibrosis (CF)
Ongoing
Phase 2B Study
In
January 2018, the Company initiated a Phase 2b study in CF which is being funded in part by a development award for up to $25
million from the Cystic Fibrosis Foundation (CFF) and the enrollment of 426 patients was completed in November 2019 in
with top line data expected in the summer of 2020. The Phase 2b multicenter, double-blinded, randomized, placebo-controlled study
has enrolled CF subjects who are at least 12 years of age and a history of increased risk for pulmonary exacerbations (PEx). The
primary outcome is the event rate of PEx which is the average number of PEx per subject per time period. Secondary efficacy outcomes
include other measures of PEx, change in Cystic Fibrosis Questionnaire-Revised Respiratory domain score and change in forced expiratory
volume in 1 second (FEV1), % predicted. The study is a multi-center international study and subjects were randomized to one of
three cohorts to receive lenabasum 20 mg twice per day, lenabasum 5 mg twice per day, or placebo twice per day for 28 weeks, with
4 weeks follow-up off active treatment. This Phase 2b CF study was designed with input from the therapeutic Development Network
of the Cystic Fibrosis Foundation and the European Cystic Fibrosis Society Clinical Trials Network.
Positive
Data from Phase 2 Cystic Fibrosis Study
In
March 2017, the Company completed a double-blind placebo-controlled Phase 2 study in CF and reported positive results. The Phase
2 study evaluated multiple doses of lenabasum compared to placebo for the treatment of patients with CF. The 16-week study dosed
85 adult CF patients with baseline (FEV1) percent predicted ≥ 40%, who were enrolled without regard to their specific CFTR
mutation or infecting pathogens and continued with all baseline treatment regimens.
Lenabasum
successfully achieved the primary objective of the study by demonstrating an acceptable safety and tolerability profile at all
doses with no serious or severe adverse events related to the study drug. Lenabasum cohorts showed a dose-dependent reduction
in a number of acute PEx defined as those requiring intravenous (IV) antibiotics compared to placebo. Additionally, lenabasum
caused a consistent reduction in multiple inflammatory cell types in sputum, including total leukocytes, neutrophils, eosinophils,
and macrophages. Inflammatory mediators, including interleukin-8, neutrophil elastase, and immunoglobulin G, were also reduced
in sputum by lenabasum in a dose-dependent manner. These patient data provide evidence of biological activity of lenabasum in
resolving ongoing innate immune responses in lungs of CF patients and support the observed reduction in PEx.
Figure
4: Lenabasum treatment was associated with longer time to PEx in Phase 2 study and consistent reduction in key inflammatory biomarkers
in sputum
The
Cystic Fibrosis Foundation Therapeutics, Inc. (“CFFT”), the non-profit drug discovery and development affiliate of
the Cystic Fibrosis Foundation supported the prior Phase 2 study with a $5 million development award. To date, the Company has
received two development awards with total potential payments of up to $30 million from the CFF to support the clinical development
of lenabasum in CF.
Dermatomyositis
(DM)
Ongoing
Phase 3 Study
In
December 2018, we initiated a Phase 3 double-blind placebo-controlled multi-center international clinical study titled DETERMINE
in DM. The DETERMINE study is a multi-center international trial expected to enroll approximately 150 subjects.
The planned duration of treatment with study drug is 52 weeks. Subjects will be randomized to receive lenabasum 20 mg twice per
day, lenabasum 5 mg twice per day, or placebo twice per day in a 2:1:2 ratio. The primary efficacy outcome at Week 52 will be
American College of Rheumatology/European League Against Rheumatism 2016 Total Improvement Score (TIS), which is a weighted composite
measure of improvement from baseline in six endpoints, including Physician Global Assessment of Disease Activity, Physician Global
Assessment of Extramuscular Disease Activity, Patient Global Assessment of Disease Activity, Health Assessment Questionnaire (patient-reported
disability), Manual Muscle Testing, and muscle enzymes. Evaluation of key organ involvement – muscle, skin, and lungs, will
be included in secondary efficacy outcomes. Change from Baseline in the Cutaneous Dermatomyositis Activity and Severity index
(“CDASI”) composite activity score will be a secondary efficacy outcome.
Encouraging
Data from Ongoing Open-Label Extension Study
Twenty
subjects with skin-predominant DM received open-label dosing with lenabasum at 20 mg twice per day following 16 weeks participation
in the preceding double-blinded placebo-controlled part of the lenabasum Phase 2 study. Patients had a mean of about 31 weeks
off treatment from the end of lenabasum dosing during the placebo-controlled period before starting open-label dosing. Lenabasum
was administered in addition to standard-of-care treatments for DM, including concomitant immunosuppressive drugs in 85% of subjects.
Efficacy
Outcomes
The
CDASI activity score improved from study start by -20.9 points at 23 months in the open label extension study (OLE). An improvement
of -4 to -5 points in CDASI activity score is considered medically important, and 72% of subjects achieved low skin activity (CDASI
≤ 14) at 23 months. Continued improvement was observed during the OLE in patient-reported global assessments of skin activity,
skin symptoms, itch and hair loss and physician-reported global disease activity, physician assessment of extramuscular disease
activity.
Figure
5: CDASI Activity Score During Open Label Extension
Positive
Data from Phase 2 Dermatomyositis Study
In
October 2017, the Company completed the double-blind, placebo-controlled portion of the Phase 2 study in skin-predominant DM and
reported positive results. The mean improvement (reduction) in the primary efficacy outcome, the CDASI activity score, an, was
9.3 points for lenabasum treatment versus a reduction of 3.7 points for placebo treatment (p = 0.04, 2-sided MMRM) at sixteen
weeks. Lenabasum also outperformed placebo in multiple secondary efficacy outcomes studied. Lenabasum was well tolerated with
no severe or serious side effects associated with the drug. No subjects dropped out. The dermatomyositis trial was funded by a
grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health to the
University of Pennsylvania Perelman School of Medicine.
The
single center trial enrolled 22 adults at a 1 to 1 ratio of lenabasum to placebo cohorts. At baseline, subjects in each cohort
had a mean CDASI activity score in the severe range and skin symptoms in the extremely severe range despite background treatment
with immunosuppressive drugs in 19 of the 22 subjects. Demographic parameters, CDASI activity scores, patient-reported outcomes,
and use of immunosuppressive drugs at baseline were similar for lenabasum and placebo cohorts. Subjects received lenabasum 20
mg QD through week 4, then lenabasum 20 mg BID through week 12 with safety and efficacy follow-up thereafter through week 16.
All subjects remained on their background standard-of-care therapy throughout the study in DM.
Figure
6-Lenabasum Demonstrated Clinically Meaningful Improvement in CDASI
Systemic
Lupus Erythematosus (SLE)
In
December 2017 a Phase 2 clinical study of lenabasum was initiated for the treatment of systemic lupus erythematosus and patient
dosing commenced in February 2018 and we expect to report top line data in 2020. The Phase 2 SLE clinical trial is being conducted
by the Autoimmunity Centers of Excellence (ACE) program, which is funded by the National Institute of Allergy and Infectious Diseases
(NIAID), part of the National Institutes of Health (NIH).
The
randomized, double-blind, placebo-controlled, Phase 2 trial is being conducted in the U.S. and is expected to enroll 100 adult
SLE patients with active musculoskeletal disease, which is the most common disease manifestation of SLE. Subjects will be randomized
in a 1:1:1:1 ratio to one of four cohorts to receive placebo or three different doses of lenabasum for 3 months, with 1-month
follow-up. The primary efficacy outcome assesses pain from active musculoskeletal disease, and secondary efficacy outcomes include
other assessments of active musculoskeletal disease, overall disease activity using SLE Responder Index, SLE Disease Activity
Index (“SLEDAI”) and British Isles Lupus Activity Group (“BILAG”) scoring systems, and patient-reported
outcomes.
Lenabasum’s
Unique and Novel Mechanism of Action as a Pro-Resolving Drug
Lenabasum
is a synthetic, rationally-designed, oral small-molecule drug that selectively binds to the cannabinoid receptor type 2, or CB2,
found on activated immune cells, fibroblasts and other cell types including muscle and bone cells. Lenabasum stimulates the production
of Specialized Pro-Resolving Lipid Mediators (SPMs) that act to resolve inflammation and halt fibrosis by activating endogenous
pathways. These pathways are activated in healthy individuals during the course of normal immune responses but are dysfunctional
in patients with chronic inflammatory and fibrotic diseases. Through its binding to the CB2 receptor, lenabasum drives innate
immune responses from the activation phase through completion of the resolution phase. The CB2 receptor plays a central role in
modulating and resolving inflammation by, in effect, turning heightened inflammation “off” and restoring homeostasis.
This has been demonstrated in animal models lacking CB2 as well as humans suffering from polymorphism in the CB2 gene, as these
exhibit abnormal immune responses and a propensity for chronic inflammation.
A
key aspect of the body’s innate immune response is its activation phase when inflammatory cells are recruited to the site
of tissue infection/injury whereupon these cells act to target the infection and/or respond to tissue damage. The next phase in
a normal innate immune response is its resolution phase, during which the nature of the infiltrating immune cells changes from
pro-inflammatory to pro-resolving, the infectious pathogens are eliminated, residual cellular debris and immune cells are cleared
from the tissue, and tissue repair processes are eventually halted when they are no longer needed. In chronic inflammatory and
fibrotic diseases, the innate immune responses are “stuck” in the initial activation phase. This failure to progress
through the resolution phase causes chronic tissue infiltration with inflammatory cells and chronic activation of healing processes
that cause tissue scarring, or fibrosis. The key event that propels an innate immune response from its activation phase to its
resolution phase is a “class switch” from production of pro-inflammatory lipid mediators such as prostaglandins and
leukotrienes to a family of SPMs (Figure 1) which include lipoxins, resolvins, protectins, and marescins. If an innate immune
response persists in the activation phase and does not progress through resolution, chronic inflammation and fibrosis can result,
causing organ dysfunction, organ failure, severe morbidity and even death. There are hundreds of life-long chronic and incurable
inflammatory diseases.
Figure
7-Lenabasum’s Mechanism of Action
Lenabasum
is designed to restore immune system homeostasis, by harnessing the body’s own physiologic pathways to transition the innate
immune response from the activation phase to the resolution phase. If the innate immune response is “stuck” in the
activation phase, tissue damage, fibrosis and persistent infection are expected consequences. Endogenous progression of the innate
immune response through its resolution phase has been shown to clear inflammation, stop fibrosis, and promote pathogen clearance.
Lenabasum’s unique mechanism of action is different than anti-inflammatory drugs that inhibit the production or functions
of distinct pro-inflammatory mediators that initiate or are active during the activation phase. Activation of an innate immune
response is necessary to clear infections, however drugs that interfere with the activation phase carry the risk of immunosuppression
and may have other undesirable side effects. In contrast, lenabasum is designed to transition an innate immune response from its
activation phase to resolution phase. Lenabasum’s CB2 agonist activity initiates a class switch in bioactive lipid mediators
from inflammation-activating mediators to pro-resolving mediators. Lenabasum acts to impact and activate multiple pathways including:
|
●
|
Increase
in production of SPMs and anti-inflammatory eicosanoids, with a concomitant decrease in production of pro-inflammatory eicosanoids.
|
|
|
|
|
●
|
Increase
in production of anti-inflammatory cytokines, coupled with a decrease in production of pro-inflammatory cytokines and pro-fibrotic
growth factors.
|
|
|
|
|
●
|
Increase
in influx of non-inflammatory macrophages with a decrease in influx and accumulation of inflammatory cells and pro-fibrotic
myofibroblasts.
|
|
●
|
Increase
in bacterial clearance. SPMs stimulate production of bactericidal peptides, enhance phagocytosis and killing of bacteria by
neutrophils and macrophages.
|
|
|
|
|
●
|
Increase
in apoptosis of inflammatory cells, including neutrophil and pro-fibrotic cells, including fibroblasts.
|
|
|
|
|
●
|
Increase
in clearance of apoptotic cells and cellular debris by non-inflammatory macrophages.
|
Effect
of Lenabasum in a Human Model of Inflammatory Resolution
Dr.
Derek Gilroy, Professor of Experimental Inflammation and Pharmacology at University College of London evaluated the effects of
lenabasum in a clinical research model of inflammation and its resolution in healthy volunteers. In this model, inflammation was
triggered in healthy individuals by the subcutaneous injection of heat-killed E. coli. Blood flow to the site of inflammation
was measured with laser Doppler techniques. Suction blisters were generated over the site of inflammation, and cells and inflammatory
mediators were measured in the blister fluid at different times after the injection of E. coli. In this study 22 subjects received
either lenabasum at 5 mg or 20 mg twice a day or placebo prior to the procedure.
The
data demonstrated that both doses of lenabasum exerted potent anti-inflammatory effects by inhibiting neutrophil infiltration
and increased the clearance of bacteria as measured by local endotoxin levels, both key determinants of inflammation. Controlling
neutrophils is considered highly important for treating many diseases driven by chronic inflammation. In addition to inhibiting
neutrophil accumulation, lenabasum also enhanced clearance of the injected bacteria. The data were published in January 2018 in
the peer-reviewed “Clinical Pharmacology & Therapeutics” journal in a paper entitled: “Potent anti-inflammatory
and pro-resolving effects of lenabasum in a human model of self-resolving acute inflammation. The findings in this paper provide
additional evidence for lenabasum’s unique mechanism of action to modulate the trafficking of key harmful effector cells
to the site of infection and injury without compromising internal host defense mechanisms, and instead enhancing it. This dual
mechanism of action of lenabasum combines the inhibition of lipid mediators that normally reduce the immune system’s ability
to clear bacteria with the inhibition of pro-inflammatory lipid mediators. This unique activity of lenabasum ultimately drives
the inflammatory response down the pro-resolution pathway.
Figure
8- Lenabasum Increases Pro-Resolving Lipid Mediators in Humans
Figure
11- Lenabasum also Decreases Inflammatory Lipid Mediators in Humans
Data
from this human clinical model demonstrated that lenabasum activates the resolution of innate immune responses and is the first
experimental therapeutic shown to activate the “pro-resolution” pathway in humans. These results are consistent with
previous findings from experiments that evaluated lenabasum’s effects in animal models of inflammation and support lenabasum’s
potential to deliver therapeutic benefit in chronic inflammatory diseases as a first-in-class pro-resolution drug. The results
identify the CB2 receptor, the therapeutic target of lenabasum, as a key link between the innate immune response and the endocannabinoid
system acting as an upstream activator of the resolution of innate immunity. The top dose of lenabasum in this study at 20 mg
twice a day is the same as the highest dose in the Phase 3 SSc clinical trial and the Phase 2b CF trial.
Clinical
Development-CRB-4001 and other synthetic cannabinoid drugs
Corbus
is developing CRB-4001, 2nd generation, peripherally restricted selective (CB1) inverse agonist for nonalcoholic steatohepatitis
(NASH) and other fibrotic diseases. CRB-4001 was developed in collaboration with and financial support from the National Institutes
of Health (NIH). CRB-4001 was specifically designed to eliminate blood-brain barrier penetration and brain CB1 receptor occupancy
that mediate the neuropsychiatric issues associated with first-generation CB1 inverse agonists, such as rimonabant. Corbus expects
data from its Phase 1 safety study in 2020.
We
are also evaluating and characterizing compounds from of our compound library to select additional clinical candidates to move
forward into clinical studies. The next clinical candidate from our proprietary platform will be selected in 2020.
Market
Opportunity for Lenabasum in Inflammatory and Fibrotic Diseases
There
are many different chronic, serious inflammatory and fibrotic diseases that could be addressed by treatment with lenabasum. Some
examples of chronic, serious diseases characterized by inflammation with variable degrees of fibrosis include genetic diseases
such as cystic fibrosis, nonalcoholic steatohepatitis (“NASH”), myelofibrosis, lung diseases including idiopathic
pulmonary fibrosis, bronchiolitis obliterans, and sarcoidosis and autoimmune diseases including systemic sclerosis, systemic lupus
erythematosus, myositis, rheumatoid arthritis, vasculitis, primary biliary cirrhosis.
Lenabasum
Market Opportunity for Current Indications Being Developed
Autoimmune
Disorders
Systemic
Sclerosis
Systemic
sclerosis (SSc) is a chronic, systemic autoimmune disease characterized by activation of innate and adaptive immune systems, an
obliterative, proliferative vasculopathy of small blood vessels, and fibrosis of the skin and multiple internal organs. Approximately
200,000 people in the U.S., Europe and Japan have SSc. The disease affects mainly adults (80% of SSc patients are women) with
mean age of onset about 46 years of age in the U.S. and the majority of patients between 45-64 years of age.
A
commonly used system classifies SSc patients into those with more wide-spread skin thickening (diffuse cutaneous SSc, about 35%
of patients) and those with more restricted skin thickening (limited cutaneous SSc, about 65% of patients). There is significant
overlap in the clinical manifestations for these two groups of SSc patients and no known significant differences in disease pathogenesis.
SSc
can affect multiple internal organs in the body, including the lungs, heart, kidneys, joints, muscles, esophagus, stomach and
intestines. Clinically apparent organ involvement that occurs in more than a third of these patients includes thickened skin,
Raynaud’s phenomenon, esophageal symptoms, pulmonary fibrosis, restrictive lung disease, edematous skin, joint contractures,
digital ulcers, and muscle weakness. Less frequently occurring, yet life-threatening manifestations include pulmonary artery hypertension
(about 1 in 5 patients), cardiac conduction blocks (about 1 in 10 patients), and renal crisis (about 1 in 50 patients). In the
U.S., SSc is the deadliest of the systemic autoimmune diseases. The median disease duration for an individual who dies of SSc
is 7.1 years from the onset of symptoms. About 85% of deaths caused by SSc are the result of pulmonary fibrosis, pulmonary artery
hypertension, or cardiovascular disease, such as sudden death.
In
SSc the innate immune system fails to transition from the activation phase to the resolution phase. Individuals with SSc who have
interstitial lung disease have an imbalance of bioactive lipid mediators, causing a predominance of inflammatory mediators versus
resolving mediators. The preponderance of inflammatory mediators correlates positively with the degree of inflammation in the
lungs and negatively with forced vital capacity, a measure of lung fibrosis. Excessive activation of the pathways which cause
fibrosis including TGFβ, myofibroblast accumulation, and production of collagen and other extracellular matrix proteins are
all present in SSc.
There
is no cure for systemic sclerosis, and there are no FDA-approved treatments for this disease. Drugs such as methotrexate, mycophenolate
and cyclophosphamide are often prescribed to treat symptoms and/or address organ specific manifestations associated with SSc.
These immunosuppressive drugs are not specifically FDA approved for SSc, do not treat the totality of the disease, and may be
associated with significant side effects, such as serious infections.
We
believe there is general agreement in the SSc community that an effective anti-inflammatory and anti-fibrotic drug that addresses
the totality of the disease and help patients function and feel better would address a significant unmet medical need in SSc,
especially a drug that is orally administered, can be used chronically with other commonly prescribed medications for SSc, and
is not immunosuppressive. We believe such a therapy would be positively received by the market.
Dermatomyositis
Dermatomyositis
(DM) is a serious and rare autoimmune idiopathic inflammatory myopathy with characteristic cutaneous findings. About 80,000 individuals
in the U.S., Europe and Japan suffer from dermatomyositis. DM usually strikes adults, with most common age of adult onset between
50-60 years.
This
systemic disorder most frequently affects the skin and muscles, and DM can also include interstitial lung disease/restrictive
lung disease, arthritis, gastrointestinal and cardiac involvement. Inflammatory muscle disease associated with DM can cause discomfort
and significant weakness of the proximal muscles of the arms and legs and of the trunk. Dermatomyositis can include damaging inflammation
elsewhere in the body, for example: lung inflammation that leads to lung fibrosis and restrictive lung disease; heart inflammation
that causes arrhythmia, congestive heart failure, and pericarditis, inflammation of muscles in the esophagus that causes swallowing
problems or aspiration pneumonia, and arthritis. DM patients may have active skin disease despite successful treatment of their
muscle and/or lung disease. The skin findings in DM can be disfiguring and are inflammatory rashes characterized by redness and
itching in exposed areas of the skin, around the eyes, on the hands, and in a “shawl” distribution on the scalp, hands,
upper back, and photo-exposed areas. Due to this chronic inflammation, patients with DM have an increased risk of malignancy,
most commonly in older patients. By itself, skin involvement in DM has a large negative impact on quality of life, comparable
to that of cutaneous lupus erythematosus and vulvodynia, and much higher than those of many dermatologic diseases. The pathophysiology
of DM is consistent with a patient’s inherent inability to adequately resolve innate immune responses.
There
is no cure for DM, a disease that continues to progressively worsen over time. Typically, people with DM are prescribed drugs
that suppress the immune system. These treatments may be associated with significant side effects, such as serious infections.
FDA-approved treatments for DM include systemic corticosteroids and adrenocorticotropic hormone analogue.
We
believe that an effective drug that controls inflammation in the skin, muscles, and other organs will address a significant unmet
medical need in DM, particularly a drug that is orally administered, can be used
chronically with other commonly prescribed medications for the disease, and is not immunosuppressive.
Systemic
Lupus Erythematosus
Systemic
lupus erythematosus (SLE) is a prototypical autoimmune disease with a wide array of clinical manifestations, including arthritis,
rash, photosensitivity, oral ulcers, pleuritis, pericarditis, kidney problems, seizures and psychosis and blood cell abnormalities.
About 550,000 individuals in the U.S., Europe and Japan suffer from SLE. The musculoskeletal system is the most commonly involved
system in SLE. Patients with SLE have an increased frequency of related autoimmune problems, such as Sjogren’s syndrome
and antiphospholipid syndrome that require additional treatments. SLE may occur with other autoimmune conditions, such as thyroiditis,
hemolytic anemia, and idiopathic thrombocytopenia purpura. Accelerated atherosclerosis among SLE patients is responsible for premature
mortality.
The
pathology of SLE involves chronic activation of the innate immune system by immune complexes, with activation of the complement
cascade, increased production of type 1 interferons and other mediators of inflammation and resultant tissue inflammation and
damage.
Medicines
specifically approved by the FDA for treatment of SLE are aspirin, hydroxychloroquine, corticosteroids (for example, prednisone),
the corticotropin injection Acthar® and the immunosuppressive drug Benlysta®. Other drugs that are not specifically
FDA approved for SLE but are often prescribed by physicians include methotrexate, mycophenolate, azathioprine and cyclophosphamide.
These treatments may be associated with significant side effects, such as serious infections.
We
believe that an effective drug that controls inflammation in the joints and skin as well as improves overall disease activity
will address a significant unmet medical need in SLE, particularly a drug that is
orally administered, can be used chronically with other commonly prescribed medications for the disease, and is not immunosuppressive.
Cystic
Fibrosis
Cystic
fibrosis (CF) is a life-long, progressive, debilitating, and life-threatening autosomal recessive disease. Cystic fibrosis is
caused by mutations in the gene Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). The
CFTR serves as a central hub to modulate transport, trafficking, and signaling in cells. Given multiple roles of CFTR in
cellular activation and homeostasis, mutation of the CFTR give rise to multiple disorders in respiratory, digestive and reproductive
organs.
The
current median life expectancy of cystic fibrosis patients is about 40 years. According to the Cystic Fibrosis Foundation, 30,000
Americans and a total of 70,000 people in the U.S. and Europe suffer from cystic fibrosis.
The
CFTR mutations lead to defective ion transport, with reduced chloride and bicarbonate secretion and sodium hyper-absorption, followed
by water hyper-absorption, by airway epithelia and other cell types. The resultant reduced height of epithelial lining fluid and
decreased hydration of mucus results in abnormally thick and sticky mucus, which obstructs the lumen into which the mucus is secreted
and reduces mucociliary clearance of bacteria. The dysfunction in ion transport in CF patients is reflected in abnormal sweat
chloride levels.
The
negative effects caused by CFTR gene mutations are not restricted to ion channels, but also extend to dysfunction of the innate
immune system. The nature of the abnormalities in CF are consistent with inability of innate immune responses to make the transition
out of the activation phase and into and through the resolution phase. Bioactive lipid mediators (SPMs) that initiate the transition
to resolution phase of innate immune responses have been found to be deficient relative to pro-inflammatory lipid mediators that
initiate its activation phase, and this reduction correlates with poor recovery of lung function following an acute pulmonary
exacerbation in children. The preponderance of activated neutrophils and pro-inflammatory macrophages in inflamed tissue, reduced
neutrophil apoptosis, high levels of neutrophil proteases that reflect persistent neutrophil activation, reduced clearance of
neutrophils by macrophages, ineffective clearance of certain bacteria such as P. aeruginosa, and excessive activation of
fibrotic pathways all show the inability of individuals with CF to resolve their innate immune responses.
An
overview of the disease progression in cystic fibrosis is provided in Figure 10.
Figure
10: Factors involved in cystic fibrosis progression
As
a result of obstructing secretions, recurrent infections, hyper-inflammation, and activated fibrotic pathways in the lungs, individuals
with CF develop bronchiectasis, pulmonary fibrosis, mixed obstructive/restrictive lung disease, and, eventually, respiratory failure.
They may also have chronic sinusitis and nasal polyps. The same pathophysiologic events of obstruction, infection, chronic inflammation,
and tissue damage/fibrosis occur in the gastrointestinal system, which can lead to bowel obstructions, fat malabsorption, bacterial
overgrowth, gut dysmotility, malnutrition, growth retardation, low weight, pancreatic insufficiency, cystic fibrosis-related diabetes,
gallstones, and liver failure including cirrhosis. Adult males with cystic fibrosis have degeneration of the ductus deferens and
sterility. End-stage organ involvement in cystic fibrosis is sometimes treated with transplantation, especially lung transplantation.
Current
therapies for cystic fibrosis include mucolytics to breakdown mucus, antibiotics to fight bacterial infection, and drugs that
act to restore some functionality to the faulty CFTR protein in patients, including Kalydeco® Orkambi®, Symdeco® and
Trikafta®. Drugs that are designed to partially restore ion channel functions of mutant CFTR protein are not necessarily able
to correct the dysfunction of the innate immune system. For example, ivacaftor treatment has not been associated with reduction
in sputum neutrophils or neutrophil derived proteases in CF patients.
All
CF patients appear to have dysfunction in resolution of the innate immune system, no matter which CFTR mutations a given patient
has. This is borne out by the incidence of pulmonary exacerbations which according to the CF registry occur at an event rate of
0.64 times per patient per year. On average, patients spend nearly 18 days hospitalized for pulmonary exacerbations per year.
A pulmonary exacerbation is acute worsening of the patient’s day-to-day signs and symptoms of lung disease and is associated
with worsening of inflammation at the start of the exacerbation. Failure to resolve lung inflammation during a pulmonary exacerbation
is associated with treatment failure, such as need to change antibiotics, prolonged antibiotic therapy, early recurrent of pulmonary
exacerbation, and failure to recover lung function lost during the exacerbation. Pulmonary exacerbations in CF are associated
with reduced survival, lung function, and patient quality of life and increased health-care burden. The annual average pulmonary
exacerbation hospitalization related costs in the U.S. vary from $30,000 for a “mild” exacerbation to as high as $120,000
in patients with severe lung disease. Currently, there are no approved drugs used to address pulmonary exacerbations, a key driver
of morbidity and mortality in cystic fibrosis.
We
believe there is general agreement in the CF community that an effective drug that will reduce hyper-inflammation and help reduce
the rate of pulmonary exacerbations would address a significant unmet medical need in CF, especially a drug that is orally administered,
can be used chronically with other prescribed medications for CF, is not immunosuppressive, and has anti-fibrotic effects.
Current
Treatment Alternatives for Chronic, Serious Diseases Characterized by Chronic Inflammation and Fibrosis
Drugs
currently used to treat chronic serious inflammatory and fibrotic diseases are divided broadly into several groups: non-steroidal
anti-inflammatory drugs (NSAIDS), anti-malarial agents, systemic corticosteroids, and other immunosuppressive agents. The choice
of agent or combination generally depends upon the underlying disease, and physician and patient preferences.
The
potency of NSAIDs in the treatment of chronic, serious diseases, inflammatory and fibrotic diseases is often too limited to control
disease activity, requiring patients to receive additional treatment with anti-malarial drugs, systemic corticosteroids or immunosuppressive
agents. Anti-malarial therapy is used as a baseline treatment for chronic inflammation in certain autoimmune diseases, typically
SLE and DM, especially in patients with milder manifestations of disease. Anti-malarial therapy is frequently ineffective in controlling
chronic, serious inflammation, or can cause adverse drug reactions. Antimalarial-refractory disease is then treated with systemic
therapies that may cause additional toxicity, including systemic corticosteroids and immunosuppressive agents.
Systemic
corticosteroids are commonly prescribed for treatment of chronic, serious diseases characterized by chronic inflammation and fibrosis,
such as cystic fibrosis, SSc, and DM. Chronic corticosteroid use is limited by toxicities that include growth retardation, iatrogenic
Cushings’s Disease, hypertension, high glucose levels/diabetes, obesity, brittle bones/osteoporosis, aseptic necrosis of
bone, immunosuppression/increased infection, glaucoma, depression, and psychosis. Thus, safer yet potent alternatives to steroids
have long been sought.
Multiple
other immunosuppressive drugs are used to treat chronic, serious, inflammatory diseases, to achieve disease control and to curtail
the need for corticosteroids. These include biological agents, such as monoclonal antibodies or fusion proteins, which target
a very specific molecule in a key disease pathway. These drugs have several disadvantages including parental administration and
increased associated incidence of malignancy and infection. Non-biologic immunosuppressive agents that are used to treat chronic,
serious inflammation include methotrexate, mycophenolate, leflunomide, cyclophosphamide, and azathioprine, among others. Intravenous
immunoglobulin is used occasionally to treat refractory chronic, serious inflammatory diseases.
Lenabasum
As a Pro Resolving Drug with a Novel Mechanism of Action Has Safety Advantages versus Anti-Inflammatory Drugs, Steroids and Immunosuppressive
Agents
Corticosteroids
and NSAIDs exert their effect by inhibiting the activation of inflammation. In simple terms, both classes of drugs inhibit inflammation
by “interfering” with the biochemical pathways in the cell that promote and sustain inflammation. For example, NSAIDs
directly inhibit the activity of the COX 1 and COX 2 enzymes that are responsible for generating pro-inflammatory eicosanoids.
A drawback of this approach is that it one arm of the eicosanoid pathway (e.g. COX but not LOX) is inhibited resulting in a build-up
in LOX-derived inflammatory mediators which leads to gastrointestinal and cardiovascular side effects (termed “molecular
shunting”). Lenabasum on the other hand triggers endogenous pathways that resolves inflammation and halts fibrosis without
immunosuppression Therefore lenabasum potentially offers a new and unique mechanism to treat a spectrum of rare, chronic, serious
inflammatory and fibrotic diseases.
Autoimmune
Disorders
Systemic
Sclerosis
Cytotoxic
and immunosuppressive medications are used to control overall disease activity in SSc. In a one-year study of 2,739 SSc patients
in the U.S., 44.3% received corticosteroids, 4.8% received mycophenolate mofetil, 2.7% received cyclophosphamide, and 0.5% received
cyclosporine. In a report of 7,655 patients in the European Scleroderma Trials and Research Group database, the percentage of
SSc patients receiving immunosuppressant treatments were: prednisone (43.5%) with median dose of 8 mg/day; cyclophosphamide (15.9%);
methotrexate (13.7%); azathioprine (6.4%); mycophenolate mofetil (4.2%), d-penicillamine (2.1%), and rituximab (1%).
DM
Current
medications for DM involve both treatments to reduce overall disease activity and specific treatments to control the muscle disease
and the skin disease. The muscle component is treated by administering corticosteroids, typically with an immunosuppressive agent.
The skin component of the disease is treated by avoiding sun exposure and by using sunscreens and photoprotective clothing, as
well as with topical corticosteroids, antimalarial agents such as hydroxychloroquine and immunosuppressive medications such as
methotrexate, azathioprine, mycophenolate mofetil, or intravenous immunoglobulin.
Systemic
Lupus Erythematosus
Similar
to DM, current medications for SLE involve treatments to reduce overall disease activity and specific treatments for a given organ
involvement. Commonly used medications include NSAIDs, topical corticosteroids, antimalarial agents, prednisone, belimumab, and
other immunosuppressive medications such as mycophenolate, methotrexate, azathioprine, and cyclophosphamide.
Cystic
Fibrosis
The
importance of treating inflammation in cystic fibrosis is confirmed in the Cystic Fibrosis Foundation’s Strategic Plan,
2014-2018. While treatment with systemic corticosteroids and ibuprofen are effective in improving the symptoms of cystic fibrosis,
the side effects associated with chronic treatment using these drugs are significant. Specifically, long term usage of oral corticosteroids
in children are associated with glucose intolerance, cataract formation, multiple bone fractures secondary to osteoporosis or
osteopenia, Cushing disease effects, and anorexia nervosa as well as growth retardation. The use of high dose ibuprofen is limited
by the years of treatment it takes to show benefit, a need to monitor levels closely in the patient, and the increased risk of
gastrointestinal bleeding. As a result, these drugs have limited long-term use in cystic fibrosis.
Other
therapies routinely used by cystic fibrosis patients routinely include antibiotics, such as Cayston from Gilead and TOBI from
Novartis, and mucolytics, such as Pulmozyme from Genentech. In addition, Vertex currently markets the only approved drugs that
specifically target the defective CFTR protein; Kalydeco, Orkambi Symdeko and Tricafta.
Competition
For
autoimmune disorders such as SSc, DM and SLE, physicians treat patients with a number of drugs including potent immunosuppressants
and cytotoxics to try to reduce the autoimmune response characteristic of the disease. These drugs have not proven to be very
effective, thus there remains a high unmet need for safe and effective drugs to treat these autoimmune disorders. Several companies,
including Boehringer Ingelheim, Galapagos, GlaxoSmithkline, Bristol Myers, Sanofi, Kadmon Holdings and Emerald Health, are actively
working to develop new drugs for treating the inflammation and/or fibrosis in SSc. To the best of our knowledge, lenabasum offers
a unique mode of action to treat SSc being one of the few oral drugs with the potential to resolve inflammation and halt fibrosis
without immunosuppression.
There
are numerous drug therapies currently used to treat CF patients, targeting different aspects of this complex disease. Inhaled
and oral antibiotics address the pulmonary microbial infection. Mucolytics address the accumulation of mucus in the lungs. Bronchodilators
and hydration agents are also used to help improve pulmonary function. Targeting of the inflammatory component of the disease
is currently done by high dose Ibuprofen and oral corticosteroids. While these offer some clinical benefit, they are not used
chronically due to their adverse side effects which include immunosuppression and metabolic changes (steroids) as well as the
risk of gastrointestinal bleeding (ibuprofen). Thus, there is a clear and urgent unmet medical need for safe and effective inflammation-targeting
drugs for the chronic treatment of CF that could potentially have a beneficial impact on morbidity and mortality. An emerging
and growing area of CF therapy has been the development and commercialization of correctors and potentiators of CFTR by Vertex
(Kalydeco® Orkambi®, and Tricafta®).
Sales
and Marketing for Lenabasum
We
are developing our marketing, commercial operation, distribution, market access and reimbursement capabilities in anticipation
of potential FDA approval for lenabasum. Our intent is to commercialize lenabasum ourselves in the United States
with a targeted customer-facing organization to call on treating specialists and payers. In Europe we are evaluating potential
partnerships as well as considering the option of commercializing ourselves. In Japan we granted exclusive license rights to Kaken
Pharmaceutical Co., Ltd., or Kaken, for the commercialization of lenabasum for the treatment of SSc and DM. Under the terms
of our agreement with Kaken, Kaken made an upfront payment to us of $27 million and we are eligible to receive up to an additional
$173 million upon achievement of certain regulatory, development and sales milestones as well as double-digit royalties.
Research
and Development
We
incurred expenses of approximately $88,605,000 and $48,614,000 for research and development activities for the years ended
December 31, 2019 and 2018, respectively. These expenses include cash and non-cash expenses relating to the development of our
clinical and pre-clinical programs for lenabasum.
Intellectual
Property
We
have filed patent applications directed to lenabasum, compositions and methods for treating disease using lenabasum. If granted,
the resulting patents would expire on dates ranging from 2031 to 2034, subject to extension under certain circumstances. The patent
application filings are directed to:
|
●
|
Compositions
including an improved ultrapure version of lenabasum and uses of the compositions for the treatment of fibrotic conditions
and inflammatory conditions;
|
|
|
|
|
●
|
The
use of lenabasum in the treatment of fibrotic diseases; and
|
|
|
|
|
●
|
Lenabasum
formulations and uses of the formulations for the treatment of disease.
|
Issued
Patents
On
August 6, 2019, the U.S. Patent and Trademark Office (“USPTO”) issued U.S. Patent No. 10,369,131 to the Company with
claims covering the use of pharmaceutical compositions comprising lenabasum for the treatment of dermatomyositis. The patent provides
exclusivity in the U.S. for this use of lenabasum to February 12, 2034.
On
December 18, 2018, USPTO issued U.S. Patent No. 10,154,986 to the Company with claims covering pharmaceutical compositions of
lenabasum. The patent provides exclusivity in the U.S. for this use of lenabasum compositions to February 12, 2034.
On
October 3, 2018, the USPTO issued U.S. Patent No. 10,085,964 to the Company with claims covering the use of pharmaceutical compositions
comprising lenabasum for the treatment of all fibrotic diseases, including Corbus’ lead indications systemic sclerosis,
dermatomyositis, cystic fibrosis and others. The patent provides exclusivity in the U.S. for this use of lenabasum to February
12, 2034.
On
October 31, 2017, the USPTO issued U.S. Patent No. 9,801,849 to the Company with claims covering the use of pharmaceutical compositions
comprising lenabasum, Corbus’ lead product in development for the treatment of inflammatory diseases. The patent provides
exclusivity in the U.S. for this use of lenabasum to February 12, 2034.
On
November 27, 2017, the USPTO issued U.S. Patent No. 9,820,964 to the Company with claims covering the use of pharmaceutical compositions
comprising lenabasum for the treatment of fibrotic diseases, encompassing the Company’s lead indications: systemic sclerosis,
DM, cystic fibrosis as well as others. The patent provides intellectual property protection in the United States for this use
of lenabasum to February 12, 2034.
On
September 20, 2018, we entered in an exclusive license agreement with Jenrin Discovery, LLC which provides us with an exclusive
worldwide license to develop and market cannabinoid compounds covered by the Jenrin issued patents and patent applications that
cover the composition and method of use of selective cannabinoid receptor modulators. The Jenrin intellectual property portfolio
includes fifteen granted U.S. patents and 23 granted or pending foreign patents and applications. This portfolio includes U.S.
Patent No 9,987,253, which granted with claims covering the cannabinoid receptor blocker CRB-4001 and methods of using the same
for treating obesity, diabetes, inflammatory disorders, cardiometabolic disorders, hepatic disorders, and/or cancers. The licensed
intellectual property portfolio provides intellectual property protection in the United States for CRB-4001 to July of 2033, not
including any potential patent term extension.
Lenabasum
has been granted Orphan Drug Designation for cystic fibrosis, dermatomyositis and systemic sclerosis in the U.S. and in the European
Union. In addition, in systemic sclerosis and in cystic fibrosis, Lenabasum has been granted a Fast Track Designation by the FDA.
We will be seeking orphan drug status for lenabasum in Japan for systemic sclerosis and eventually in DM. Orphan designation for
lenabasum may be pursued for other inflammatory diseases in the U.S. and in Europe. Orphan drug status provides seven years of
market exclusivity in the U.S. and ten years in Europe and Japan beginning on the date of drug approval.
Our
commercial success depends in part on our ability to obtain and maintain patent and other proprietary protection for lenabasum
and to operate without infringing the proprietary right of others and to prevent others from infringing our proprietary rights.
We strive to protect our intellectual property through a combination of patents and trademarks as well as through the confidentiality
provisions in our contracts. With respect to lenabasum, we endeavor to obtain and maintain patent protection in the U.S. and internationally
on all patentable aspects of the drug. We cannot be sure that the patents will be granted with respect to any patent applications
we may own or license in the future, nor can we be sure that any patents issued or licensed to us in the future will be useful
in protecting our technology. For this and more comprehensive risks related to our intellectual property, please see “Risk
Factors—Risks Relating to Our Intellectual Property Rights.”
In
addition to patent protection, we rely on trade secrets and know-how to develop and maintain our competitive position. For example,
aspects of our proprietary technology platform are based on unpatented trade secrets and know-how related to the manufacturing
of lenabasum. Trade secrets and know-how can be difficult to protect. We seek to protect our proprietary technology and processes,
in part, by confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors,
contractors and commercial partners. These agreements are designed to protect our proprietary information and, in the case of
the invention assignment agreements, to grant us ownership of technologies that are developed through a relationship with a third
party. We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security
of our premises and physical and electronic security of our information technology systems. While we have confidence in these
individuals, organizations and systems, agreements or security measures may be breached, and we may not have adequate remedies
for any breach. In addition, our trade secrets may otherwise become known or be independently discovered by competitors. To the
extent that our contractors use intellectual property owned by others in their work for us, disputes may arise as to the rights
in related or resulting know-how and inventions.
We
also plan to seek trademark protection in the U.S. and outside of the U.S. where available and when appropriate. We intend to
use these registered marks in connection with our pharmaceutical research and development as well as our product candidates.
Manufacturing
and Supply for Lenabasum
We
have developed and validated a good manufacturing practice, or GMP, process to manufacture lenabasum active pharmaceutical ingredient
(“API”) and drug product through our contract manufacturers. Our existing API contract manufacturer has produced multi-Kg
scale bulk batches under GMP for our on-going clinical studies and is under agreement to produce sufficient API required prior
to submitting an NDA filing with the FDA. We do not own or operate manufacturing facilities for the production of lenabasum. We
expect to depend on third-party suppliers and manufacturing organizations for all of our clinical trial quantities of raw materials
and drug substance. Lenabasum is a synthetic molecule and there are readily available supplies of all raw materials necessary
for the manufacture of lenabasum.
Regulatory
Matters
Government
Regulation
The
process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes
and regulations require the expenditure of substantial time and financial resources. Failure to comply with the applicable requirements
at any time during the product development process, approval process or after approval, may subject an applicant to administrative
or judicial sanctions. These sanctions could include the US FDA’s refusal to approve pending applications, withdrawal of
an approval, a clinical hold, warning letters, product recalls or withdrawals from the market, product seizures, total or partial
suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement, or
civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us.
Any
product development activities related to lenabasum or products that we may develop or acquire in the future will be subject to
extensive regulation by various government authorities, including the FDA, other federal, state and local agencies and comparable
regulatory authorities in other countries, which regulate the design, research, clinical and non-clinical development, testing,
manufacturing, storage, distribution, import, export, labeling, advertising and marketing of pharmaceutical products and devices.
Generally, before a new drug can be sold, considerable data demonstrating its quality, safety and efficacy must be obtained, organized
into a format specific to each regulatory authority, submitted for review and approved by the regulatory authority. The data are
often generated in two distinct development states: pre-clinical and clinical.
Development
of Drugs in the U.S.
Lenabasum
or other products that we may develop or acquire in the future must be approved by the FDA before they may be legally marketed
in the United States. For new chemical entities, the pre-clinical development stage generally involves synthesizing the active
component, developing the formulation and determining the manufacturing process, as well as carrying out non-human toxicology,
pharmacology and drug metabolism studies that support subsequent clinical testing. These pre-clinical laboratory and animal tests
are often performed under the FDA’s Good Laboratory Practices regulations. A drug’s sponsor must submit the result
of the pre-clinical tests, together with manufacturing information, analytical data and any available clinical data or literature
and a proposed clinical protocol to the FDA as part of an IND application, which is a request for authorization from the FDA to
administer an investigational drug or biological product to humans. Similar filings are required in other countries.
The
clinical stage of development can generally be divided into three sequential phases that may overlap, Phase 1, Phase 2 and Phase
3 clinical trials. In Phase 1, generally, small numbers of healthy volunteers are initially exposed to single escalating doses
and then multiple escalating doses of the product candidate. The primary purpose of these studies is to assess the metabolism,
pharmacologic action and general safety of the drug. Phase 2 trials typically involve studies in disease-affected patients to
determine the dose required to produce the desired benefits, common short-term side effects and risks. Phase 2 studies are typically
well-controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several
hundred subjects. Phase 3 trials are intended to gather the additional information about effectiveness and safety that is needed
to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase 3
studies usually include from several hundred to several thousand subjects and are closely controlled and monitored. In addition
to these Phase 1-3 trials, other trials may be conducted to gather additional safety, pharmacokinetic and pharmacodynamic information.,
Pharmaceutical products with active ingredients equal or similar to those already approved by the FDA often have more streamlined
development programs than compounds entirely new to the agency, often skipping Phase 1 and 2 trials.
A
clinical plan must be submitted to the FDA prior to commencement of a clinical trial. If the FDA has concerns about the clinical
plan or the safety of the proposed studies, they may suspend or terminate the study at any time. Studies must be conducted in
accordance with good clinical practice and reporting of study progress and any adverse experiences is required. Studies are also
subject to review by independent institutional review boards responsible for overseeing studies at particular sites and protecting
human research study subjects. An independent institutional review board may also suspend or terminate a study once initiated.
Accordingly, we cannot be sure that submission of an IND will result in the FDA allowing clinical trials to begin, or that once
begun, issues will not arise that could cause the trial to be suspended or terminated.
Post-approval
studies, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval. Sometimes, these
studies are used to gain additional experience from the treatment of patients in the intended therapeutic condition. In certain
instances, the FDA may mandate the performance of Phase 4 studies. In other situations, post-approval studies aim to gain additional
indications for a medication.
Special
Protocol Assessment
The
Federal Food, Drug, and Cosmetic Act directs the FDA to meet with sponsors, pursuant to a sponsor’s written request, for
the purpose of reaching agreement on the design and size of clinical trials intended to form the primary basis of an efficacy
claim in an NDA. If an agreement is reached, the FDA will reduce the agreement to writing and make it part of the administrative
record. This agreement is called a special protocol assessment, or SPA. While the FDA’s guidance on SPAs states that documented
SPAs should be considered binding on the review division, the FDA has latitude to change its assessment if certain exceptions
apply. Exceptions include public health concerns emerging that were unrecognized at the time of the protocol assessment, identification
of a substantial scientific issue essential to the safety or efficacy testing that later comes to light, a sponsor’s failure
to follow the protocol agreed upon, or the FDA’s reliance on data, assumptions or information that are determined to be
wrong.
Review
and Approval in the U.S.
Following
pivotal or Phase 3 trial completion, data are analyzed to determine safety and efficacy. Data are then filed with the FDA in a
New Drug Application, or an NDA, along with proposed labeling for the product and information about the manufacturing and testing
processes and facilities that will be used to ensure product quality. In the United States, FDA approval of an NDA must be obtained
before marketing a pharmaceutical product. The NDA must contain proof of safety, purity, potency and efficacy, which entails extensive
pre-clinical and clinical testing.
The
FDA will likely re-analyze the clinical trial data, which could result in extensive discussions between the FDA and us during
the review process. The review and evaluation of applications by the FDA is extensive and time consuming and may take several
years to complete. The FDA may conduct a pre-approval inspection of the manufacturing facilities for the new product to determine
whether they comply with current good manufacturing practice requirements and may also audit data from clinical and pre-clinical
trials.
There
is no assurance that the FDA will act favorably or quickly in making such reviews and significant difficulties or costs may be
encountered in our efforts to obtain FDA approvals. The FDA may require that certain contraindications, warnings or precautions
be including in the product labeling, or may condition the approval of the NDA on other changes to the proposed labeling, development
of adequate controls and specifications, or a commitment to conduct post-marketing testing or clinical trials and surveillance
programs to monitor the safety of approved products that have been commercialized. Further, the FDA may place conditions on approvals
including the requirement for a risk evaluation and mitigation strategy, or REMS, to assure the safe use of the drug. If the FDA
concludes a REMS is needed, the sponsor of the NDA must submit a proposed REMS; the FDA will not approve the NDA without an approved
REMS, if required. A REMS could include medication guides, physician communication plans, or elements to assure safe use, such
as restricted distribution methods, patient registries and other risk minimization tools. Any of these limitations on approval
or marketing could restrict the commercial promotion, distribution, prescription or dispensing of products. Product approvals
may be withdrawn for non-compliance with regulatory standards or if problems occur.
Orphan
Drug Designation
Under
the Orphan Drug Act, the FDA may grant orphan drug designation to a drug intended to treat a rare disease or condition, which
is generally a disease or condition that affects fewer than 200,000 individuals in the United States. Orphan product designation
must be requested before submitting an NDA. After the FDA grants orphan drug designation, the identity of the therapeutic agent
and its potential orphan use are disclosed publicly by the FDA. Orphan product designation does not convey any advantage in or
shorten the duration of regulatory review and approval process. In addition to the potential period of exclusivity, orphan designation
makes a company eligible for grant funding of up to $500,000 per year for four years to defray costs of clinical trial expenses,
tax credits for clinical research expenses and potential exemption from the FDA application user fee.
If
a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has
such designation, the product is entitled to orphan drug exclusivity, which means the FDA may not approve any other applications
to market the same drug for the same indication for seven years, except in limited circumstances, such as (i) the drug’s
orphan designation is revoked; (ii) its marketing approval is withdrawn; (iii) the orphan exclusivity holder consents to the approval
of another applicant’s product; (iv) the orphan exclusivity holder is unable to assure the availability of a sufficient
quantity of drug; or (v) a showing of clinical superiority to the product with orphan exclusivity by a competitor product. If
a drug designated as an orphan product receives marketing approval for an indication broader than what is designated, it may not
be entitled to orphan drug exclusivity. We have received orphan drug designation for lenabasum for cystic fibrosis and systemic
sclerosis. There can be no assurance that we will receive orphan drug designation for lenabasum for DM, or additional orphan diseases.
Drug
Development in Europe
In
the European Union, our future products may also be subject to extensive regulatory requirements. Similar to the U.S., the marketing
of medicinal products is subject to the granting of marketing authorizations by regulatory agencies. Also, as in the U.S., the
various phases of pre-clinical and clinical research in the European Union are subject to significant regulatory controls.
Review
and Approval in the European Union
In
the European Union, approval of new medicinal products can be obtained through one of three processes: the mutual recognition
procedure, the centralized procedure and the decentralized procedure. We intend to determine which process we will follow, if
any, in the future.
Mutual
Recognition Procedure: An applicant submits an application in one European Union member state, known as the reference member state.
Once the reference member state has granted the marketing authorization, the applicant may choose to submit applications in other
concerned member states, requesting them to mutually recognize the marketing authorizations already granted. Under this mutual
recognition process, authorities in other concerned member states have 55 days to raise objections, which must then be resolved
by discussion among the concerned member states, the reference member state and the applicant within 90 days of the commencement
of the mutual recognition procedure. If any disagreement remains, all considerations by authorities in the concerned member states
are suspended and the disagreement is resolved through an arbitration process. The mutual recognition procedure results in separate
national marketing authorizations in the reference member state.
Centralized
Procedure: This procedure is currently mandatory for products developed by means of a biotechnological process and optional for
new active substances and other “innovative medicinal products with novel characteristics.” Under this procedure,
an application is submitted to the European Agency for the Evaluation of Medical Products. Two European Union member states are
appointed to conduct an initial evaluation of each application. These countries each prepare an assessment report that is then
used as the basis of a scientific opinion of the Committee on Proprietary Medical Products. If this opinion is favorable, it is
sent to the European Commission, which drafts a decision. After consulting with the member states, the European Commission adopts
a decision and grants a marketing authorization, which is valid throughout the European Union and confers the same rights and
obligations in each of the member states as a marketing authorization granted by that member state.
Decentralized
Procedure: The most recently introduced of the three processes for obtaining approval of new medicinal processes in the European
Union, the decentralized procedure is similar to the mutual recognition procedure described above, but with differences in the
timing that key documents are provided to concerned member states by the reference member state, the overall timing of the procedure
and the possibility of, among other things, “clock stops” during the procedure.
Post-Marketing
Requirements
Following
approval of a new product, a pharmaceutical company and the approved product are subject to continuing regulation by the FDA and
other federal and state regulatory authorities, including, among other things, monitoring and recordkeeping activities, reporting
to applicable regulatory authorities of adverse experiences with the product, providing the regulatory authorities with updated
safety and efficacy information, product sampling and distribution requirements, and complying with promotion and advertising
requirements, which include, among others, standards for direct-to-consumer advertising, restrictions on promoting drugs for uses
or in patient populations not described in the drug’s approved labeling (known as “off-label use”), and limitations
on industry-sponsored scientific and educational activities. Although physicians may prescribe legally available drugs for off-label
uses, manufacturers may not market or promote such off-label uses. Modifications or enhancements to the products or labeling or
changes of site of manufacture are often subject to the approval of the FDA and other regulators, which may or may not be received
or may result in a lengthy review process. The FDA regulations require the products be manufactured in specific approved facilities
and in accordance with current good manufacturing practices, and NDA holders must list their products and register their manufacturing
establishments with the FDA. These regulations also impose certain organizational, procedural and documentation requirements with
respect to manufacturing and quality assurance activities. Drug manufacturers and other entities involved in the manufacture and
distribution of approved drugs are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance
with current good manufacturing practice and other laws. NDA holders using contract manufacturers, laboratories or packagers are
responsible for the selection and monitoring of qualified firms. These firms are subject to inspections by the FDA at any time,
and the discovery of violative conditions could result in enforcement actions that interrupt the operation of any such facilities
or the ability to distribute products manufactured, processed or tested by them.
Other
Regulatory Matters
Manufacturing,
sales, promotion and other activities following product approval are also subject to regulation by numerous regulatory authorities
in addition to the FDA, including, in the United States, the Centers for Medicare & Medicaid Services, or CMS, other divisions
of the Department of Health and Human Services, the Drug Enforcement Administration, the Consumer Product Safety Commission, the
Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency, and state
and local governments. These regulations include:
●
the federal healthcare program anti-kickback law which prohibits, among other things, persons from soliciting, receiving or providing
remuneration, directly or indirectly, to induce either the referral of an individual, for an item or service or the purchasing
or ordering of a good or service, for which payment may be made under federal healthcare programs such as the Medicare and Medicaid
programs;
●
federal false claims laws which prohibit, among other things, individuals or entities from knowingly presenting, or causing to
be presented, claims for payment from Medicare, Medicaid, or other government reimbursement programs that are false or fraudulent.
The government may assert that a claim including items or services resulting from a violation of the federal healthcare program
anti-kickback law or related to off-label promotion constitutes a false or fraudulent claim for purposes of the federal false
claims laws;
●
the Federal Physician Payments Sunshine Act within the ACA, and its implementing regulations, require that certain manufacturers
of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid or the Children’s
Health Insurance Program (with certain exceptions) to report information related to certain payments or other transfers of value
made or distributed to physicians and teaching hospitals, or to entities or individuals at the request of, or designated on behalf
of, the physicians and teaching hospitals and to report annually certain ownership and investment interests held by physicians
and their immediate family members; and
●
the Health Insurance Portability and Accountability Act, or HIPAA, as amended by the Health Information Technology for Economic
and Clinical Health Act, or HITECH, and its implementing regulations, imposes certain requirements relating to the privacy, security
and transmission of individually identifiable health information. Among other things, HITECH makes HIPAA’s privacy and security
standards directly applicable to “business associates”—independent contractors or agents of covered entities
that receive or obtain protected health information in connection with providing a service on behalf of a covered entity. HITECH
also created four new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable
to business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages
or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing
federal civil actions.
●
applicable child-resistant packaging requirements under the U.S. Poison Prevention Packaging Act.
●
The Lanham Act and federal antitrust laws.
●
state law equivalents of each of the above federal laws, such as anti-kickback and false claims laws, which may apply to items
or services reimbursed by any third party payer, including commercial insurers, and state laws governing the privacy and security
of health information in certain circumstances, many of which differ from each other in significant ways and often are not preempted
by federal laws, thus complicating compliance efforts.
Distribution
of pharmaceutical products is subject to additional requirements and regulations, including extensive record-keeping, licensing,
traceability, and storage and security requirements intended to prevent the unauthorized sale of pharmaceutical products
The
handling of any controlled substances must comply with the U.S. Controlled Substances Act and the Controlled Substances Import
and Export Act. In the U.S., our product candidate, lenabasum, is currently classified as Schedule I controlled substance as defined
in the Controlled Substance Act (“CSA”). This designation is based on lenabasum’s chemical structure and pharmacology
(namely, it being a synthetic endocannabinoid mimetic that binds to the CB2 receptor). Even though lenabasum’s mechanism
of action is to modulate the immune system and results to date from clinical studies have demonstrated the drug has no psychotropic
effects (which we believe is unlike other members of its chemical class), the DEA classifies lenabasum as a Schedule I substance.
Schedule
I controlled substances are pharmaceutical products subject to specific regulations under the CSA, that establishes, among other
things, certain registration, manufacturing quotas, security, recordkeeping, reporting, import, export and other requirements
administered by the DEA. All parties responsible for the manufacturing, distribution and testing the drug in clinical studies
must apply for and obtain a license from the DEA before they are permitted to perform these activities with lenabasum. Furthermore,
these parties must have the security, control, recordkeeping, reporting and inventory mechanisms required by the DEA to prevent
drug loss and diversion. All licensed facilities are required to renew their registrations annually if they intend to continue
to work with our drug. The DEA conducts periodic inspections of certain registered establishments that handle controlled substances.
We have been working with our manufacturers, distributors, exporters and clinical sites to obtain the necessary licenses to work
with lenabasum. The parties responsible for the manufacturing, distribution and export of lenabasum have already applied for and
have been granted DEA licenses and a number of institutions responsible for conducting our current clinical studies have also
been granted DEA licenses.
Individual
states have also established controlled substance laws and regulations. Though state-controlled substances laws often mirror federal
law, because the states are separate jurisdictions, they may separately schedule drugs, as well. While some states automatically
schedule a drug based on federal action, other states schedule drugs through rulemaking or a legislative action. The requirement
for state registrations could also result in delay of the manufacturing, distribution of lenabasum or in the completion of our
current clinical studies. We and our manufacturing vendors and clinical sites must also obtain separate state registrations, permits
or licenses in order to be able to obtain, handle, and distribute controlled substances for clinical trials or commercial sale,
and failure to meet applicable regulatory requirements could lead to enforcement and sanctions by the states in addition to those
from the DEA or otherwise arising under federal law.
Third-Party
Payer Coverage and Reimbursement
Significant
uncertainty exists as to the coverage and reimbursement status of any of our drug candidates that ultimately may obtain regulatory
approval. In both the United States and foreign markets, our ability to commercialize our product candidates successfully, and
to attract commercialization partners for our product candidates, depends in significant part on the availability of adequate
financial coverage and reimbursement from third-party payers, including, in the United States, governmental payers such as the
Medicare and Medicaid programs, managed care organizations, and private health insurers. Medicare is a federally funded program
managed by the CMS, through local fiscal intermediaries and carriers that administer coverage and reimbursement for certain healthcare
items and services furnished to the elderly and disabled. Medicaid is an insurance program for certain categories of patients
whose income and assets fall below state defined levels and who are otherwise uninsured that is both federally and state funded
and managed by each state. The federal government sets general guidelines for Medicaid and each state creates specific regulations
that govern its individual program. Each payer has its own process and standards for determining whether it will cover and reimburse
a procedure or particular product. Private payers often rely on the lead of the governmental payers in rendering coverage and
reimbursement determinations. Therefore, achieving favorable CMS coverage and reimbursement is usually a significant gating issue
for successful introduction of a new product. The competitive position of some of our products will depend, in part, upon the
extent of coverage and adequate reimbursement for such products and for the procedures in which such products are used. Prices
at which we or our customers seek reimbursement for our product candidates can be subject to challenge, reduction or denial by
the government and other payers.
The
United States Congress and state legislatures may, from time to time, propose and adopt initiatives aimed at cost containment,
which could impact our ability to sell our product candidates profitably. For example, the two-year spending law signed by the
President of United States on February 9, 2018 includes a provision raising the manufacturer discount to 70% in 2019 in the Medicare
Part D coverage gap, also known as the “donut hole.” Under prior law, manufacturers were required to provide a 50%
discount on prescription drugs purchased in the donut hole. Manufacturers of branded drugs will face much higher liabilities from
donut hole payments beginning in 2019, estimated at multiple billions of dollars for some of the largest companies.
The
cost of pharmaceuticals continues to generate substantial governmental and third-party payer interest. We expect that the pharmaceutical
industry will experience pricing pressures due to the trend toward managed healthcare, the increasing influence of managed care
organizations and additional legislative proposals. Our results of operations could be adversely affected by current and future
healthcare reforms.
Some
third-party payers also require pre-approval of coverage for new or innovative devices or drug therapies before they will reimburse
healthcare providers that use such therapies. While we cannot predict whether any proposed cost-containment measures will be adopted
or otherwise implemented in the future, the announcement or adoption of these proposals could have a material adverse effect on
our ability to obtain adequate prices for our product candidates and operate profitably.
In
addition, in some foreign countries, the proposed pricing for a drug must be approved before it may be lawfully marketed. The
requirements governing drug pricing vary widely from country to country. For example, the European Union provides options for
its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement
and to control the prices of medicinal products for human use. A member state may approve a specific price for the medicinal product
or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product
on the market. There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical
products will allow favorable reimbursement and pricing arrangements for any of our products. Historically, products launched
in the European Union do not follow price structures of the United States and generally tend to be significantly lower.
Employees
We
had 141 full-time employees at December 31, 2019. All of our employees are engaged in administration, finance, clinical, manufacturing,
regulatory and business development functions. We believe our relations with our employees are good. We anticipate that the number
of employees will grow as we continue to develop our product candidates. In addition, we utilize and will continue to utilize
consultants, clinical research organizations and third parties to perform our pre-clinical studies, clinical studies, manufacturing
and regulatory functions.
Corporate
Information
Corbus
Pharmaceuticals, Inc. (formerly known as JB Therapeutics Inc.), was incorporated on April 24, 2009 under the laws of the State
of Delaware. On April 11, 2014, JB Therapeutics, Inc. completed a merger with Corbus Pharmaceuticals Holdings, Inc. and changed
its name to Corbus Pharmaceuticals, Inc. Upon the consummation of the merger, Corbus Pharmaceuticals, Inc. became a wholly owned
subsidiary of Corbus Pharmaceuticals Holdings, Inc. which continues to operate the business of Corbus Pharmaceuticals, Inc. Our
principal executive offices are located at 500 River Ridge Drive, Norwood, Massachusetts 02062, and our telephone number is (619)
963-0100. Our website address is www.corbuspharma.com.
We
make available free of charge on or through the Investor Relations link on our website, www.corbuspharma.com, access to
press releases and investor presentations, as well as all materials that we file electronically with the SEC, including our annual
report on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports, filed or furnished
pursuant to Section 13(a) or 15(d) of the Exchange Act as soon as reasonably practicable after electronically filing such materials
with, or furnishing them to, the SEC. During the period covered by this Form 10-K, we made all such materials available through
our website as soon as reasonably practicable after filing such materials with the SEC. In addition, the SEC maintains an Internet
website, www.sec.gov, that contains reports, proxy and information statements and other information that we file electronically
with the SEC.
This
report and the information incorporated herein by reference contain references to trademarks, service marks and trade names owned
by us or other companies. Solely for convenience, trademarks, service marks and trade names referred to in this report and the
information incorporated herein, including logos, artwork, and other visual displays, may appear without the ® or ™
symbols, but such references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable
law, our rights or the rights of the applicable licensor to these trademarks, service marks and trade names. We do not intend
our use or display of other companies’ trade names, service marks or trademarks to imply a relationship with, or endorsement
or sponsorship of us by, any other companies. Other trademarks, trade names and service marks appearing in this report are the
property of their respective owners.
ITEM
1A. RISK FACTORS
An
investment in our common stock is speculative and illiquid and involves a high degree of risk including the risk of a loss of
your entire investment. You should carefully consider the risks and uncertainties described below and the other information contained
in this report and our other reports filed with the Securities and Exchange Commission. The risks set forth below are not the
only ones facing us. Additional risks and uncertainties may exist that could also adversely affect our business, operations and
financial condition. If any of the following risks actually materialize, our business, financial condition and/or operations could
suffer. In such event, the value of our common stock could decline, and you could lose all or a substantial portion of the money
that you pay for our common stock.
Risk
Related to our Company and our Business
Risks
Related to Our Financial Position and Need for Capital
We
are a clinical stage pharmaceutical company with a limited operating history.
We
are a clinical stage pharmaceutical company with a limited operating history. We must complete clinical studies and receive regulatory
approval of a New Drug Application, or NDA, before commercial sales of a product can commence. The likelihood of success of our
business plan must be considered in light of the problems, substantial expenses, difficulties, complications and delays frequently
encountered in connection with developing and expanding early-stage businesses and the regulatory and competitive environment
in which we operate. Pharmaceutical product development is a highly speculative undertaking, involves a substantial degree of
risk and is a capital-intensive business.
Accordingly,
you 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 pharmaceutical companies such as ours. Potential investors should carefully
consider the risks and uncertainties that a company with a limited operating history will face. In particular, potential investors
should consider that we cannot assure you that we will be able to:
|
●
|
successfully
implement or execute our current business plan, and we cannot assure you that our business plan is sound;
|
|
●
|
successfully
manufacture our clinical products and establish commercial drug supply;
|
|
●
|
obtain
Drug Enforcement Administration, or DEA, licenses necessary for the manufacturing of lenabasum and for evaluating lenabasum
in our clinical trials;
|
|
●
|
successfully
complete the clinical trials necessary to obtain regulatory approval for the marketing of our drug candidates, including lenabasum
and CRB-4001;
|
|
●
|
secure
market exclusivity and/or adequate intellectual property protection for our drug candidates;
|
|
●
|
attract
and retain an experienced management and advisory team;
|
|
●
|
secure
acceptance of our drug candidates in the medical community and with third party payors and consumers;
|
|
●
|
launch
commercial sales of our drug candidates, whether alone or in collaboration with others; and
|
|
●
|
raise
sufficient funds in the capital markets to effectuate our business plan.
|
If
we cannot successfully execute any one of the foregoing, our business may not succeed and your investment will be adversely affected.
We
have incurred operating losses in each year since our inception and expect to continue to incur substantial losses for the foreseeable
future. We may never become profitable or, if we achieve profitability, be able to sustain profitability.
We
expect to incur substantial expenses without corresponding revenues unless and until we are able to obtain regulatory approval
and successfully commercialize any of our drug candidates. To date, we have not generated any revenue from our drug candidates
and we expect to incur significant expense to complete our clinical program for our drug candidates in the United States and elsewhere.
We may never be able to obtain regulatory approval for the marketing of our drug candidates in any indication in the United States
or internationally. Even if we are able to commercialize our drug candidates, there can be no assurance that we will generate
significant revenues or ever achieve profitability. Our net losses for the years ended December 31, 2019 and December 31, 2018
were approximately $71,454,000 and $55,672,000, respectively. As of December 31, 2019, we had an accumulated deficit of approximately
$192.8 million.
If
we were to obtain FDA approval for lenabasum, we would expect that our research and development expenses will continue to increase
as we advance clinical trials for additional indications. We may elect to pursue FDA approval for lenabasum in other indications
and for other drug candidates, which will result in significant additional research and development expenses. As a result, we
expect to continue to incur substantial losses for the foreseeable future, and these losses will increase. We are uncertain when
or if we will be able to achieve or sustain profitability. If we achieve profitability in the future, we may not be able to sustain
profitability in subsequent periods. Failure to become and remain profitable would impair our ability to sustain operations and
adversely affect the price of our common stock and our ability to raise capital.
Our
recurring losses from operations have raised substantial doubt regarding our ability to continue as a going concern.
We have incurred recurring losses since inception and as of December
31, 2019, had an accumulated deficit of approximately $192.8 million. We anticipate operating losses to continue for the foreseeable
future due to, among other things, costs related to research funding, development of our product candidates and preclinical and
clinical programs, strategic alliances and the development of our administrative organization. We expect the cash and cash equivalents
of approximately $31.7 million at December 31, 2019 plus the approximately $43.0 million of net proceeds from the February 2020
Offering and the remaining $7.5 million of proceeds that we expect to receive under the 2018 Award before the end of the fourth
quarter of 2020 to be sufficient to meet our operating and capital requirements into the fourth quarter of 2020, based on planned
expenditures. Our forecast of the period of time through which our current financial resources will be adequate to support our
operations and the costs to support our general and administrative, sales and marketing and research and development activities
are forward-looking statements and involve risks and uncertainties. The consolidated financial statements do not include any adjustments
that might be necessary should we be unable to continue as a going concern.
Our
ability to continue as a going concern is dependent on our ability to raise additional equity or debt capital or spin-off
non-core assets to raise additional cash. Should we be unable to raise sufficient additional capital, we may be required to undertake
cost-cutting measures including delaying or discontinuing certain clinical activities. We will need to raise significant additional
capital to continue to fund the clinical trials for lenabasum and CRB-4001. We may seek to sell common or preferred equity or
convertible debt securities, enter into a credit facility or another form of third-party funding, or seek other debt financing.
The sale of equity and convertible debt securities may result in dilution to our stockholders and certain of those securities
may have rights senior to those of our common stock. If we raise additional funds through the issuance of preferred stock, convertible
debt securities or other debt financing, these securities or other debt could contain covenants that would restrict our operations.
Any other third-party funding arrangement could require us to relinquish valuable rights.
The
source, timing and availability of any future financing will depend principally upon market conditions, and, more specifically,
on the progress of our clinical development programs. Funding may not be available when needed, at all, or on terms acceptable
to us. Lack of necessary funds may require us, among other things, to delay, scale back or eliminate some or all of our planned
clinical trials. These factors among others create a substantial doubt about our ability to continue as a going concern.
Our
cash or cash equivalents will only fund our operations for a limited time and we will need to raise additional capital to support
our development and commercialization efforts.
We
are currently operating at a loss and expect our operating costs will increase significantly as we incur further costs related
to preclinical development and the clinical trials for our drug candidates. As of December 31, 2019, we held cash and cash equivalents
of approximately $31.7 million.
On
January 26, 2018, we entered into the Cystic Fibrosis Program Related Investment Agreement (the “Investment Agreement”)
with the Cystic Fibrosis Foundation (“CFF”), a non-profit drug discovery and development corporation, pursuant to
which we received a development award for up to $25 million in funding (the “2018 CFF Award”) to support a Phase 2b
clinical trial (the “Phase 2b Clinical Trial”) of lenabasum in patients with cystic fibrosis, of which we received
$17.5 million to date. The remainder of the 2018 CFF Award is payable to us incrementally upon the achievement of the remaining
milestones related to the progress of the Phase 2b Clinical Trial, as set forth in the Investment Agreement and we expect to
receive the remainder before the end of the fourth quarter of 2020.
On
January 3, 2019, we entered into a strategic collaboration with Kaken Pharmaceutical Co., Ltd. (“Kaken”) for the development
and commercialization in Japan of lenabasum for the treatment of SSc and DM. Under the terms of the agreement, Kaken receives
an exclusive license to commercialize and market lenabasum in Japan for SSc and DM. Kaken made an upfront payment to us of $27
million. We are eligible to receive in addition up to $173 million upon achievement of certain regulatory, development and sales
milestones as well as double-digit royalties.
On
January 30, 2019, we consummated an underwritten public offering of shares of our common stock pursuant to which we sold an aggregate
of 6,198,500 shares of its common stock at a purchase price of $6.50 per share with gross proceeds to us totaling $40,290,250,
less estimated issuance costs incurred of approximately $2,572,000 (“January 2019 Offering”). On February 11, 2020,
we consummated an underwritten public offering of shares of our common stock pursuant to which we sold an aggregate of 7,666,667
shares of our common stock at a purchase price of $6.00 per share with gross proceeds to us totaling $46,000,000, less estimated
issuance costs incurred of approximately $3,010,000 (“February 2020 2019 Offering”).
We
expect the cash and cash equivalents of approximately $31.7 million at December 31, 2019 plus the approximately $43.0 million
of net proceeds from the February 2020 Offering and the remaining $7.5 million of proceeds that we expect to receive under the
2018 Award before the end of the fourth quarter of 2020, to be sufficient to meet our operating and capital requirements
into the fourth quarter of 2020, based on planned expenditures.
Other
than the Investment Agreement, we do not currently have any arrangements or credit facilities in place as a source of funds, and
there can be no assurance that we will be able to raise sufficient additional capital on acceptable terms, or at all, including
pursuant to the Investment Agreement due to the dependency of our receiving future payments thereunder on our achieving certain
milestones described therein. If we are not successful in raising additional capital, we may not be able to continue as a going
concern. We may seek additional capital through a combination of private and public equity offerings, debt financings and strategic
collaborations. Debt financing, if obtained, may involve agreements that include covenants limiting or restricting our ability
to take specific actions, such as incurring additional debt, and could increase our expenses and require that our assets secure
such debt.
Equity
financing, if obtained, could result in dilution to our then existing stockholders and/or require such stockholders to waive certain
rights and preferences. If such financing is not available on satisfactory terms, or is not available at all, we may be required
to delay, scale back or eliminate the development of business opportunities and our operations and financial condition may be
materially adversely affected. We can provide no assurances that any additional sources of financing will be available to us on
favorable terms, if at all. In addition, if we are unable to secure sufficient capital to fund our operations, we may choose to
pursue, as an alternative, strategic collaborations that could require us to share commercial rights to our drug candidates with
third parties in ways that we currently do not intend or on terms that may not be favorable to us. If we choose to pursue additional
indications and/or geographies for our drug candidates or otherwise expand more rapidly than we presently anticipate we may also
need to raise additional capital sooner than expected.
Risks
Related to Product Development, Regulatory Approval, Manufacturing and Commercialization
We
depend heavily on the success of lenabasum. If we are unable to generate revenues from lenabasum, our ability to create stockholder
value will be limited.
Our
most advanced product candidate currently is lenabasum, for which we have completed Phase 1 safety studies and Phase 2 clinical
studies and which we are evaluating in subsequent clinical studies. We do not generate revenues from any FDA approved drug products
and have no other product candidates in development other than CRB-4001 and the other compounds we licensed from Jenrin, which
are in the early stages of development. There is no guarantee that our clinical trials will be successful or that we will continue
with clinical studies to support an approval from the FDA of any of our product candidates for any indication. We note that most
drug candidates never reach the clinical development stage and even those that do have only a small chance of successfully completing
clinical development and gaining regulatory approval. Therefore, our business currently depends heavily on the successful development,
regulatory approval and commercialization of lenabasum, which may never occur.
Outbreaks of communicable diseases,
including the coronavirus COVID-19, may materially and adversely affect our business, financial condition and results of operations.
We face risks related to health
epidemics or outbreaks of communicable diseases, for example, the recent outbreak around the world, including in China and Italy,
of the highly transmissible and pathogenic coronavirus COVID-19. The outbreak of such communicable diseases could result in a
widespread health crisis that could adversely affect general commercial activity and the economies and financial markets of many
countries.
Since some of our business
partners and manufacturing operations are in China and Italy, including manufacturing for our commercial and clinical active pharmaceutical
ingredient, the continued impact resulting from the COVID-19 outbreak in these areas or in other areas where we have operations,
or the perception that such an outbreak could occur, and the measures taken by the governments of countries affected could adversely
affect our business, financial condition or results of operations. For example, an outbreak could significantly disrupt our business
and our ability to complete our clinical trials by limiting our ability to travel or ship materials within or outside China or
Italy or forcing temporary closure of facilities that we rely upon.
We face risks related to health epidemics
and outbreaks, including the COVID-19 coronavirus, which could significantly disrupt our preclinical studies and clinical trials,
and therefore our receipt of necessary regulatory approvals could be delayed or prevented.
In December 2019, a novel strain
of coronavirus COVID-19 was reported to have surfaced in Wuhan, China. The extent to which COVID-19 may impact our preclinical
and clinical trial operations will depend on future developments, which are highly uncertain and cannot be predicted with confidence,
such as the duration and geographic reach of the outbreak, the severity of COVID-19, and the effectiveness of actions to contain
and treat COVID-19. We are currently conducting our clinical trials in multiple countries, including South Korea and Italy, and
enrollment in certain of our trials, including our Phase 3 DETERMINE study, is ongoing. The continued spread of COVID-19 globally
could adversely impact our clinical trial operations, including our ability to recruit and retain patients and principal investigators
and site staff who, as healthcare providers, may have heightened exposure to COVID-19 if an outbreak occurs in their geography.
Disruptions or restrictions on our ability to travel to monitor data from our clinical trials, or to conduct clinical trials,
or the ability of patients enrolled in our studies to travel, or the ability of staff at study sites to travel, as well as temporary
closures of our facilities or the facilities of our clinical trials partners and their contract manufacturers, would negatively
impact our clinical trial activities. In addition, we rely on independent clinical investigators, contract research organizations
and other third-party service providers to assist us in managing, monitoring and otherwise carrying out our preclinical studies
and clinical trials, including the collection of data from our clinical trials, and the outbreak may affect their ability to devote
sufficient time and resources to our programs or to travel to sites to perform work for us. Similarly, our preclinical trials
could be delayed and/or disrupted by the outbreak. As a result, the expected timeline for data readouts of our preclinical studies
and clinical trials and certain regulatory filings may be negatively impacted, which would adversely affect our ability to obtain
regulatory approval for and to commercialize our product candidates, increase our operating expenses and have a material adverse
effect on our financial results.
If
we are not able to obtain any required regulatory approvals for our drug candidates, we will not be able to commercialize our
product candidates and our ability to generate revenue will be limited.
Our
clinical trials may be unsuccessful, which would materially harm our business. Even if our ongoing clinical trials are successful,
we will be required to conduct additional clinical trials to establish the safety and efficacy of our drug candidates, before
a New Drug Application, or NDA, can be filed with the FDA for marketing approval of any of our drug candidates.
Clinical
testing is expensive, is difficult to design and implement, can take many years to complete and is uncertain as to outcome. Success
in early phases of pre-clinical and clinical trials does not ensure that later clinical trials will be successful, and interim
results of a clinical trial do not necessarily predict final results. A failure of one or more of our clinical trials can occur
at any stage of testing. We may experience numerous unforeseen events during, or as a result of, the clinical trial process that
could delay or prevent our ability to receive regulatory approval or commercialize our drug candidates. The research, testing,
manufacturing, labeling, packaging, storage, approval, sale, marketing, advertising and promotion, pricing, export, import and
distribution of drug products are subject to extensive regulation by the FDA and other regulatory authorities in the United States
and other countries, which regulations differ from country to country. We are not permitted to market any of our drug candidates
as prescription pharmaceutical products in the United States until we receive approval of an NDA from the FDA or in foreign markets
until we receive the requisite approval from comparable regulatory authorities in such countries. In the United States, the FDA
generally requires the completion of clinical trials of each drug to establish its safety and efficacy and extensive pharmaceutical
development to ensure its quality before an NDA is approved. Regulatory authorities in other jurisdictions impose similar requirements.
Of the large number of drugs in development, only a small percentage result in the submission of an NDA to the FDA and even fewer
are eventually approved for commercialization. We have never submitted an NDA to the FDA or any comparable applications to other
regulatory authorities. If our development efforts for our drug candidates, including regulatory approval, are not successful
for our planned indications, or if adequate demand for our drug candidates is not generated, our business will be harmed.
Receipt
of necessary regulatory approval is subject to a number of risks, including the following:
|
■
|
the
FDA or comparable foreign regulatory authorities or institutional review boards, or IRBs, may disagree with the design or
implementation of our clinical trials;
|
|
|
|
|
■
|
we
may not be able to provide acceptable evidence of the safety and efficacy of our drug candidates;
|
|
|
|
|
■
|
the
results of our clinical trials may not be satisfactory or may not meet the level of statistical or clinical significance required
by the FDA, the European Medicines Agency, or EMA, or other comparable foreign regulatory authorities for marketing approval;
|
|
|
|
|
■
|
the
dosing of our drug candidates in a particular clinical trial may not be at an optimal level;
|
|
|
|
|
■
|
patients
in our clinical trials may suffer adverse effects for reasons that may or may not be related to our drug candidates;
|
|
|
|
|
■
|
the
data collected from clinical trials may not be sufficient to support the submission of an NDA or other submission or to obtain
regulatory approval in the United States or elsewhere;
|
|
|
|
|
■
|
the
FDA or comparable foreign regulatory authorities may fail to approve the manufacturing processes or facilities of third-party
manufacturers with which we contract for clinical and commercial supplies;
|
|
|
|
|
■
|
the
approval policies or regulations of the FDA or comparable foreign regulatory authorities may significantly change in a manner
rendering our clinical data insufficient for approval; and
|
|
|
|
|
■
|
the
FDA or comparable foreign regulatory authorities may decide that the clinical trial endpoints we have chosen such as ACR CRSS
score at week 52, the statistical analysis plans that we use, or any other parameter that we rely on to show the safety and
efficacy of our drugs, are not parameters that can be used to support approval of our products.
|
Failure
to obtain regulatory approval for any of our drug candidates for the foregoing or any other reasons will prevent us from commercializing
such product candidate as a prescription product, and our ability to generate revenue will be materially impaired. We cannot guarantee
that regulators will agree with the endpoints that we have chosen to use in our clinical trials, our assessment of the results
of our clinical trials or that such trials will be considered by regulators to have shown safety or efficacy of our product candidates.
The FDA, EMA and other regulators have substantial discretion in the approval process and may refuse to accept any application
or may decide that our data is insufficient for approval and require additional clinical trials, or pre-clinical or other studies.
In addition, varying interpretations of the data obtained from pre-clinical and clinical testing could delay, limit or prevent
regulatory approval of a product candidate.
We
have only limited experience in filing the applications necessary to gain regulatory approvals and expect to rely on consultants
and third party contract research organizations, or CROs, with expertise in this area to assist us in this process. Securing FDA
approval requires the submission of pre-clinical, clinical and/or pharmacokinetic data, information about product manufacturing
processes and inspection of facilities and supporting information to the FDA for each therapeutic indication to establish a product
candidate’s safety and efficacy for each indication. Our drug candidates may prove to have undesirable or unintended side
effects, toxicities or other characteristics that may preclude our obtaining regulatory approval or prevent or limit commercial
use with respect to one or all intended indications.
The
process of obtaining regulatory approvals is expensive, often takes many years, if approval is obtained at all, and can vary substantially
based upon, among other things, the type, complexity and novelty of the product candidates involved, the jurisdiction in which
regulatory approval is sought and the substantial discretion of regulatory authorities. Changes in the regulatory approval policy
during the development period, changes in or the enactment of additional statutes or regulations, or changes in regulatory review
for a submitted product application may cause delays in the approval or rejection of an application. Regulatory approval obtained
in one jurisdiction does not necessarily mean that a product candidate will receive regulatory approval in all jurisdictions in
which we may seek approval, but the failure to obtain approval in one jurisdiction may negatively impact our ability to seek approval
in a different jurisdiction. Failure to obtain regulatory marketing approval for any of our drug candidates in any indication
will prevent us from commercializing such product candidates, and our ability to generate revenue will be materially impaired.
Clinical
drug development involves a lengthy and expensive process with an uncertain outcome, and results of earlier studies and trials
may not be predictive of future trial results.
Clinical
testing is expensive and can take many years to complete, and its outcome is inherently uncertain. Failure can occur at any time
during the clinical trial process. The results of pre-clinical studies and early clinical trials may not be predictive of the
results of later-stage clinical trials. We cannot assure you that the FDA will view the results as we do or that any future trials
of our drug candidates will achieve positive results. Product candidates in later stages of clinical trials may fail to show the
desired safety and efficacy traits despite having progressed through pre-clinical studies and initial clinical trials. A number
of companies in the pharmaceutical industry have suffered significant setbacks in advanced clinical trials due to lack of efficacy
or adverse safety profiles, notwithstanding promising results in earlier trials. Any future clinical trial results for our drug
candidates may not be successful.
In
addition, a number of factors could contribute to a lack of favorable safety and efficacy results for our drug candidates. For
example, such trials could result in increased variability due to varying site characteristics, such as local standards of care,
differences in evaluation period and surgical technique, and due to varying patient characteristics, including demographic factors
and health status.
Even
if we receive regulatory approval for our drug candidates, we still may not be able to successfully commercialize any of our products,
and the revenue that we generate from sales, if any, may be limited.
If
approved for marketing, the commercial success of our drug candidates will depend upon their acceptance by the medical community,
including physicians, patients and health care payors. The degree of market acceptance of our drug candidates will depend on a
number of factors, including:
|
■
|
demonstration
of clinical safety and efficacy;
|
|
|
|
|
■
|
relative
convenience, pill burden and ease of administration;
|
|
|
|
|
■
|
the
prevalence and severity of any adverse effects;
|
|
|
|
|
■
|
the
willingness of physicians to prescribe our drug candidates and of the target patient population to try new therapies;
|
|
|
|
|
■
|
safety,
tolerability and efficacy of our drug candidates compared to competing products;
|
|
|
|
|
■
|
the
introduction of any new products that may in the future become available to treat indications for which our drug candidates
may be approved;
|
|
|
|
|
■
|
new
procedures or methods of treatment that may reduce the incidences of any of the indications
in which our drug candidates may show utility;
|
|
|
|
|
■
|
pricing
and cost-effectiveness;
|
|
|
|
|
■
|
the
inclusion or omission of our drug candidates in applicable treatment guidelines;
|
|
■
|
the
effectiveness of our or any future collaborators’ sales and marketing strategies;
|
|
|
|
|
■
|
limitations
or warnings contained in FDA-approved labeling;
|
|
|
|
|
■
|
our
ability to obtain and maintain sufficient third-party coverage or reimbursement from government health care programs, including
Medicare and Medicaid, private health insurers and other third-party payors; and
|
|
|
|
|
■
|
the
willingness of patients to pay out-of-pocket in the absence of third-party coverage or reimbursement.
|
If
any of our drug candidates are approved, but do not achieve an adequate level of acceptance by physicians, health care payors
and patients, we may not generate sufficient revenue and we may not be able to achieve or sustain profitability. Our efforts to
educate the medical community and third-party payors on the benefits of our drug candidates may require significant resources
and may never be successful.
In
addition, even if we obtain regulatory approvals, the timing or scope of any approvals may prohibit or reduce our ability to commercialize
our drug candidates successfully. For example, if the approval process takes too long, we may miss market opportunities and give
other companies the ability to develop competing products or establish market dominance. Any regulatory approval we ultimately
obtain may be limited or subject to restrictions or post-approval commitments that render our drug candidates not commercially
viable. For example, regulatory authorities may approve our drug candidates for fewer or more limited indications than we request,
may not approve the prices we intend to charge for our drug candidates, may grant approval contingent on the performance of costly
post-marketing clinical trials, or may approve our drug candidates with labels that do not include the labeling claims necessary
or desirable for the successful commercialization of a particular indication. Further, the FDA or comparable foreign regulatory
authorities may place conditions on approvals, such as risk management plans and a Risk Evaluation and Mitigation Strategy, or
REMS, to assure the safe use of the drug. If the FDA concludes a REMS is needed, the sponsor of the NDA must submit a proposed
REMS; the FDA will not approve the NDA without an approved REMS, if required. A REMS could include medication guides, physician
communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk
minimization tools. The FDA may also require a REMS for an approved product when new safety information emerges. Any of these
limitations on approval or marketing could restrict the commercial promotion, distribution, prescription or dispensing of our
drug candidates. Moreover, product approvals may be withdrawn for non-compliance with regulatory standards or if problems occur
following the initial marketing of the product. Any of the foregoing scenarios could materially harm the commercial success of
our drug candidates.
Even
if we obtain marketing approval for our drug candidates, we will be subject to ongoing obligations and continued regulatory review,
which may result in significant additional expense. Additionally, our drug candidates could be subject to labeling and other restrictions
and withdrawal from the market and we may be subject to penalties if we fail to comply with regulatory requirements or if we experience
unanticipated problems with our drug candidates.
Even
if we obtain United States regulatory approval of our drug candidates for an indication, the FDA may still impose significant
restrictions on their indicated uses or marketing or the conditions of approval, or impose ongoing requirements for potentially
costly and time-consuming post-approval studies, including Phase 4 clinical trials, and post-market surveillance to monitor safety
and efficacy. Our drug candidates will also be subject to ongoing regulatory requirements governing the manufacturing, labeling,
packaging, storage, distribution, safety surveillance, advertising, promotion, recordkeeping and reporting of adverse events and
other post-market information. These requirements include registration with the FDA, continued compliance with current Good Clinical
Practices regulations, or cGCPs, for any clinical trials that we conduct post-approval, continued compliance with the CSA and
ongoing review by the DEA. In addition, manufacturers of drug products and their facilities are subject to continual review and
periodic inspections by the FDA and other regulatory authorities for compliance with current Good Manufacturing Practices, or
cGMP, requirements relating to quality control, quality assurance and corresponding maintenance of records and documents.
With
respect to sales and marketing activities by us or any future partner, advertising and promotional materials must comply with
FDA rules in addition to other applicable federal, state and local laws in the United States and similar legal requirements in
other countries. In the United States, the distribution of product samples to physicians must comply with the requirements of
the U.S. Prescription Drug Marketing Act. Application holders must obtain FDA approval for product and manufacturing changes,
depending on the nature of the change. We may also be subject, directly or indirectly through our customers and partners, to various
fraud and abuse laws, including, without limitation, the U.S. Anti-Kickback Statute, U.S. False Claims Act, and similar state
laws, which impact, among other things, our proposed sales, marketing, and scientific/educational grant programs. If we participate
in the U.S. Medicaid Drug Rebate Program, the Federal Supply Schedule of the U.S. Department of Veterans Affairs, or other government
drug programs, we will be subject to complex laws and regulations regarding reporting and payment obligations. All of these activities
are also potentially subject to U.S. federal and state consumer protection and unfair competition laws. Similar requirements exist
in many of these areas in other countries.
In
addition, if any of our drug candidates are approved for an indication, our product labeling, advertising and promotion would
be subject to regulatory requirements and continuing regulatory review. The FDA strictly regulates the promotional claims that
may be made about prescription products. In particular, a product may not be promoted for uses that are not approved by the FDA
as reflected in the product’s approved labeling. If we receive marketing approval for any of our drug candidates, physicians
may nevertheless legally prescribe such products to their patients in a manner that is inconsistent with the approved label. However,
if we are found to have promoted such off-label uses, we may become subject to significant liability and government fines. The
federal government has levied large civil and criminal fines against companies for alleged improper promotion and has enjoined
several companies from engaging in off-label promotion. The FDA has also requested that companies enter into consent decrees of
permanent injunctions under which specified promotional conduct is changed or curtailed.
If
we or a regulatory agency discover previously unknown problems with a product, such as adverse events of unanticipated severity
or frequency or problems with the facility where the product is manufactured, or if we or our manufacturers fail to comply with
applicable regulatory requirements, we may be subject to the following administrative or judicial sanctions:
|
■
|
restrictions
on the marketing or manufacturing of the product, withdrawal of the product from the market, or voluntary or mandatory product
recalls;
|
|
|
|
|
■
|
issuance
of warning letters or untitled letters;
|
|
|
|
|
■
|
injunctions
or the imposition of civil or criminal penalties or monetary fines;
|
|
|
|
|
■
|
suspension
of any ongoing clinical trials;
|
|
|
|
|
■
|
refusal
to approve pending applications or supplements to approved applications filed by us, or suspension or revocation of product
license approvals;
|
|
|
|
|
■
|
suspension
of, or imposition of restrictions on, operations, including costly new manufacturing requirements; or
|
|
|
|
|
■
|
product
seizure or detention or refusal to permit the import or export of product.
|
The
occurrence of any event or penalty described above may inhibit our ability to commercialize our drug candidates and generate revenue.
Adverse regulatory action, whether pre- or post-approval, can also potentially lead to product liability claims and increase our
product liability exposure.
The
collaboration and license agreement, or the Collaboration Agreement, with Kaken Pharmaceuticals Co., Ltd., or Kaken, is important
to our business. If we or Kaken fail to adequately perform under the Collaboration Agreement, or if we or Kaken terminate the
Collaboration Agreement, the development and commercialization of lenabasum for the treatment of SSc and DM in Japan would be
delayed or terminated and our business would be adversely affected.
On
January 3, 2019, we entered into the Collaboration Agreement with Kaken, pursuant to which we granted to Kaken an exclusive license
to commercialize and market lenabasum for the prevention and treatment of DM and SSc in Japan. Our ability to generate revenue
under the Collaboration Agreement will depend in large part on our success in further clinical development of lenabasum and Kaken’s
success in achieving regulatory approval for, and commercializing lenabasum, in Japan. Such efforts are subject to significant
uncertainty. We have no control over the resources, time and effort that Kaken may devote to the commercialization of lenabasum.
Any of several events or factors could have a material adverse effect on our ability to generate revenue from Kaken’s commercialization
of lenabasum in Japan. For example, Kaken:
|
■
|
may
not achieve satisfactory levels of market acceptance and reimbursement by physicians, patients and third-party payers for
lenabasum for the treatment of DM and SSc;
|
|
|
|
|
■
|
may
not compete successfully against other products and therapies for DM and SSc;
|
|
|
|
|
■
|
may
have to comply with additional requests and recommendations from foreign regulatory authorities;
|
|
|
|
|
■
|
may
not make all regulatory filings and obtain all necessary approvals from foreign regulatory agencies and all commercially necessary
reimbursement approvals;
|
|
|
|
|
■
|
may
not commit sufficient resources to the marketing and distribution of lenabasum, whether for competitive or strategic reasons
or otherwise due to a change in business priorities; and
|
|
|
|
|
■
|
may
cease to perform its obligations under the terms of the Collaboration Agreement.
|
In
addition, pursuant to the Collaboration Agreement, we and Kaken have agreed to negotiate in good faith to enter into a supply
agreement and a quality agreement. There can be no assurance that we will be able to reach mutually agreeable terms on such agreements
with Kaken, and the absence of agreement on such terms would prevent us from gaining the expected benefit of the Collaboration
Agreement.
Further,
we and Kaken agreed to provide mutual indemnification against losses in connection with third-party claims arising out of breaches
of or inaccuracies in the Collaboration Agreement, gross negligence or willful misconduct, and the development or commercialization
of lenabasum pursuant to the Collaboration Agreement. Conflicts may arise in connection with these indemnification obligations.
After
a specified period of time, Kaken may unilaterally terminate the Collaboration Agreement on 180 days’ prior written notice
without any reason and without any further commitment. Kaken may also terminate in the event of certain safety concerns and clinical
failures, and either we or Kaken may terminate in the case of the other party’s material breach or insolvency. Termination
of the Collaboration Agreement could cause significant delays in our product candidate development and commercialization efforts,
which could prevent us from commercializing lenabasum without first expanding our internal capabilities or entering into another
agreement with a third party. Any suitable alternative collaboration or license agreement would take considerable time to negotiate
and could also be on less favorable terms to us.
We
have entered into, and may in the future enter into, collaboration agreements for the licensing, development and ultimate commercialization
of some of our drug candidates. In such cases, we will depend greatly on our third-party collaborators to license, develop and
commercialize such drug candidates, and they may not meet our expectations.
We
may enter into further co-development and commercialization partnerships for our drug candidates where appropriate. The process
of identifying collaborators and negotiating collaboration agreements for the licensing, development and ultimate commercialization
of some of our drug candidates may cause delays and increased costs. We may not be able to enter into collaboration agreements
on terms favorable to us or at all. Furthermore, some of those agreements may give substantial responsibility over our drug candidates
to the collaborator. Some collaborators may be unable or unwilling to devote sufficient resources to develop our drug candidates
as their agreements require. They often face business risks similar to ours, and this could interfere with their efforts. Also,
collaborators may choose to devote their resources to products that compete with ours. If a collaborator does not successfully
develop any one of our products, we will need to find another collaborator to do so. The success of our search for a new collaborator
will depend on our legal right to do so at the time and whether the product remains commercially viable.
If
we enter into collaboration agreements for one or more of our drug candidates, the success of such drug candidates will depend
in great part upon our and our collaborators’ success in promoting them as superior to other treatment alternatives. We
believe that our drug candidates can be proven to offer disease treatment with notable advantages over drugs in terms of patient
compliance and effectiveness. However, there can be no assurance that we will be able to prove these advantages or that the advantages
will be sufficient to support the successful commercialization of our drug candidates.
We
currently have a limited sales and marketing organization. If we are unable to secure a sales and marketing partner or establish
satisfactory sales and marketing capabilities, we may not successfully commercialize our drug candidates.
At
present, we have just started building a commercial organization in order to commercialize products that are approved for commercial
sales. We must either collaborate with third parties that have such commercial infrastructure or continue to develop our own sales
and marketing infrastructure. If we are not successful in entering into appropriate collaboration arrangements, or recruiting
sales and marketing personnel or in building a sales and marketing infrastructure, we will have difficulty successfully commercializing
our drug candidates, which would adversely affect our business, operating results and financial condition.
We
may not be able to enter into collaboration agreements on terms acceptable to us or at all. In addition, even if we enter into
such relationships, we may have limited or no control over the sales, marketing and distribution activities of these third parties.
Our future revenues may depend heavily on the success of the efforts of these third parties. If we elect to establish a sales
and marketing infrastructure we may not realize a positive return on this investment. In addition, we will have to compete with
established and well-funded pharmaceutical and biotechnology companies to recruit, hire, train and retain sales and marketing
personnel. Factors that may inhibit our efforts to commercialize our drug candidates without strategic partners or licensees include:
|
■
|
our
inability to recruit and retain adequate numbers of effective sales and marketing personnel;
|
|
|
|
|
■
|
the
inability of sales personnel to obtain access to or persuade adequate numbers of physicians to prescribe our drug candidates;
|
|
|
|
|
■
|
the
lack of complementary products to be offered by sales personnel, which may put us at a competitive disadvantage relative to
companies with more extensive product lines; and
|
|
|
|
|
■
|
unforeseen
costs and expenses associated with creating an independent sales and marketing organization.
|
We
face competition from other biotechnology and pharmaceutical companies and our operating results will suffer if we fail to compete
effectively.
The
biotechnology and pharmaceutical industries are intensely competitive and subject to rapid and significant technological change.
We have competitors in a number of jurisdictions, many of which have substantially greater name recognition, commercial infrastructures
and financial, technical and personnel resources than we have. Established competitors may invest heavily to quickly discover
and develop novel compounds that could make our drug candidates obsolete or uneconomical. Any new product that competes with an
approved product may need to demonstrate compelling advantages in efficacy, cost, convenience, tolerability and safety to be commercially
successful. Other competitive factors, including generic competition, could force us to lower prices or could result in reduced
sales. In addition, new products developed by others could emerge as competitors to our drug candidates. If we are not able to
compete effectively against our current and future competitors, our business will not grow and our financial condition and operations
will suffer.
Recently
enacted and future legislation may increase the difficulty and cost for us to obtain marketing approval of and commercialize our
drug candidates and affect the prices we 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 prevent or delay marketing approval for our drug candidates, restrict or regulate
post-approval activities and affect our ability to profitably sell our drug candidates. Legislative and regulatory proposals have
been made to expand post-approval requirements and restrict sales and promotional activities for pharmaceutical products. We do
not know 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 drug candidates, if any, may be. In addition,
increased scrutiny by the U.S. Congress of the FDA’s approval process may significantly delay or prevent marketing approval,
as well as subject us to more stringent product labeling and post-marketing testing and other requirements.
In
the United States, under the Medicare Modernization Act, or MMA, Medicare Part D provides coverage to the elderly and disabled
for outpatient prescription drugs by approving and subsidizing prescription drug plans offered by private insurers. The MMA also
authorizes Medicare Part D prescription drug plans to use formularies where they can limit the number of drugs that will be covered
in any therapeutic class. The Part D plans use their formulary leverage to negotiate rebates and other price concessions from
drug manufacturers. Also under the MMA, Medicare Part B provides coverage to the elderly and disabled for physician-administered
drugs on the basis of the drug’s average sales price, a price that is calculated according to regulatory requirements and
that the manufacturer reports to Medicare quarterly.
Both
Congress and the Centers for Medicare & Medicaid Services (CMS), the agency that administers the Medicare program, from time
to time consider legislation, regulations, or other initiatives to reduce drug costs under Medicare Parts B and D. For example,
under the 2010 Affordable Care Act, drug manufacturers are required to provide a 50% discount on prescriptions for branded drugs
filled while the beneficiary is in the Medicare Part D coverage gap, also known as the “donut hole.” There have been
legislative proposals to repeal the “non-interference” provision of the MMA to allow CMS to leverage the Medicare
market share to negotiate larger Part D rebates. Further cost reduction efforts could decrease the coverage and price that we
receive for our drug candidates and could seriously harm our business. Private payors often follow Medicare coverage policy and
payment limitations in setting their own reimbursement rates, and any reduction in reimbursement under the Medicare program may
result in a similar reduction in payments from private payors.
The
2010 Affordable Care Act is intended to broaden access to health insurance and reduce or constrain the growth of healthcare spending.
Further, the Affordable Care Act imposes a significant annual fee on companies that manufacture or import branded prescription
drug products. It also increased the amount of the rebates drug manufacturers must pay to state Medicaid programs, required that
Medicaid rebates be paid on managed Medicaid utilization, and increased the additional rebate on “line extensions”
(such as extended release formulations) of solid oral dosage forms of branded products. The law also contains substantial provisions
affecting fraud and abuse compliance and transparency, which may require us to modify our business practices with healthcare practitioners,
and incur substantial costs to ensure compliance.
The
President and the majority party in both Houses of the U.S. Congress have indicated their desire to repeal the Affordable Care
Act. It is unclear whether, when and how that repeal will be effectuated and what the effect on the healthcare sector will be.
In addition to the potential repeal of the Affordable Care Act, there are indications that the Medicaid program may be restructured,
which could lead to revisions in Medicaid coverage for prescription drugs. While we are unable to predict what legislation, if
any, may potentially be enacted, to the extent that future changes affect how our product candidates could be paid for and/or
reimbursed by the government and private payers, our business could be adversely affected.
In
addition, other legislative changes have been proposed and adopted in the United States since the ACA was enacted. For example,
the Budget Control Act of 2011 included, among other things, provisions that have led to 2% across-the-board reductions in Medicare
payment amounts. Several states have adopted or are considering adopting laws that require pharmaceutical companies to provide
notice prior to raising prices and to justify price increases. We expect that additional healthcare reform measures will be adopted
in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services,
and in turn could significantly reduce the projected value of certain development projects and reduce our profitability.
Our
future growth depends, in part, on our ability to enter into and succeed in markets outside of the United States, where we may
choose to rely on third party collaborations and will be subject to additional regulatory and commercial burdens, risks and other
uncertainties.
Our
future profitability will depend, in part, on our ability to gain approval of and commercialize our drug candidates in non-U.S.
markets. In some or all of these non-U.S. markets, we intend to enter into licensing and contractual collaborations with third
parties, such as Kaken, to handle some or all of the tasks and responsibilities necessary to succeed. Our activities in non-U.S.
markets are subject to additional risks and uncertainties, including:
|
■
|
our
ability to enter into favorable licensing and contractual arrangements with our partners;
|
|
|
|
|
■
|
our
ability to select partners who are capable of achieving success at the tasks they agree to perform;
|
|
|
|
|
■
|
obtaining
timely and sufficient favorable approval terms for our drug candidates;
|
|
|
|
|
■
|
obtaining
favorable pricing and reimbursement;
|
|
|
|
|
■
|
our
inability to directly control commercial activities because we are relying on third parties;
|
|
|
|
|
■
|
the
burden of complying with complex and changing foreign regulatory, tax, accounting and legal requirements;
|
|
|
|
|
■
|
different
medical practices and customs in foreign countries affecting acceptance in the marketplace;
|
|
|
|
|
■
|
import
or export licensing requirements;
|
|
|
|
|
■
|
longer
accounts receivable collection times;
|
|
|
|
|
■
|
longer
lead times for shipping;
|
|
|
|
|
■
|
language
barriers for technical training;
|
|
|
|
|
■
|
reduced
protection of intellectual property rights in some foreign countries;
|
|
|
|
|
■
|
foreign
currency exchange rate fluctuations; and
|
|
|
|
|
■
|
the
interpretation of contractual provisions governed by foreign laws in the event of a contract dispute.
|
International
sales of our drug candidates could also be adversely affected by the imposition of governmental controls, political and economic
instability, and trade restrictions and changes in tariffs, any of which may adversely affect our results of operations.
If
we market our drug candidates in a manner that violates healthcare fraud and abuse laws, or if we violate government price reporting
laws, we may be subject to civil or criminal penalties.
The
FDA enforces laws and regulations which require that the promotion of pharmaceutical products be consistent with the approved
prescribing information. While physicians may prescribe an approved product for a so-called “off label” use, it is
unlawful for a pharmaceutical company to promote its products in a manner that is inconsistent with its approved label and any
company which engages in such conduct may be subject to significant liability. Similarly, industry codes in the European Union
and other foreign jurisdictions prohibit companies from engaging in off-label promotion and regulatory agencies in various countries
enforce violations of the code with civil penalties. While we intend to ensure that our promotional materials are consistent with
our label, regulatory agencies may disagree with our assessment and may issue untitled letters, warning letters or may institute
other civil or criminal enforcement proceedings. In addition to FDA restrictions on marketing of pharmaceutical products, several
other types of state and federal healthcare fraud and abuse laws have been applied in recent years to restrict certain marketing
practices in the pharmaceutical industry. These laws include the U.S. Anti-Kickback Statute, U.S. False Claims Act and similar
state laws. Because of the breadth of these laws and the narrowness of the safe harbors, it is possible that some of our business
activities could be subject to challenge under one or more of these laws.
The
U.S. Anti-Kickback Statute prohibits, among other things, knowingly and willfully offering, paying, soliciting or receiving remuneration
to induce, or in return for, purchasing, leasing, ordering or arranging for the purchase, lease or order of any healthcare item
or service reimbursable under Medicare, Medicaid or other federally financed healthcare programs. This statute has been interpreted
broadly to apply to arrangements between pharmaceutical manufacturers on the one hand and prescribers, purchasers and formulary
managers on the other. Although there are several statutory exemptions and regulatory safe harbors protecting certain common activities
from prosecution, the exemptions and safe harbors are drawn narrowly, and practices that involve remuneration intended to induce
prescribing, purchasing or recommending may be subject to scrutiny if they do not qualify for an exemption or safe harbor. Our
practices may not, in all cases, meet all of the criteria for safe harbor protection from anti-kickback liability. Moreover, recent
health care reform legislation has strengthened these laws. For example, the Health Care Reform Law, among other things, amends
the intent requirement of the U.S. Anti-Kickback Statute and criminal health care fraud statutes; a person or entity no longer
needs to have actual knowledge of this statute or specific intent to violate it. In addition, the Health Care Reform Law provides
that the government may assert that a claim including items or services resulting from a violation of the U.S. Anti-Kickback Statute
constitutes a false or fraudulent claim for purposes of the U.S. False Claims Act. Federal false claims laws prohibit any person
from knowingly presenting, or causing to be presented, a false claim for payment to the federal government or knowingly making,
or causing to be made, a false statement to get a false claim paid.
Over
the past few years, pharmaceutical and other healthcare companies have been prosecuted under these laws for a variety of alleged
promotional and marketing activities, such as: allegedly providing free trips, free goods, sham consulting fees and grants and
other monetary benefits to prescribers; reporting to pricing services inflated average wholesale prices that were then used by
federal programs to set reimbursement rates; engaging in off-label promotion that caused claims to be submitted to Medicare or
Medicaid for non-covered, off-label uses; and submitting inflated best price information to the Medicaid Rebate Program to reduce
liability for Medicaid rebates. Most states also have statutes or regulations similar to the U.S. Anti-Kickback Statute and the
U.S. False Claims Act, which apply to items and services reimbursed under Medicaid and other state programs, or, in several states,
apply regardless of the payor. Sanctions under these federal and state laws may include substantial civil monetary penalties,
exclusion of a manufacturer’s products from reimbursement under government programs, substantial criminal fines and imprisonment.
We
are, and will be, completely dependent on third parties to manufacture our drug candidates, and our commercialization of our drug
candidates could be halted, delayed or made less profitable if those third parties fail to obtain manufacturing approval from
the FDA or comparable foreign regulatory authorities, fail to provide us with sufficient quantities of our drug candidates or
fail to do so at acceptable quality levels or prices.
We
do not currently have, nor do we plan to acquire, the capability or infrastructure to manufacture the active pharmaceutical ingredients
of our drug candidates, or the finished drug products, for use in our clinical trials or for commercial product, if any. As a
result, we will be obligated to rely on contract manufacturers if and when our drug candidates are approved for commercialization.
We
currently rely on a single foreign supplier for manufacturing the starting chemical intermediates and finished bulk drug product
for lenabasum. We also rely on a single foreign supplier for the manufacturing of the finished lenabasum capsules. The facilities
used by our two contract manufacturers to manufacture lenabasum must be approved by the FDA pursuant to inspections that will
be conducted after we submit our NDAs to the FDA. We do not control the manufacturing processes of, and are completely dependent
on, our two contract manufacturing partners for compliance with cGMPs for manufacture of all active drug substances and finished
drug products. These cGMP regulations cover all aspects of the manufacturing, testing, quality control and record keeping relating
to our drug candidates. If our contract manufacturers cannot successfully manufacture material that conforms to our specifications
and the strict regulatory requirements of the FDA or others, they will not be able to secure and/or maintain regulatory approval
for their manufacturing facilities. If the FDA or a comparable foreign regulatory authority does not approve these facilities
for the manufacture of lenabasum or our other product candidates or if it withdraws any such approval in the future, we may need
to find alternative manufacturing facilities, which would significantly impact our ability to develop, obtain regulatory approval
for or market our drug candidates, if approved.
Our
contract manufacturers will be subject to ongoing periodic unannounced inspections by the FDA and corresponding state and foreign
agencies for compliance with cGMPs and similar regulatory requirements. We will not have control over our contract manufacturers’
compliance with these regulations and standards. Failure by any of our contract manufacturers to comply with applicable regulations
could result in sanctions being imposed on us, including fines, injunctions, civil penalties, failure to grant approval to market
our drug candidates, delays, suspensions or withdrawals of approvals, operating restrictions and criminal prosecutions, any of
which could significantly and adversely affect our business. In addition, we will not have control over the ability of our contract
manufacturers to maintain adequate quality control, quality assurance and qualified personnel. Failure by our contract manufacturers
to comply with or maintain any of these standards could adversely affect our ability to develop, obtain regulatory approval for
or market our drug candidates.
If
for any reason, these third parties are unable or unwilling to perform, we may not be able to terminate our agreements with them,
and we may not be able to locate alternative manufacturers or formulators or enter into favorable agreements with them and we
cannot be certain that any such third parties will have the manufacturing capacity to meet future requirements. If these manufacturers
or any alternate manufacturer of finished drug product experiences any significant difficulties in its respective manufacturing
processes for our active pharmaceutical ingredient, or API, or our finished products or should cease doing business with us, we
could experience significant interruptions in the supply of our drug candidates or may not be able to create a supply of our drug
candidates at all. Were we to encounter manufacturing issues, our ability to produce a sufficient supply of our drug candidates
might be negatively affected. Our inability to coordinate the efforts of our third party manufacturing partners, or the lack of
capacity available at our third party manufacturing partners, could impair our ability to supply our drug candidates at required
levels. Because of the significant regulatory requirements that we would need to satisfy in order to qualify a new bulk or finished
product manufacturer, if we face these or other difficulties with our current manufacturing partners, we could experience significant
interruptions in the supply of our drug candidates if we decided to transfer the manufacture of our drug candidates to one or
more alternative manufacturers in an effort to deal with the difficulties.
Any
manufacturing problem or the loss of a contract manufacturer could be disruptive to our operations and result in lost sales. Additionally,
we rely on third parties to supply the raw materials needed to manufacture our potential products. 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 a future contract manufacturer caused by problems
at suppliers could delay shipment of our drug candidates, increase our cost of goods sold and result in lost sales.
We
cannot guarantee that our manufacturing and supply partners will be able to manufacture our drug candidates at commercial scale
on a cost-effective basis. If the commercial-scale manufacturing costs of our drug candidates are higher than expected, these
costs may significantly impact our operating results. In order to reduce costs, we may need to develop and implement process improvements.
However, in order to do so, we will need, from time to time, to notify or make submissions with regulatory authorities, and the
improvements may be subject to approval by such regulatory authorities. We cannot be sure that we will receive these necessary
approvals or that these approvals will be granted in a timely fashion. We also cannot guarantee that we will be able to enhance
and optimize output in our commercial manufacturing process. If we cannot enhance and optimize output, we may not be able to reduce
our costs over time.
There
are risks associated with scaling up manufacturing to commercial scale. If our contract manufacturers are unable to manufacture
our drug candidates on a commercial scale, this could potentially delay regulatory approval and commercialization or materially
adversely affect our results of operations.
There
are risks associated with scaling up manufacturing to commercial volumes including, among others, cost overruns, technical problems
with process scale-up, process reproducibility, stability issues, and lot consistency. Even if we obtain regulatory approval for
our drug candidates, there is no assurance that our contract manufacturers will be able to manufacture the approved products to
specifications acceptable to the FDA or other regulatory authorities, to produce them in sufficient quantities to meet the requirements
for the potential launch of the product or to meet potential future demand. If our manufacturers are unable to produce sufficient
quantities of approved products for commercialization, either on a timely basis or at all, our commercialization efforts would
be impaired, which would have a material adverse effect on our business, financial condition, results of operations and growth
prospects.
Our
lead product candidate, lenabasum, is currently classified as a Schedule I controlled substance subject to U.S. controlled substance
laws and regulations, including regulations of the Drug Enforcement Agency and the U.S. Food and Drug Administration. Failure
to obtain the necessary licenses and registrations and failure to comply with these laws could result in the delay in the manufacturing
and distribution of lenabasum and could delay the completion of clinical studies. Such delays and the cost of compliance with
these laws and regulations, could adversely affect our business operations and our financial condition.
In
the United States, our lead product candidate, lenabasum, is currently classified as a Schedule I controlled substance as defined
in the Controlled Substance Act, or CSA. This designation is based on lenabasum’s chemical structure and pharmacology (namely,
it being a synthetic endocannabinoid mimetic that binds to the CB2 receptor). Even though lenabasum’s mechanism of action
is to modulate the immune system and results to date from clinical trials indicate that the drug has no psychotropic effects (which
we believe is unlike other members of its chemical class), the DEA classifies lenabasum as a Schedule I substance.
Schedule
I controlled substances are pharmaceutical products subject to specific regulations under the CSA, which establishes, among other
things, certain registration, manufacturing quotas, security, recordkeeping, reporting, import, export and other requirements
administered by the DEA. All parties responsible for the manufacturing, distribution and testing of the drug in clinical studies
must apply for and obtain a license from the DEA before they are permitted to perform these activities with lenabasum. Furthermore,
these parties must have the security, control, recordkeeping, reporting and inventory mechanisms required by the DEA to prevent
drug loss and diversion. All licensed facilities are required to renew their registrations annually if they intend to continue
to work with our drug. The DEA conducts periodic inspections of certain registered establishments that handle controlled substances.
We have been working with our manufacturers, distributors, exporters and clinical sites to obtain the necessary licenses to work
with lenabasum. The parties responsible for the manufacturing, distribution and export of lenabasum have already applied for and
have been granted DEA licenses and a number of institutions responsible for conducting our current clinical studies have also
been granted DEA licenses. However, the failure to maintain the necessary registrations, and the delay or failure of additional
clinical sites to obtain DEA registrations, could delay the manufacturing, distribution and export of lenabasum and could delay
the completion of the clinical studies. Furthermore, failure to maintain compliance with the CSA, particularly non-compliance
resulting in loss or diversion, could result in regulatory action that could have a material adverse effect on our business, financial
condition and results of operations. The DEA may seek civil penalties, refuse to renew necessary registrations, or initiate proceedings
to restrict, suspend or revoke those registrations. In certain circumstances, violations could lead to criminal proceedings. In
addition, if the FDA, DEA, or any foreign regulatory authority determines that lenabasum may have potential for abuse, it may
require us to generate more clinical or other data than we currently anticipate to establish whether or to what extent the substance
has an abuse potential, which could increase the cost and/or delay the launch of lenabasum.
Individual
states have also established controlled substance laws and regulations. Though state-controlled substances laws often mirror federal
law, because the states are separate jurisdictions, they may separately schedule drugs, as well. While some states automatically
schedule a drug based on federal action, other states schedule drugs through rulemaking or a legislative action. The requirement
for state registrations could also result in delay of the manufacturing and distribution of lenabasum or in the completion of
our clinical studies. We and our manufacturing vendors and clinical sites must also obtain separate state registrations, permits
or licenses in order to be able to obtain, handle and distribute controlled substances for clinical trials or commercial sale,
and failure to meet applicable regulatory requirements could lead to enforcement and sanctions by the states in addition to those
from the DEA or otherwise arising under federal law.
The
manufacturing and distribution of lenabasum is subject to the DEA’s annual manufacturing and procurement quota requirements.
The annual quota allocated to us or our contract manufacturers for the controlled substances in lenabasum may not be sufficient
to complete clinical trials. Consequently, any delay or refusal by the DEA in establishing our, or our contract manufacturers’,
procurement and/or production quota for controlled substances could delay or stop our clinical trials or product launches, which
could have a material adverse effect on our business, financial position and operations.
While
lenabasum is a Schedule I controlled substance, if lenabasum is approved for medical use by the FDA, it will have satisfied the
“accepted medical use” requirement of the CSA. If and when lenabasum receives FDA approval, the DEA will make a scheduling
determination and place lenabasum in a schedule other than Schedule I or declassify it in order for it to be prescribed to patients
in the United States. As part of the scheduling determination, FDA will assess the abuse and dependence potential of lenabasum
and make a scheduling recommendation to DEA. If approved by the FDA, the length of time the DEA takes to complete the rescheduling
or declassification of lenabasum is uncertain and could be lengthy and we will not be able to sell the drug until the rescheduling
is complete. Any delays in the rescheduling could have a material adverse impact on our results of operations.
Delays
in shipping our drug candidates could have a material adverse effect on our business, results of operations and financial condition.
The
import and export of our drug candidates requires import and export licenses. In addition, because lenabasum is currently a Schedule
I controlled substance in the United States, in addition to the FDA and U.S. Customs and Border Protection, its import and export
is also regulated by the DEA. We may not be granted, or if granted, maintain, such licenses for import or export from the authorities
these regulatory agencies. Even if we obtain the relevant licenses, shipments of our drug candidates may be held up in transit
by any of these authorities, which could cause significant delays and may lead to product batches which no longer meet specifications
for use in clinical trials or commercial distribution. Such events could result in delayed development timelines, increased expenses
and partial or total loss of revenue from our drug candidates.
We
expect that we will rely on third parties to assist us in conducting clinical trials for our drug candidates. If these third parties
do not successfully carry out their contractual duties or meet expected deadlines, we may not be able to obtain regulatory approval
for or commercialize our drug candidates and our business would be substantially harmed.
We
expect to enter into agreements with third-party CROs to assist us in conducting and managing our clinical programs, including
contracting with clinical sites to perform our clinical studies. We plan to rely on these parties for execution of clinical studies
for our drug candidates and we will control only certain aspects of conducting the clinical studies. Nevertheless, we will be
responsible for ensuring that each of our studies is conducted in accordance with the applicable protocol, legal, regulatory and
scientific standards, and our reliance on CROs and clinical sites will not relieve us of our regulatory responsibilities. We and
our CROs will be required to comply with cGCPs, which are regulations and guidelines enforced by the FDA, the Competent Authorities
of the Member States of the European Economic Area and comparable foreign regulatory authorities for any products in clinical
development. The FDA enforces these cGCP regulations through periodic inspections of trial sponsors, principal investigators and
trial sites. If we or our CROs fail to comply with applicable cGCPs, the clinical data generated in our clinical trials may be
deemed unreliable and the FDA or comparable foreign regulatory authorities may require us to perform additional clinical trials
before approving our marketing applications. We cannot assure you that, upon inspection, the FDA will determine that any of our
clinical trials comply with cGCPs. In addition, our clinical trials must be conducted with products produced under cGMP regulations
and will require a large number of test subjects. Our failure or the failure of our CROs or clinical sites to comply with these
regulations may require us to repeat clinical trials, which would delay the regulatory approval process and could also subject
us to enforcement action up to and including civil and criminal penalties.
Although
we intend to design the clinical trials for our drug candidates in consultation with CROs, we expect that the CROs will manage
and assist us with the clinical trials conducted at contracted clinical sites. As a result, many important aspects of our drug
development programs would be outside of our direct control. In addition, the CROs and clinical sites may not perform all of their
obligations under arrangements with us or in compliance with regulatory requirements. If the CROs or clinical sites do not perform
clinical trials in a satisfactory manner, or if they breach their obligations to us or fail to comply with regulatory requirements,
the development and commercialization of our drug candidates for the subject indications may be delayed or our development program
materially and irreversibly harmed. We cannot control the amount and timing of resources these CROs and clinical sites will devote
to our program or our drug candidates. If we are unable to rely on clinical data collected by our CROs, we could be required to
repeat, extend the duration of, or increase the size of our clinical trials, which could significantly delay commercialization
and require significantly greater expenditures.
If
any of our relationships with these third-party CROs or clinical sites terminate, we may not be able to enter into arrangements
with alternative CROs or clinical sites. If CROs do not successfully carry out their contractual duties or obligations or meet
expected deadlines, if they need to be replaced or if the quality or accuracy of the clinical data they obtain is compromised
due to the failure to adhere to our clinical protocols, regulatory requirements or for other reasons, any such clinical trials
may be extended, delayed or terminated, and we may not be able to obtain regulatory approval for or successfully commercialize
our drug candidates. As a result, our financial results and the commercial prospects for our drug candidates would be harmed,
our costs could increase and our ability to generate revenue could be delayed.
Any
termination or suspension of or delays in the commencement or completion of any necessary studies of our drug candidates for any
indications could result in increased costs to us, delay or limit our ability to generate revenue and adversely affect our commercial
prospects.
The
commencement and completion of clinical studies can be delayed for a number of reasons, including delays related to:
|
■
|
the
FDA failing to grant permission to proceed and placing the clinical study on hold;
|
|
|
|
|
■
|
subjects
failing to enroll or remain in our trials at the rate we expect;
|
|
|
|
|
■
|
a
facility manufacturing any of our drug candidates being ordered by the FDA or other government or regulatory authorities to
temporarily or permanently shut down due to violations of cGMP requirements or other applicable requirements, or cross-contaminations
of product in the manufacturing process;
|
|
|
|
|
■
|
any
changes to our manufacturing process that may be necessary or desired;
|
|
|
|
|
■
|
subjects
choosing an alternative treatment for the indications for which we are developing our
drug candidates, or participating in competing clinical studies;
|
|
|
|
|
■
|
subjects
experiencing severe or unexpected drug-related adverse effects;
|
|
|
|
|
■
|
reports
of similar technologies and products raising safety and/or efficacy concerns;
|
|
|
|
|
■
|
third-party
clinical investigators losing their license or permits necessary to perform our clinical
trials, not performing our clinical trials on our anticipated schedule or employing methods
consistent with the clinical trial protocol, cGCP requirements, or other third parties
not performing data collection and analysis in a timely or accurate manner;
|
|
|
|
|
■
|
inspections
of clinical study sites by the FDA or IRBs finding regulatory violations that require us to undertake corrective action, result
in suspension or termination of one or more sites or the imposition of a clinical hold on the entire study, or that prohibit
us from using some or all of the data in support of our marketing applications;
|
|
|
|
|
■
|
third-party
contractors becoming debarred or suspended or otherwise penalized by the FDA or other government or regulatory authorities
for violations of regulatory requirements, in which case we may need to find a substitute contractor, and we may not be able
to use some or any of the data produced by such contractors in support of our marketing applications;
|
|
■
|
one
or more IRBs refusing to approve, suspending or terminating the study at an investigational site precluding enrollment of
additional subjects, or withdrawing its approval of the trial; reaching agreement on acceptable terms with prospective CROs
and clinical trial sites, the terms of which can be subject to extensive negotiation and may vary significantly among different
CROs and trial sites;
|
|
|
|
|
■
|
deviations
of the clinical sites from trial protocols or dropping out of a trial;
|
|
|
|
|
■
|
adding
new clinical trial sites;
|
|
|
|
|
■
|
the
inability of the CRO to execute any clinical trials for any reason; and
|
|
|
|
|
■
|
government
or regulatory delays or “clinical holds” requiring suspension or termination of a trial.
|
Product
development costs for our drug candidates will increase if we have delays in testing or approval or if we need to perform more
or larger clinical studies than planned. Additionally, changes in regulatory requirements and policies may occur and we may need
to amend study protocols to reflect these changes. Amendments may require us to resubmit our study protocols to the FDA and IRBs
for reexamination, which may impact the costs, timing or successful completion of that study. If we experience delays in completion
of, or if we, the FDA or other regulatory authorities, any IRBs, or other reviewing entities, or any of our clinical study sites
suspend or terminate any of our clinical studies of our drug candidates, our commercial prospects may be materially harmed and
our ability to generate product revenues will be delayed. Any delays in completing our clinical trials will increase our costs,
slow down our development and approval process and jeopardize our ability to commence product sales and generate revenues. Any
of these occurrences may harm our business, financial condition and prospects significantly. In addition, many of the factors
that cause, or lead to, termination or suspension of, or a delay in the commencement or completion of, clinical studies may also
ultimately lead to the denial of regulatory approval of our drug candidates. In addition, if one or more clinical studies are
delayed, our competitors may be able to bring products to market before we do, and the commercial viability of our drug candidates
could be significantly reduced.
We
may not be able to obtain or maintain orphan drug designation or exclusivity for our product candidates.
We
have been granted orphan drug designation in the United States and in the European Union for lenabasum for the treatment of CF,
SSc and DM. Upon receipt of regulatory approval, orphan drug status will provide us with seven years of market exclusivity in
the United States under the Orphan Drug Act. However, there is no guarantee that the FDA will grant orphan drug designation for
any of our drug candidates for any future indication, which would make us ineligible for the additional exclusivity and other
benefits of orphan drug designation. Moreover, there can be no assurance that another company
also holding orphan drug designation for the same indication or which may receive orphan drug designation in the future will not
receive approval prior to us, in which case our competitor would have the benefit of the seven years of market exclusivity, and
we would be unable to commercialize our product for the same indication until the expiration of such seven-year period. Even if
we are the first to obtain approval for the orphan drug indication, there are circumstances under which a competing product may
be approved for the same indication during our seven-year period of exclusivity.
Under
the Orphan Drug Act, the FDA may grant orphan drug designation to a drug intended to treat a rare disease or condition, which
is generally a disease or condition that affects fewer than 200,000 individuals in the United States and for which there is no
reasonable expectation that the cost of developing and making a drug available in the Unites States for this type of disease or
condition will be recovered from sales of the product. Orphan drug designation must be requested before submitting an NDA. After
the FDA grants orphan drug designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly
by the FDA. Orphan designation does not convey any advantage in or shorten the duration of regulatory review and approval process.
In addition to the potential period of exclusivity, orphan designation makes a company eligible for grant funding of up to $400,000
per year for four years to defray costs of clinical trial expenses, tax credits for clinical research expenses and potential exemption
from the FDA application user fee.
If
a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has
such designation, the product is entitled to orphan drug exclusivity, which means the FDA may not approve any other applications
to market the same drug for the same indication for seven years, except in limited circumstances, such as (i) the drug’s
orphan designation is revoked; (ii) its marketing approval is withdrawn; (iii) the orphan exclusivity holder consents to the approval
of another applicant’s product; (iv) the orphan exclusivity holder is unable to assure the availability of a sufficient
quantity of drug; or (v) a showing of clinical superiority to the product with orphan exclusivity by a competitor product. If
a drug designated as an orphan product receives marketing approval for an indication broader than what is designated, it may not
be entitled to orphan drug exclusivity. There can be no assurance that we will receive orphan drug designation for any of our
drug candidates for any additional indications, if we elect to seek such designation.
Any
fast track designation or grant of priority review status by the FDA may not actually lead to a faster development or regulatory
review or approval process, nor will it assure FDA approval of our product candidates. Additionally, our product candidates may
treat indications that do not qualify for priority review vouchers.
We
have received fast track designation for lenabasum for the treatment of cystic fibrosis and systemic sclerosis in the United States
and European Union and may seek fast track designation or priority review of applications for approval of our product candidate
for future indications. If a drug is intended for the treatment of a serious or life-threatening condition and the drug demonstrates
the potential to address unmet medical needs for this condition, the drug sponsor may apply for FDA fast track designation. If
a product candidate offers major advances in treatment, the FDA may designate it eligible for priority review. The FDA has broad
discretion whether or not to grant these designations, so even if we believe a particular product candidate is eligible for these
designations, we cannot assure you that the FDA would decide to grant them. Even if we do receive fast track designation or priority
review, we may not experience a faster development process, review or approval compared to conventional FDA procedures. The FDA
may withdraw fast track designation if it believes that the designation is no longer supported by data from our clinical development
program.
Any
breakthrough therapy designation granted by the FDA for our product candidate may not lead to a faster development or regulatory
review or approval process, and it does not increase the likelihood that our product candidate will receive marketing approval.
We
have applied for, and may in the future apply for, a breakthrough therapy designation of our product candidates for future indications.
A breakthrough therapy is defined as a drug that is intended, alone or in combination with one or more other drugs, to treat a
serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial
improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed
early in clinical development. For drugs and biologics that have been designated as breakthrough therapies, interaction and communication
between the FDA and the sponsor of the trial can help to identify the most efficient path for clinical development while minimizing
the number of patients placed in ineffective control regimens. Drugs designated as breakthrough therapies by the FDA may also
be eligible for accelerated approval if the relevant criteria are met.
Designation
of a product candidate as a breakthrough therapy is within the discretion of the FDA. Accordingly, even if we believe our product
candidate meets the criteria for designation as a breakthrough therapy, the FDA may disagree and instead determine not to make
such designation. In any event, the receipt of a breakthrough therapy designation for a product candidate may not result in a
faster development process, review or approval compared to drugs considered for approval under conventional FDA procedures and
does not assure ultimate approval by the FDA. In addition, even if one or more of our product candidates qualify as breakthrough
therapies, the FDA may later decide that the products no longer meet the conditions for qualification or decide that the time
period for FDA review or approval will not be shortened.
Third-party
coverage and reimbursement and health care cost containment initiatives and treatment guidelines may constrain our future revenues.
Our
ability to successfully market our drug candidates will depend in part on the level of reimbursement that government health administration
authorities, private health coverage insurers and other organizations provide for the cost of our products and related treatments.
Countries in which our drug candidates are expected to be sold through reimbursement schemes under national health insurance programs
frequently require that manufacturers and sellers of pharmaceutical products obtain governmental approval of initial prices and
any subsequent price increases. In certain countries, including the United States, government-funded and private medical care
plans can exert significant indirect pressure on prices. We may not be able to sell our drug candidates profitably if adequate
prices are not approved or coverage and reimbursement is unavailable or limited in scope. Increasingly, third-party payors attempt
to contain health care costs in ways that are likely to impact our development of products including:
|
■
|
failing
to approve or challenging the prices charged for health care products;
|
|
|
|
|
■
|
introducing
reimportation schemes from lower priced jurisdictions;
|
|
|
|
|
■
|
limiting
both coverage and the amount of reimbursement for new therapeutic products;
|
|
|
|
|
■
|
denying
or limiting coverage for products that are approved by the regulatory agencies but are considered to be experimental or investigational
by third-party payors; and
|
|
|
|
|
■
|
refusing
to provide coverage when an approved product is used in a way that has not received regulatory marketing approval.
|
If
the FDA determines that endpoints we have chosen for our RESOLVE-1 Phase 3 clinical trial in SSc do not sufficiently demonstrate
the efficacy of lenabasum for the treatment of SSc, we may not receive regulatory approval for lenabasum for the treatment of
SSc even if the results of our RESOLVE-1 Phase 3 clinical trial are positive.
In
April 2019, we announced that we changed the primary efficacy endpoint of our ongoing RESOLVE-1 Phase 3 trial for SSc in the U.S.
to the American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis, or ACR CRISS, score at
Week 52 from the previous primary endpoint, change in modified Rodnan Skin core, or mRSS. We made this change following a Type
C meeting with the FDA, which we had asked for in order to seek the FDA’s feedback on this and certain other changes in
the RESOLVE-1 trial protocol. In considering our requested change, the FDA noted drawbacks in both the mRSS and ACR CRISS as primary
endpoints. The FDA informed us that while it could not agree to using the ACR CRISS score as a primary endpoint at that time,
it recognized it was at our discretion and risk to change the primary endpoint to ACR CRISS. Also during the Type C meeting, the
FDA stated that components of ACR CRISS, which include mRSS, reflect relevant aspects of SSc, and it will consider the totality
of the data during review of any marketing application in SSc. In addition, the FDA stated that it was interested in working with
us to develop a more interpretable and meaningful ACR CRISS instrument for use as a study endpoint in patients with SSc. Although
we believe that using the ACR CRISS instrument as the primary efficacy endpoint for the RESOLVE-1 Phase 3 trial increases our
probability of obtaining FDA approval of lenabasum for the treatment of SSc in the U.S., there can be no guarantee that the FDA
will approve lenabasum based on the endpoints we have chosen for the RESOLVE-1 Phase 3 trial. The FDA may determine the endpoints
that we have chosen to use in our RESOLVE-1 Phase 3 trial do not sufficiently demonstrate the efficacy of lenabasum even if the
results of the clinical trial are positive.
Risks
Relating to Our Intellectual Property Rights
It
is difficult and costly to protect our intellectual property rights, and we cannot ensure the protection of these rights.
Our
commercial success will depend, in part, on maintaining and obtaining additional patent protection for our technologies, products
and processes, successfully defending these patents against third-party challenges and successfully enforcing these patents against
third party competitors. The patent positions of pharmaceutical companies can be highly uncertain and involve complex legal, scientific
and factual questions for which important legal principles remain unresolved. Changes in either the patent laws or in interpretations
of patent laws may diminish the value of our intellectual property. Accordingly, we cannot predict the breadth of claims that
may be allowable in our pending applications or, the enforceability of our existing and future patents. Our pending patent applications
for lenabasum and its uses may never be approved by United States or foreign patent offices and the existing patents and patent
applications relating to lenabasum and related technologies may be challenged, invalidated or circumvented by third parties and
may not protect us against competitors with similar products or technologies.
The
degree of our current and future protection for our proprietary rights is uncertain, because legal means afford only limited protection
and may not adequately protect our rights, permit us to gain or keep our competitive advantage, or provide us with any competitive
advantage at all. For example, others have filed, and in the future are likely to file, patent applications covering products
and technologies that are similar, identical or competitive to lenabasum, or important to our business. We cannot be certain that
any patents or patent application owned by a third party will not have priority over patents and patent applications filed by
us, or that we will not be involved in interference, opposition or invalidity proceedings before United States or foreign patent
offices.
We
also rely on trade secrets to protect technology, especially in cases when we believe patent protection is not appropriate or
obtainable. However, trade secrets are difficult to protect. While we require employees, academic collaborators, consultants and
other contractors to enter into confidentiality agreements, we may not be able to adequately protect our trade secrets or other
proprietary or licensed information. Typically, research collaborators and scientific advisors have rights to publish data and
information in which we may have rights. If we cannot maintain the confidentiality of our proprietary technology and other confidential
information, our ability to receive patent protection and our ability to protect valuable information owned by us may be imperiled.
Enforcing a claim that a third-party entity illegally obtained and is using any of our trade secrets is expensive and time consuming,
and the outcome is unpredictable. In addition, courts are sometimes less willing to protect trade secrets than patents. Moreover,
our competitors may independently develop equivalent knowledge, methods and know-how.
If
we fail to maintain or obtain additional patent protection or trade secret protection for lenabasum or our technologies, third
parties could use our proprietary information, which could impair our ability to compete in the market and adversely affect our
ability to generate revenues and attain profitability.
We
may also rely on the trademarks we may develop to distinguish our products from the products of our competitors. We cannot guarantee
that any trademark applications filed by us or our business partners will be approved. Third parties may also oppose such trademark
applications, or otherwise challenge our use of the trademarks. In the event that the trademarks we use are successfully challenged,
we could be forced to rebrand our products, which could result in loss of brand recognition, and could require us to devote resources
to advertising and marketing new brands. Further, we cannot provide assurance that competitors will not infringe the trademarks
we use, or that we will have adequate resources to enforce these trademarks.
We
have in-licensed a portion of our intellectual property, and if we fail to comply with our obligations under these arrangements,
we could lose such intellectual property rights or owe damages to the licensor of such intellectual property.
We
are a party to a license agreement with Jenrin pursuant to which we licensed the exclusive worldwide rights to develop, manufacture
and market drug candidates from Jenrin. This agreement is important to our business, and we may enter into additional license
agreements in the future. Certain of our in-licensed intellectual property covers, or may cover, CRB-4001 and other potential
developmental candidates. Our existing license agreement imposes, and we expect that future license agreements will impose, various
diligence, milestone payment, royalty and other obligations on us. If there is any conflict, dispute, disagreement or issue of
non-performance between us and our licensing partners regarding our rights or obligations under the license agreements, including
any such conflict, dispute or disagreement arising from our failure to satisfy payment obligations under any such agreement, we
may owe damages, our licensor may have a right to terminate the affected license, and our ability to utilize the affected intellectual
property in our product discovery and development efforts and our ability to enter into collaboration or marketing agreements
for an affected product candidate may be adversely affected.
Lenabasum
and our other product candidates may infringe the intellectual property rights of others, which could increase our costs and delay
or prevent our development and commercialization efforts.
Our
success depends in part on avoiding infringement of the proprietary technologies of others. The pharmaceutical industry has been
characterized by frequent litigation regarding patent and other intellectual property rights. Identification of third-party patent
rights that may be relevant to our proprietary technology is difficult because patent searching is imperfect due to differences
in terminology among patents, incomplete databases and the difficulty in assessing the meaning of patent claims. Additionally,
because patent applications are maintained in secrecy until the application is published, we may be unaware of third-party patents
that may be infringed by commercialization of lenabasum or any of our other product candidates. There may be certain issued patents
and patent applications claiming subject matter that we may be required to license in order to research, develop or commercialize
lenabasum or our other product candidates, and we do not know if such patents and patent applications would be available to license
on commercially reasonable terms, or at all. Any claims of patent infringement asserted by third parties would be time-consuming
and may:
|
■
|
result
in costly litigation;
|
|
|
|
|
■
|
divert
the time and attention of our technical personnel and management;
|
|
|
|
|
■
|
prevent
us from commercializing a product until the asserted patent expires or is held finally invalid or not infringed in a court
of law;
|
|
|
|
|
■
|
require
us to cease or modify our use of the technology and/or develop non-infringing technology; or
|
|
|
|
|
■
|
require
us to enter into royalty or licensing agreements.
|
Although
no third party has asserted a claim of infringement against us, others may hold proprietary rights that could prevent our product
candidates from being marketed. Any patent-related legal action against us claiming damages and seeking to enjoin commercial activities
relating to our product candidates or our processes could subject us to potential liability for damages and require us to obtain
a license to continue to manufacture or market lenabasum or any other product candidates. We cannot predict whether we would prevail
in any such actions or that any license required under any of these patents would be made available on commercially acceptable
terms, if at all. In addition, we cannot be sure that we could redesign lenabasum or any other product candidates or processes
to avoid infringement, if necessary. Accordingly, an adverse determination in a judicial or administrative proceeding, or the
failure to obtain necessary licenses, could prevent us from developing and commercializing lenabasum or another product candidate,
which could harm our business, financial condition and operating results.
A
number of companies, including several major pharmaceutical companies, have conducted research on anti-inflammatory and anti-fibrosis
therapies which resulted in the filing of many patent applications related to this research. If we were to challenge the validity
of these or any issued United States patent in court, we would need to overcome a statutory presumption of validity that attaches
to every issued United States patent. This means that, in order to prevail, we would have to present clear and convincing evidence
as to the invalidity of the patent’s claims.
If
we were to challenge the validity of these or any issued United States patent in an administrative trial before the Patent Trial
and Appeal Board in the United States Patent and Trademark Office, we would have to prove that the claims are unpatentable by
a preponderance of the evidence. There is no assurance that a jury and/or court would find in our favor on questions of infringement,
validity or enforceability.
We
may be subject to claims that we have wrongfully hired an employee from a competitor or that we or our employees have wrongfully
used or disclosed alleged confidential information or trade secrets of their former employers.
As
is commonplace in our industry, we employ individuals who were previously employed at other pharmaceutical companies, including
our competitors or potential competitors. Although no claims against us are currently pending, we may be subject in the future
to claims that our employees or prospective employees are subject to a continuing obligation to their former employers (such as
non-competition or non-solicitation obligations) or claims that our employees or we have inadvertently or otherwise used or disclosed
trade secrets or other proprietary information of their former employers. Litigation may be necessary to defend against these
claims. Even if we are successful in defending against these claims, litigation could result in substantial costs and be a distraction
to management.
We
may be subject to claims challenging the inventorship of our patents and other intellectual property.
Although
we are not aware of any asserted third-party claims challenging inventorship on our patents or ownership of our intellectual property,
we may in the future be subject to claims that former employees, strategic partners, commercial counterparties or other third
parties associated with us or one of our predecessors in ownership of lenabasum have an interest in our patents or other intellectual
property as an inventor or co-inventor. While it is our policy to require our employees and contractors who may be involved in
the conception or development of intellectual property to execute agreements assigning such intellectual property to us, we cannot
fully control the enforcement of these policies by third parties with which we contract, nor can we be certain that assignment
agreements between us and our employees, between us and our counterparties, or between our counterparties and their employees
or between our predecessors of ownership and their employees and counterparties, will effectively protect our interests as to
any party who conceives or develops intellectual property that we regard as our own. Among other issues, the assignment of intellectual
property rights may not be self-executing, the assignment agreements may be breached, or we may have disputes arise from conflicting
obligations of consultants or others who are involved in developing our product candidates. As we approach potential commercialization
of our product candidates, we are more closely analyzing all facts that we believe might be used to assert an inventorship claim
against us. Determinations like these involve complex sets of fact and applications of sometimes-unsettled patent law, resulting
in inherent uncertainties regarding ownership rights. Determining the history of development of certain of our intellectual property
is made more difficult by the fact that certain of our intellectual property was developed by other companies for other indications
before being acquired by us. Consequently, we cannot be sure that we have all of the documentary records relevant to such an analysis.
In the course of our analysis we identified a potential issue regarding incomplete inventorship on certain aspects of our lenabasum
portfolio that were developed prior to our acquisition of lenabasum. Since identifying this potential issue, we reached agreement
with the relevant third-party co-inventors and received assignments of such co-inventors’ rights in and to the relevant
patents.
If
claims challenging inventorship are made against us, we may need to resort to litigation to resolve those claims. If we fail in
defending against any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights,
such as exclusive ownership of valuable intellectual property rights or the right to assert those rights against third-parties
marketing competing products. Even if we are successful in defending against such claims, litigation could result in substantial
costs and be a distraction to management and other employees.
There
are risks to our Intellectual Property based on our international business operations.
We
may face risks to our technology and intellectual property as a result of our conducting business outside of the United States,
including as a result of our license and collaboration agreement with Kaken, and particularly in jurisdictions that do not have
comparable levels of protection of corporate proprietary information and assets such as intellectual property, trademarks, trade
secrets, know-how and customer information and records. While these risks are common to many companies, conducting business in
certain foreign jurisdictions, housing technology, data and intellectual property abroad, or licensing technology to joint ventures
with foreign partners may have more significant exposure. Pursuant to our license and collaboration agreement with Kaken, we have
granted Kaken an exclusive license to commercialize lenabasum in Japan, and an exclusive, worldwide license for the development
and manufacturing of lenabasum in connection with Kaken’s commercialization efforts. As a result, and in the event Kaken
partners with other companies in other foreign jurisdictions in connection with the development and manufacturing of lenabasum,
we may be exposed to material risks of theft of our proprietary information and other intellectual property, including technical
data, manufacturing processes, data sets or other sensitive information. For example, our products or components may be reverse
engineered by other business partners or other parties, which could result in our patents being infringed or our know-how or trade
secrets stolen. The risk can be by direct intrusion wherein technology and intellectual property is stolen or compromised through
cyber intrusions or physical theft through corporate espionage, including with the assistance of insiders, or via more indirect
routes.
General
Company-Related Risks
We
will need to grow the size of our organization, and we may experience difficulties in managing this growth.
As
of December 31, 2019, we had 141 full-time employees. As our development and commercialization plans and strategies develop, we
will need to expand the size of our employee base for managerial, operational, sales, marketing, financial and other resources.
Future growth would impose significant added responsibilities on members of management, including the need to identify, recruit,
maintain, motivate and integrate additional employees. In addition, our management may have to divert a disproportionate amount
of its attention away from our day-to-day activities and devote a substantial amount of time to managing these growth activities.
Our future financial performance and our ability to commercialize our drug candidates and our ability to compete effectively will
depend, in part, on our ability to effectively manage our future growth.
Future
capital raises may dilute our existing stockholders’ ownership and/or have other adverse effects on our operations.
If
we raise additional capital by issuing equity securities, our existing stockholders’ percentage ownership will be reduced
and these stockholders may experience substantial dilution. We may also issue equity securities that provide for rights, preferences
and privileges senior to those of our common stock. If we raise additional funds by issuing debt securities, these debt securities
would have rights senior to those of our common stock and the terms of the debt securities issued could impose significant restrictions
on our operations, including liens on our assets. If we raise additional funds through collaborations and licensing arrangements,
we may be required to relinquish some rights to our technologies or candidate products, or to grant licenses on terms that are
not favorable to us.
If
we are not successful in attracting and retaining highly qualified personnel, we may not be able to successfully implement our
business strategy. In addition, the loss of the services of certain key employees, including Yuval Cohen, our Chief Executive
Officer, Barbara White, our Chief Medical Officer, Craig Millian, our Chief Commercial Officer, Robert Discordia, our Chief Operating
Officer, and Sean Moran, our Chief Financial Officer would adversely impact our business prospects.
Our
ability to compete in the highly competitive pharmaceuticals industry depends in large part upon our ability to attract highly
qualified managerial, scientific and medical personnel. In order to induce valuable employees to remain with us, we intend to
provide employees with stock options that vest over time. The value to employees of stock options that vest over time will be
significantly affected by movements in the price of our common stock that we will not be able to control and may at any time be
insufficient to counteract more lucrative offers from other companies.
Our
management team has expertise in many different aspects of drug development and commercialization. However, we will need to hire
additional personnel as we further develop our drug candidates. Competition for skilled personnel in our market is intense and
competition for experienced scientists may limit our ability to hire and retain highly qualified personnel on acceptable terms.
Despite our efforts to retain valuable employees, members of our management, scientific and medical teams may terminate their
employment with us on short notice. We have entered into employment agreements with certain of our executive officers. However,
these employment arrangements provide for at-will employment, which means that any of our employees could leave our employment
at any time, with or without notice. The loss of the services of any of our executive officers or other key employees could potentially
harm our business, operating results or financial condition. In particular, we believe that the loss of the services of Yuval
Cohen, Ph.D., our Chief Executive Officer, Barbara White, M.D., our Chief Medical Officer, Craig Millian, our Chief Commercial
Officer and Sean Moran, C.P.A., M.B.A., our Chief Financial Officer, would have a material adverse effect on our business. Our
success also depends on our ability to continue to attract, retain and motivate highly skilled junior, mid-level, and senior managers
as well as junior, mid-level, and senior scientific and medical personnel.
Other
pharmaceutical companies with which we compete for qualified personnel have greater financial and other resources, different risk
profiles, and a longer history in the industry than we do. They also may provide more diverse opportunities and better chances
for career advancement. Some of these characteristics may be more appealing to high-quality candidates than what we have to offer.
If we are unable to continue to attract and retain high-quality personnel, the rate and success at which we can develop and commercialize
product candidates would be limited.
If
product liability lawsuits are brought against us, we may incur substantial liabilities and may be required to limit commercialization
of our drug candidates.
We
face a potential risk of product liability as a result of the clinical testing of our drug candidates and will face an even greater
risk if we commercialize our drug candidates. For example, we may be sued if any product we develop or any materials that we use
in our products allegedly causes injury or is found to be otherwise unsuitable during product 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 and 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 drug candidates. Even successful defense would require
significant financial and management resources. Regardless of the merits or eventual outcome, liability claims may result in:
|
●
|
decreased
demand for our drug candidates;
|
|
●
|
injury
to our reputation;
|
|
●
|
withdrawal
of clinical trial participants;
|
|
●
|
costs
to defend the related litigation;
|
|
●
|
a
diversion of management’s time and our resources;
|
|
●
|
substantial
monetary awards to trial participants or patients;
|
|
●
|
product
recalls, withdrawals or labeling, marketing or promotional restrictions;
|
|
●
|
the
inability to commercialize our drug candidates; and
|
|
●
|
a
decline in the value of our stock.
|
Our
inability to obtain and retain sufficient product liability insurance at an acceptable cost to protect against potential product
liability claims could prevent or inhibit the commercialization of products we develop. We intend to obtain product liability
insurance covering our clinical trials. Although we will maintain such insurance, any claim that may be brought against us could
result in a court judgment or settlement in an amount that is not covered, in whole or in part, by our insurance or that is in
excess of the limits of our insurance coverage. Our insurance policies also have various exclusions, and we may be subject to
a product liability claim for which we have no coverage. We may have to pay any amounts awarded by a court or negotiated in a
settlement that exceed our coverage limitations or that are not covered by our insurance, and we may not have, or be able to obtain,
sufficient capital to pay such amounts.
We
may acquire businesses, assets or products, or form strategic alliances, in the future, and we may not realize the benefits of
such acquisitions.
We
may acquire additional businesses, assets or products, form strategic alliances or create joint ventures with third parties that
we believe will complement or augment our existing business. If we acquire businesses with promising markets or technologies,
we may not be able to realize the benefit of acquiring such businesses if we are unable to successfully integrate them with our
existing operations and company culture. We may encounter numerous difficulties in developing, manufacturing and marketing any
new delay or prevent us from realizing their expected benefits or enhancing our business. We cannot assure you that, following
any such acquisition, we will achieve the expected synergies to justify the transaction.
Risks
Related to our Common Stock
Our
affiliates may control our company for the foreseeable future, including the outcome of matters requiring stockholder approval.
Our
officers, directors, and five percent stockholders collectively owned approximately 26.3% of our outstanding shares of common
stock as of December 31, 2019. This concentration of voting power and control could have a significant effect in delaying, deferring
or preventing an action that might otherwise be beneficial to our other stockholders and be disadvantageous to our stockholders
with interests different from those entities and individuals. Certain of these individuals also have significant control over
our business, policies and affairs as officers or directors of our company. Therefore, you should not invest in reliance on your
ability to have any control over our company.
An
active, liquid trading market for our common stock may not be sustained.
Presently,
our common stock is traded on the Nasdaq Global Market, or Nasdaq, and as we are in our early stages, an investment in our company
may require a long-term commitment, with no certainty of return. If we are unable to maintain an active, liquid active trading
market:
|
●
|
investors
may have difficulty buying and selling or obtaining market quotations;
|
|
●
|
market
visibility for shares of our common stock may be limited; and
|
|
●
|
a
lack of visibility for shares of our common stock may have a depressive effect on the market price for shares of our common
stock.
|
The
lack of an active market could impair your ability to sell your shares at the time you wish to sell them or at a price that you
consider reasonable. The lack of an active market may also reduce the fair market value of your shares. An inactive market may
also impair our ability to raise capital to continue to fund operations by selling shares and may impair our ability to acquire
additional intellectual property assets by using our shares as consideration.
We
are currently listed on the Nasdaq Global Market. If we are unable to maintain listing of our securities on the Nasdaq Global
Market or any stock exchange, our stock price could be adversely affected and the liquidity of our stock and our ability to obtain
financing could be impaired and it may be more difficult for our stockholders to sell their securities.
Although
our common stock is currently listed on the Nasdaq Global Market, we may not be able to continue to meet the exchange’s
minimum listing requirements or those of any other national exchange. If we are unable to maintain listing on Nasdaq or if a liquid
market for our common stock does not develop or is sustained, our common stock may remain thinly traded.
The
Listing Rules of Nasdaq require listing issuers to comply with certain standards in order to remain listed on its exchange. If,
for any reason, we should fail to maintain compliance with these listing standards and Nasdaq should delist our securities from
trading on its exchange and we are unable to obtain listing on another national securities exchange, a reduction in some or all
of the following may occur, each of which could have a material adverse effect on our stockholders:
|
●
|
the
liquidity of our common stock;
|
|
●
|
the
market price of our common stock;
|
|
●
|
our
ability to obtain financing for the continuation of our operations;
|
|
●
|
the
number of institutional and general investors that will consider investing in our common stock;
|
|
●
|
the
number of investors in general that will consider investing in our common stock;
|
|
●
|
the
number of market makers in our common stock;
|
|
●
|
the
availability of information concerning the trading prices and volume of our common stock; and
|
|
●
|
the
number of broker-dealers willing to execute trades in shares of our common stock.
|
The
market price of our common stock may be significantly volatile.
The
market price for our common stock may be volatile and subject to wide fluctuations in response to factors including the following:
|
●
|
actual
or anticipated fluctuations in our quarterly or annual operating results;
|
|
●
|
changes
in financial or operational estimates or projections;
|
|
●
|
conditions
in markets generally;
|
|
●
|
changes
in the economic performance or market valuations of companies similar to ours; and
|
|
●
|
general
economic or political conditions in the United States or elsewhere.
|
In
particular, the market prices of biotechnology companies like ours have been highly volatile due to factors, including, but not
limited to:
|
●
|
any
delay or failure to conduct a clinical trial for our product or receive approval from the FDA and other regulatory agencies;
|
|
●
|
developments
or disputes concerning a company’s intellectual property rights;
|
|
●
|
technological
innovations of such companies or their competitors;
|
|
●
|
changes
in market valuations of similar companies;
|
|
●
|
announcements
by such companies or their competitors of significant contracts, acquisitions, strategic partnerships, joint ventures, capital
commitments, new technologies, or patents; and
|
|
●
|
failure
to complete significant transactions or collaborate with vendors in manufacturing a product.
|
The
securities market has from time to time experienced significant price and volume fluctuations that are not related to the operating
performance of particular companies. These market fluctuations may also materially and adversely affect the market price of shares
of our common stock.
Future
sales of shares by existing stockholders could cause our stock price to decline.
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, 2019, we had outstanding options to purchase an aggregate of 13,245,366 shares of our common stock at a weighted
average exercise price of $5.19 per share and warrants to purchase an aggregate of 1,000,000 shares of our common stock at a weighted
average exercise price of $13.20 per share. The exercise of such outstanding options and warrants will result in further dilution
of your investment. If our existing stockholders sell substantial amounts of our common stock in the public market, or if the
public perceives that such sales could occur, this could have an adverse impact on the market price of our common stock, even
if there is no relationship between such sales and the performance of our business.
We
do not currently intend to pay dividends on our common stock in the foreseeable future, and consequently, your ability to achieve
a return on your investment will depend on appreciation in the price of our common stock.
We
have never declared or paid cash dividends on our common stock and do not anticipate paying any cash dividends to holders of our
common stock in the foreseeable future. Consequently, investors must rely on sales of their common stock after price appreciation,
which may never occur, as the only way to realize any future gains on their investments. There is no guarantee that shares of
our common stock will appreciate in value or even maintain the price at which our investors have purchased their shares.
We
incur significant costs and devote substantial management time as a result of operating as a public company, and we expect those
costs to increase, particularly after we are no longer an “emerging growth company.”
As
a public company, we incur significant legal, accounting and other expenses. For example, we are required to comply with certain
of the requirements of the Sarbanes-Oxley Act and the Dodd-Frank Wall Street Reform and Consumer Protection Act, as well as rules
and regulations subsequently implemented by the SEC, including the establishment and maintenance of effective disclosure and financial
controls and changes in corporate governance practices. We expect that compliance with these requirements will increase our legal
and financial compliance costs and will make some activities more time consuming and costly. In addition, we expect that our management
and other personnel will need to divert attention from operational and other business matters to devote substantial time to these
public company requirements. In particular, we expect to incur significant expenses and devote substantial management effort toward
ensuring compliance with the requirements of Section 404 of the Sarbanes-Oxley Act. In addition, we expect to incur additional
management time and cost to comply with the more stringent reporting requirements applicable to companies that are deemed accelerated
filers or large accelerated filers, including complying with the auditor attestation requirements of Section 404 of the Sarbanes-Oxley
Act. We currently do not have an internal audit function, and we will need to hire or contract for additional accounting and financial
staff with appropriate public company experience and technical accounting knowledge.
We
cannot predict or estimate the amount of additional costs we may incur as a result of becoming a public company or the timing
of such costs.
There
may be limitations on the effectiveness of our internal controls, and a failure of our control systems to prevent error or fraud
may materially harm our company.
We
are required, pursuant to Section 404 of the Sarbanes-Oxley Act, to furnish a report by our management on, among other things,
the effectiveness of our internal control over financial reporting. This assessment will need to include disclosure of any material
weaknesses identified by our management in our internal control over financial reporting. A material weakness is a deficiency,
or combination of deficiencies, in internal control over financial reporting such that there is a reasonable possibility that
a material misstatement of annual or interim financial statements will not be prevented or detected on a timely basis.
As
of December 31, 2019, we have identified material weaknesses in our internal control over financial reporting related to our control
environment over the internal control activities and our information technology general controls. If our steps are insufficient
to successfully remediate these material weaknesses and otherwise maintain an effective system of internal control over financial
reporting, the reliability of our financial reporting, investor confidence in us and the value of our common stock could be adversely
affected.
Effective
internal control over financial reporting is necessary for us to provide reliable and timely financial reports and, together with
adequate disclosure controls and procedures, are designed to reasonably detect and prevent fraud. Any failure to implement required
new or improved controls, or difficulties encountered in their implementation could cause us to fail to meet our reporting obligations.
Undetected material weaknesses in our internal control over financial reporting could lead to financial statement restatements
and require us to incur the expense of remediation.
Moreover,
we do not expect that disclosure controls or internal control over financial reporting will prevent all error and all fraud. A
control system, no matter how well designed and operated, can provide only reasonable, not absolute, assurance that the control
system’s objectives will be met. Further, the design of a control system must reflect the fact that there are resource constraints
and the benefits of controls must be considered relative to their costs. Because of the inherent limitations in all control systems,
no evaluation of controls can provide absolute assurance that all control issues and instances of fraud, if any, have been detected.
Failure of our control systems to detect or prevent error or fraud could materially adversely impact us.
Our
remediation efforts may not enable us to avoid a material weakness in our internal control over financial reporting in the future.
Any of the foregoing occurrences, should they come to pass, could negatively impact the public perception of our company, which
could have a negative impact on our stock price.
We
may be unable to complete our analysis of our internal controls over financial reporting in a timely manner, or these internal
controls may not be determined to be effective, which may adversely affect investor confidence in our company and, as a result,
the value of our common stock.
We
may not be able to complete our evaluation and testing of our internal control over financial reporting and any
required remediation in a timely fashion. During the evaluation and testing process, if we identify one or more material weaknesses
in our internal control over financial reporting, we will be unable to assert that our internal controls are effective.
If
we are unable to assert that our internal control over financial reporting is effective, or, if applicable, our independent registered
public accounting firm is unable to express an opinion on the effectiveness of our internal controls, we could lose investor confidence
in the accuracy and completeness of our financial reports, which would cause the price of our common stock to decline, and we
may be subject to investigation or sanctions by the SEC. We will also be required to disclose changes made in our internal control
and procedures on a quarterly basis.
Our
remediation efforts may not enable us to avoid a material weakness in our internal control over financial reporting in the future.
Any of the foregoing occurrences, should they come to pass, could negatively impact the public perception of our company, which
could have a negative impact on our stock price.
Upon
dissolution of our company, you may not recoup all or any portion of your investment.
In
the event of a liquidation, dissolution or winding-up of our company, whether voluntary or involuntary, the proceeds and/or assets
of our company remaining after giving effect to such transaction, and the payment of all of our debts and liabilities and distributions
required to be made to holders of any outstanding preferred stock will then be distributed to the stockholders of common stock
on a pro rata basis. There can be no assurance that we will have available assets to pay to the holders of common stock, or any
amounts, upon such a liquidation, dissolution or winding-up of our Company. In this event, you could lose some or all of your
investment.
Our
ability to use our net operating loss carryforwards and certain other tax attributes may be limited.
As
a result of our merger in April 2014 with Corbus Pharmaceuticals, Inc., our wholly-owned subsidiary, our ability to utilize our
federal net operating loss, carryforwards and federal tax credit prior to that date may be limited under Sections 382 of the Internal
Revenue Code. The limitations apply if an “ownership change,” as defined by Section 382, occurs. Generally, an ownership
change occurs if the percentage of the value of the stock that is owned by one or more direct or indirect “five percent
shareholders” increases by more than 50 percentage points over their lowest ownership percentage at any time during the
applicable testing period (typically three years). In addition, future changes in our stock ownership, which may be outside of
our control, may trigger an “ownership change” and, consequently, Section 382 limitations. As a result, if we earn
net taxable income, our ability to use our pre-change net operating loss carryforwards and other tax attributes to offset United
States federal taxable income may be subject to limitations, which could potentially result in increased future tax liability
to us.
The
2017 comprehensive tax reform bill could adversely affect our business and financial condition.
On
December 22, 2017, President Trump signed into law new tax legislation, or the Tax Act, which significantly reforms the Internal
Revenue Code of 1986, as amended. The Tax Act, among other things, contains significant changes to corporate taxation, including
reduction of the corporate tax rate from a top marginal rate of 35% to a flat rate of 21%; limitation of the tax deduction for
interest expense to 30% of adjusted earnings (except for certain small businesses); limitation of the deduction of net operating
losses generated in tax years beginning after December 31, 2017 to 80% of taxable income, indefinite carryforward of net operating
losses generated in tax years after 2018 and elimination of net operating loss carrybacks; changes in the treatment of offshore
earnings regardless of whether they are repatriated; current inclusion in U.S. federal taxable income of certain earnings of controlled
foreign corporations, mandatory capitalization of research and development expenses beginning in 2022; immediate deductions for
certain new investments instead of deductions for depreciation expense over time; further deduction limits on executive compensation;
and modifying, repealing and creating many other business deductions and credits, including the reduction in the orphan drug credit
from 50% to 25% of qualifying expenditures. We continue to examine the impact this tax reform legislation may have on our business.
Notwithstanding the reduction in the corporate income tax rate, the overall impact of the Tax Act is uncertain and our business
and financial condition could be adversely affected. The impact of this tax reform on holders of our common stock is also uncertain
and could be adverse. This periodic report does not discuss any such tax legislation or the manner in which it might affect us
or our stockholders in the future. We urge our stockholders to consult with their legal and tax advisors with respect to such
legislation.
Our
certificate of incorporation, as amended, allows for our board to create new series of preferred stock without further approval
by our stockholders, which could adversely affect the rights of the holders of our common stock.
Our
board of directors has the authority to fix and determine the relative rights and preferences of preferred stock. We anticipate
that our board of directors will have the authority to issue up to 10,000,000 shares of our preferred stock without further stockholder
approval. As a result, our board of directors could authorize the issuance of a series of preferred stock that would grant to
holders the preferred right to our assets upon liquidation and the right to receive dividend payments before dividends are distributed
to the holders of common stock. In addition, our board of directors could authorize the issuance of a series of preferred stock
that has greater voting power than our common stock or that is convertible into our common stock, which could decrease the relative
voting power of our common stock or result in dilution to our existing stockholders.