General
Lipocine
Inc. (“Lipocine” or the “Company”) was originally incorporated on June 19, 1997, under the laws of the State
of Delaware.
We
are a clinical-stage biopharmaceutical company focused on applying our oral drug delivery technology for the development of pharmaceutical
products focusing on neuroendocrine and metabolic disorders. Our proprietary delivery technologies are designed to improve
patient compliance and safety through orally available treatment options. Our primary development programs are based on oral delivery
solutions for poorly bioavailable drugs. We have a portfolio of differentiated innovative product candidates that target high unmet
needs for neurological and psychiatric CNS disorders, liver diseases, and hormone supplementation for men and women.
We
entered into a license agreement for the development and commercialization our product candidate, TLANDO®, an oral testosterone replacement
therapy (“TRT”) comprised of testosterone undecanoate (“TU”). TLANDO is a registered trademark assigned to Antares.
On October 14, 2021, we entered into a license agreement (the “Antares License Agreement”) with Antares Pharma, Inc. (“Antares”
or our “Licensee”), pursuant to which we granted to Antares an exclusive, royalty-bearing, sublicensable right and license
to develop and commercialize, upon final approval of TLANDO from the United States Food and Drug Administration (“FDA”),
the TLANDO product for TRT in the U.S. Any FDA required post-marketing studies will also be the responsibility of our licensee,
Antares. Prior to entering into the License Agreement, on December 8, 2020, we received tentative approval from the FDA
regarding our new drug application (“NDA”) filed in February 2020 for TLANDO as a TRT in adult males for conditions associated
with a deficiency of endogenous testosterone, also known as hypogonadism. In granting tentative approval, the FDA concluded that TLANDO
has met all required quality, safety and efficacy standards necessary for approval. However, TLANDO has not received final approval and
is not eligible for final approval to market in the U.S. until the expiration of the exclusivity period previously granted to Clarus
Therapeutics, Inc. (“Clarus”) with respect to Jatenzo®, which expires
on March 27, 2022. The FDA has affirmed to Antares the acceptance of the resubmission of the NDA for TLANDO filed on January 28, 2022.
The FDA has designated the NDA as a Class 1 resubmission with a two-month review goal period and set a target action date of March
28, 2022 under the Prescription Drug User Fee Act (PDUFA).
Additional
pipeline candidates include: LPCN 1148 comprising a novel prodrug of testosterone, testosterone laurate (“TL”), for the management
of decompensated cirrhosis; LPCN 1144, an oral prodrug of androgen receptor modulator for the treatment of non-cirrhotic non-alcoholic
steatohepatitis (“NASH”) which has completed phase 2 testing; LPCN 1111 (TLANDO® XR), a next generation oral TRT product
comprised of testosterone tridecanoate (“TT”) with the potential for once daily dosing which has completed Phase 2 testing;
LPCN 1107, potentially the first oral hydroxy progesterone caproate (“HPC”) product indicated for the prevention of recurrent
preterm birth (“PTB”), which has completed a dose finding clinical study in pregnant women and has been granted orphan
drug designation by the FDA; and neuroactive steroids (“NAS”) including LPCN 1154 for postpartum depression (PPD) and
LPCN 2101 for epilepsy.
The
following chart summarizes the status of our product candidate development programs:
Impact
of COVID-19 Pandemic
The
ongoing COVID-19 pandemic has disrupted and may continue to disrupt our business and delay our preclinical and clinical programs and
timelines. The extent to which the COVID-19 pandemic may impact our future operating results and financial condition is uncertain. We
initiated our LPCN 1148 Phase 2 trial for the management of cirrhosis in 2021. The COVID-19 surge observed in the fourth quarter of 2021
and the first quarter of 2022 has impacted enrollment in this study. We do not yet know the full extent, if any, of any potential delays or commercial
challenges, which could prevent or delay Antares from commercially launching TLANDO. For more information regarding risks related to
the ongoing COVID-19 pandemic, please see the risk factor entitled “The ongoing outbreak of coronavirus around the world could
adversely impact our business and operating results,” in Part I. Item 1A of this Annual Report on Form 10-K. To the
extent the ongoing COVID-19 pandemic adversely affects our business and financial results, it may also have the effect of heightening
many of the other risks set forth under “Risk Factors” in this Annual Report on Form 10-K.
Strategy
Our
goal is to become a leading biopharmaceutical company focused on applying our proprietary drug delivery technology for the development
of pharmaceutical products focusing on neuroendocrine and metabolic disorders. The key components of our strategy are to:
Build
a diversified multi-asset pipeline of novel therapies. We intend to employ a value-driven strategy based on our proprietary technology
platform to identify and develop product candidates for neuroendocrine and metabolic disorders including Central Nervous System
(CNS) disorders and end stage diseases such as decompensated cirrhosis. We intend to focus on product candidates that we believe are
differentiated, have attractive profiles, and address a clear unmet medical need that we can advance quickly and efficiently into late-stage
development.
Advance
LPCN 1148, a unique prodrug of androgen receptor agonist to manage end stage (decompensated) liver cirrhosis disease. We believe
LPCN 1148, a novel prodrug of testosterone, could address a significant unmet medical need in patients with decompensated liver
cirrhosis accompanied with muscle disorder such as secondary sarcopenia. Sarcopenia in male cirrhotic patients is known to be independently
associated with poor outcomes including quality of life, increased decompensation events such as hepatic encephalopathy, increased hospital
admissions, and increased mortality rate. We believe LPCN 1148 may be eligible for an orphan drug designation. Enrollment in a multi-center
placebo-controlled phase 2 trial is currently ongoing.
Support
our licensee in commercialization of our licensed oral TRT option. We believe the TRT market needs a differentiated, convenient
oral option. We have exclusively licensed rights to TLANDO to Antares for commercialization of TLANDO in the US. We plan to support our
licensee’s efforts to effectively enable the availability of TLANDO to patients in a timely manner, in addition to receiving
milestone and royalty payments associated with TLANDO commercialization as agreed to in the Antares License Agreement.
Develop
partnership(s) to continue the advancement of pipeline assets. We continuously strive to prioritize our resources in seeking co-development
partnerships of our pipeline assets. We currently plan to explore partnering of LPCN 1144, our candidate for treatment of non-cirrhotic
NASH, LPCN 1107, our candidate for prevention of pre-term birth, and LPCN 1111, a once-a-day therapy candidate for TRT.
LPCN
1148: Oral Product Candidate for the Management of Decompensated Cirrhosis
We
are currently evaluating LPCN 1148 comprising testosterone laurate (TL) for the management of decompensated cirrhosis. We
believe LPCN 1148 targets unmet needs for cirrhosis subjects including improvement in the quality of life of patients while on the
liver transplant waiting list, prevention or reduction in the occurrence of new decompensation events, and improvement
in post liver transplant survival, including outcomes and costs.
We
are currently conducting a Phase 2 POC study (NCT04874350) in male cirrhotic subjects to evaluate the therapeutic potential of LPCN 1148
for the management of sarcopenia. The ongoing Phase 2 POC study is a prospective, multi-center, randomized, placebo-controlled
study in male sarcopenic cirrhotic patients. Subjects will be randomized 1:1 to one of two arms. The treatment arm is an oral dose of
LPCN 1148, and the second arm is a matching placebo. The primary endpoint is change in skeletal muscle index at week 24 with key secondary
endpoints including change in liver frailty index, rates of breakthrough hepatic encephalopathy, and number of waitlist events,
including all-cause mortality. Total treatment is expected to be 52 weeks. We currently expect enrollment in the Phase 2 study to be
complete by the end of the second or third quarter of 2022 and top-line 24-week results by the end of 2022 or during the first
quarter of 2023.
Key
outcomes of interest from the Phase 2 study include clinical outcomes such as overall survival and new decompensation events (including hepatic
encephalopathy and/or ascites occurrences), rates of survival to transplant, rates of hospitalizations, infections, etc.,
muscle changes such as muscle mass, body composition, myosteatosis (muscle fat), functional capacity changes such as liver frailty
index (LFI), patient reported outcomes (PROs), and biochemical markers including hematocrit for anemia status, albumin,
creatinine/kidney function, etc.
Disease
Overview – Cirrhosis
There
are over 2 million cases of cirrhosis worldwide,
with over 500,000 people living with decompensated cirrhosis in the U.S. and nonalcoholic fatty liver disease is the most
rapidly increasing indication for liver transplant. 62% of those on the liver transplant (LT) waitlist are male. The economic burden
(approximately $812,500/transplant) is high and continues to increase. Each year about half of the approximately 17,000
people in U.S. on the LT waitlist undergo transplant, while nearly 3000 patients either die or are removed from the list because
they were “too sick to transplant.”
Liver
cirrhosis is defined as the histological development of regenerative nodules surrounded by fibrous bands. Cirrhotic patients typically
have a years-long silent, asymptomatic phase (compensated cirrhosis) until decreasing liver function and increasing portal pressure move
the patient into the symptomatic phase (decompensated cirrhosis). Transition to decompensated cirrhosis is marked by clinical events
including ascites, encephalopathy, jaundice, and/or variceal hemorrhage. Decompensated subjects survive on average less than 2 years.
Common causes of liver cirrhosis include alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), chronic hepatitis B and
C, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and cryptogenic.
Common
complications in cirrhotic patients may include: compromised liver function, portal hypertension, varices in GI tract with internal bleeding,
edema, ascites, hepatic encephalopathy, compromised immunity with post-transplant acute rejection risk, high sodium levels, increased
bilirubin, low albumin level, insulin resistance with impaired peripheral uptake of glucose, depression, accelerated muscle disorder
in the form of sarcopenia, myosteotosis, and frailty with compromised energetics, bone diseases (e.g., osteoporosis), high alkaline phosphatase
(ALP), cachexia, malnutrition, weight loss (>5%), symptoms of hypogonadism such as abnormal hair distribution, anemia, sexual dysfunction,
testicular atrophy, muscle wasting, fatigue, osteoporosis, gynecomastia, inflammation with elevated cytokines, and infection risk leading
to hospital admissions and possibly death.
Hepatic
encephalopathy (“HE”), a significant
decompensation event in patient with cirrhosis, is a brain dysfunction caused by liver insufficiency and/or portal systemic shunting.
Because the damaged liver cannot function normally (as in cirrhosis), neurotoxins such as ammonia are inadequately removed
from systemic circulation and travel to the brain, where they affect neurotransmission. This can cause episodes of HE, which may
present as alterations in consciousness, cognition, and behavior that range from minimal to severe. Overt HE occurs in 30% to 40% of
patients with cirrhosis at some point during the clinical course of their disease. As the burden of chronic liver disease and cirrhosis
is increasing, the frequency of HE is also increasing.
Muscle
Disorders and Cirrhosis
Muscle
disorders secondary to cirrhosis could be manifested in the form of several inter-related characteristics such as sarcopenia, myosteotosis,
and frailty impacting muscle mass, strength, quality, and function. Chronic inflammation and oxidative stress have also been reported
to accelerate muscle wasting. Muscle also plays a significant compensatory role in detoxifying ammonia, a neurotoxin and a myotoxin
implicated in precipitation of HE in cirrhosis patients.
Sarcopenia
and associated frailty affect up to 70% of cirrhotic men and are a leading cause of patients being removed from the LT wait list. Due
to the lack of available organs and aging demographics of those on the waitlist, patients that do receive a transplant are “increasingly
being described as frail”. The presence of sarcopenia or frailty is associated with increased risk of hospitalization and hepatic
decompensation, a two-fold increase in waitlist mortality, poor post-transplant outcomes, and reportedly is equivalent to adding 9-10
points to the Model for End-Stage Liver Disease (MELD) score.
Sarcopenia
is typically associated with body composition changes with decreased muscle mass and/or low skeletal muscle index. Change in one
or more of appendicular lean mass, total lean mass, fat mass, high VAT (visceral adipose tissue), waist circumference, weight,
and/or BMI are notable features. Myosteotosis (fat infiltration in muscles) is indicative of poor muscle quality. Frailty is a state
of low energetics accompanied with low physical performance/mobility probably because of poor muscle strength/function and is assessed
via various measures such as decreased gait speed, weak hand grip; slow rising from a chair, balance, isometric knee extension peak torque
or a composite measure such as liver frailty index (LFI).
Reportedly,
as shown in the figure below, muscle disorder such as sarcopenia and myosteotosis in cirrhosis could be a clinically meaningful predictor
of survival and mortality with lower survival in cirrhotic patients with accompanying muscle disorders.
Montano-Loza,
J Cachexia Sarcopenia Muscle. 2016 May; 7(2): 126–135
Muscle Disorders and Mortality
in Liver Cirrhosis
Sarcopenia
develops in the majority of male cirrhosis patients. The main mechanisms associated with sarcopenia and decompensated cirrhosis
include a catabolic state, progressive immobility, imbalance between muscle breakdown and formation, and hormonal changes. Patients are
typically diagnosed with decompensated cirrhosis upon development of cirrhotic symptoms (e.g., jaundice, HE), and the diagnosis is
confirmed via various liver function/imaging tests (e.g., MELD score, liver biopsy, CT scan). A variety of clinical evaluations for
muscle mass, strength, and function are typically used to diagnose sarcopenia. Sarcopenia in cirrhosis also correlates with decompensation
events, particularly HE (sarcopenia is about 2-fold more prevalent in overt HE patients than those without overt HE). Notably,
low testosterone in males is associated with sarcopenia, severity of cirrhosis, and mortality.
Reportedly,
as shown in figure below, sarcopenia is a predictor for increased mortality in cirrhosis (about 2-fold higher compared to no sarcopenia).
Tantai
et al. J. Hepatol. 2022, 76, 588–599
Reportedly,
as shown in figure below, pre transplant sarcopenia in liver cirrhosis often produces poor post-transplant outcomes with higher mortality
rates. Longer post-transplant hospitalization and rehabilitation can be demanding on the individual, both physically and financially.
Englesbe
et al. J Am Coll Surg. 2010 Aug;211(2):271-8
Myosteatosis
in cirrhosis
Myosteatosis,
fat infiltration in muscles, has been found
in many cirrhotic patients undergoing liver transplant evaluation, and studies have associated it with more complications and poor survival.
Myosteatosis is characteristically associated with liver steatosis in NAFLD, resulting from ectopic fat accumulation in skeletal muscle.
Myosteatosis may affect many individuals who do not meet the anthropometric criteria for sarcopenia or obesity. The accumulation of excess
fat in extramyocellular compartments is mostly pathologic. It can be defined as intramuscular (between muscle fibers) or intermuscular
(between muscle fascicles) and is associated with lower muscle function and strength, muscle atrophy, and physical disabilities.
Frailty
and cirrhosis
Frailty
is a state of low energetics accompanied with low physical performance/mobility, usually as a result of poor muscle strength/function
and its presence is assessed via various measures such as decreased gait speed, weak hand grip, slow rising from a chair,
poor balance, low isometric knee extension peak torque or a composite measure such as liver frailty index (LFI).
Reportedly,
as shown in figure below, frailty predicts LT waitlist mortality among outpatients with cirrhosis regardless of the MELD score.
Lai
et al. Am J Transplant. 2014 Aug;14(8):1870-9
The
presence of frailty is associated with increased waitlist death/delisting
Moreover,
it has also been reported, as shown in figure below, that there is a higher incidence of waitlist mortality as the frailty
worsened.
Lai
et al. J Hepatol. 2020 Sep;73(3):575-581.
Trajectory
of liver frailty and mortality
Currently,
there are no FDA approved drugs to treat secondary sarcopenia in cirrhosis. Lipocine is the only clinical-stage company pursuing decompensation
in sarcopenic cirrhotic patients, and no regulatory precedent currently exists for the approval of decompensation or sarcopenia-targeted
therapies. We believe LPCN 1148 has the potential to aid the management of decompensation events in male sarcopenic cirrhotic
patients through the following possible mechanisms of action: myo-augmentation (impact muscle mass and/or quality and/or
function) via myostatin inhibition, myosteatosis reduction, anti-catabolic effect, changes in body composition (increase lean
mass and/or reduce fat mass) and slowing muscle autophagy; inducing hepato-effective actions with improved key liver injury markers;
increase protein synthesis; improve anemia, induce immunomodulation with improvement of immuno-dysregulation, and to lower
infection rates; anti-inflammatory/antioxidant effects by lowering undesirable cytokines such as IL-1, IL-6, and TNF-α;
and to improve mitochondrial function.(1)
| |
(1) |
Ref: Leise.
Mayo Clin Proc. 2014.; Hudson. Eur J Gastroenterol. 2019.; Bajaj. Clin Gastroenterol Hepatol. 2017.; Bohra. World J Gastroenterol.
2020.; Carey, Hepatology, 2019; Sinclair, Ailment Pharmacol Ther, 2016; Lai, Am J Transplant, 2014; Montano-Loza, Clin Transl
Gastroenterol, 2015; Kahn, Clin Transp, 2018; Montano-Loza, J Cach, Sarco, and Musc, 2016. |
LPCN
1144: An Oral Prodrug of Bioidentical Testosterone Product Candidate for the Treatment of NASH
We
are currently evaluating LPCN 1144, an oral prodrug of bioidentical testosterone comprised of TU, for the treatment of non-cirrhotic
NASH.
Disease
Overview – NASH
NASH
is a more advanced state of non-alcoholic fatty liver disease (“NAFLD”) and can progress to a cirrhotic liver or liver failure,
require liver transplant, and can result in hepatocellular carcinoma/ liver cancer, and death. Progression of NASH to end stage
liver disease will soon surpass all other causes of liver failure requiring liver transplantation. Importantly, beyond these critical
conditions, NASH and NAFLD patients additionally suffer heightened cardiovascular risk and, in fact, die more frequently from cardiovascular
events than from liver disease. NAFLD/NASH is becoming more common due to its strong correlation with obesity and metabolic syndrome,
including components of metabolic syndrome such as diabetes, cardiovascular disease and high blood pressure. Twenty to thirty percent
of the U.S. population is estimated to suffer from NAFLD and fifteen to twenty percent of this group progresses to NASH, which
is a substantially large population that lacks an effective therapy. NASH is a silent killer that affects millions in the U.S. Diagnoses
have been on the rise and are expected to increase dramatically in the next decade. Approximately 50% of NASH patients are in adult males.
In men, especially with comorbidities associated with NAFLD/NASH, testosterone deficiency has been associated with an increased visceral
adipose tissue and insulin resistance, which could be factors contributing to NAFLD/NASH. There is currently no approved therapy for
the treatment of NASH although there are several drug candidates currently under development with many clinical failures to date.
The
critical pathophysiologic mechanisms underlying the development and progression of NASH include reduced ability to handle lipids, increased
insulin resistance, injury to hepatocytes and liver fibrosis in response to hepatocyte injury. NASH patients have an excessive accumulation
of fat in the liver resulting primarily from a caloric intake above and beyond energy needs. A healthy liver contains less than 5% fat,
but a liver in someone with NASH can contain more than 20% fat. This abnormal liver fat contributes to the progression to NASH, a liver
necro-inflammatory state that can lead to scarring, also known as fibrosis, and, for some, can progress to cirrhosis and liver failure.
Markers
of Liver Cell Death
Alanine
aminotransferase (“ALT”) is an enzyme that is produced in liver cells and is naturally found in the blood of healthy individuals.
In liver disease, liver cells are damaged and, as a consequence, ALT is released into the blood, increasing ALT levels above the normal
range. Physicians routinely test blood levels of ALT to monitor the health of a patient’s liver. ALT level is a clinically important
biochemical marker of the severity of liver inflammation and ongoing liver disease. Elevated levels of ALT represent general markers
of liver cell death and inflammation without regard to any specific mechanism. Aspartate aminotransferase (“AST”) is a second
enzyme found in the blood that is produced in the liver and routinely measured by physicians along with ALT. As with ALT, AST is often
elevated in liver disease and, like ALT, is considered an overall marker of liver inflammation.
Diagnosis
Most
people with NASH are asymptomatic and their disease is often discovered incidentally following a liver imaging procedure, such as an
ultrasound, prescribed for other reasons or as part of an investigation for elevated liver enzymes. Once suspected clinically, a liver
biopsy is required to definitively diagnose NASH, which necessitates the joint presence of steatosis, ballooning and lobular inflammation.
Once pathologically confirmed, the severity of NAFLD and NASH is determined using the histologically validated NAFLD activity score,
which grades disease activity on a scale of 0 to 8. The NAFLD activity score is the sum of the individual scores for steatosis
(0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) but does not include a score for fibrosis. Fibrosis staging
(F0-F4) relies on the NASH CRN classification (F0 = no fibrosis; F1 = perisinusoidal or portal/periportal fibrosis (not
both); F2 = both perisinusoidal and portal/periportal fibrosis; F3 = bridging fibrosis; F4 = cirrhosis).
Histological
diagnosis remains the gold standard for assessment of NASH and fibrosis. However, given that liver biopsy is associated with risks of
pain, bleeding and other morbidity, as well as significant cost, the procedure is not practical for general patient screening. Several
non-invasive tools such as clinical risk scores and imaging techniques are increasingly used to assess potential NASH patients.
Clinical risk scores such as the NAFLD fibrosis score, Fibrosis-4 index, the Enhanced Liver Fibrosis score and vibration-controlled transient
elastography (“VCTE”), have been validated and are increasingly used. These tools have an excellent negative predictive value
and an acceptable positive predictive value for detection of advanced (≥ F3) fibrosis and are increasingly used in clinical settings.
Extensive efforts are also under way to develop non-invasive means to identify patients with NAS ≥
4 or fibrosis ≥ F2 without a liver biopsy. In draft guidance, the FDA encouraged sponsors to identify biochemical
or noninvasive imaging biomarkers that, once characterized and agreed by the FDA, could replace liver biopsies for patient selection
and efficacy assessment in clinical trials.
We
expect that the validation and subsequent adoption of these new tools will result in an increase in the diagnosis and treatment rates
for NASH in the future.
Current
Status
We
have recently completed the LiFT Phase 2 clinical study in biopsy-confirmed non-cirrhotic NASH subjects. The LiFT
clinical study was a prospective, multi-center, randomized, double-blind, placebo-controlled multiple-arm study in biopsy-confirmed hypogonadal
and eugonadal male NASH subjects with grade F1-F3 fibrosis and a target NAFLD Activity Score ≥ 4 with a 36-week
treatment period. The LiFT clinical study enrolled 56 biopsy confirmed NASH male subjects. Subjects were randomized 1:1:1 to one
of three arms (Treatment A is a twice daily oral dose of 142 mg testosterone equivalent, Treatment B is a twice daily oral dose of 142
mg testosterone equivalent formulated with 217 mg of d-alpha tocopherol equivalent, and the third arm is twice daily matching placebo).
The
primary endpoint of the LiFT clinical study was change in hepatic fat fraction via MRI-PDFF and exploratory liver fat/marker end
points post 12 weeks of treatment. Additionally, key secondary endpoints post 36 weeks of treatment included assessment of histological
change for NASH resolution and/or fibrosis improvement (biopsy) as well as liver fat data (MRI-PDFF). The LiFT clinical
study was not powered to assess statistical significance of any of the secondary endpoints. Other important endpoints included the following:
change in liver injury markers, anthropomorphic measurements, lipids, insulin resistance and inflammatory/fibrosis markers; as well as
patient reported outcomes.
Additionally,
subjects have access to LPCN 1144 through an open label extension (“OLE”) study. The extension study will enable
the collection of additional data on LPCN 1144 for up to a total of 72 weeks of therapy, as well as data for 36 weeks of therapy for
those subjects on placebo in the LiFT study. The OLE is currently on-going and has enrolled 25 subjects. We expect topline results
from the OLE study mid-2022.
Treatments
with LPCN 1144 post 12 weeks of treatment resulted in robust liver fat reduction, assessed by MRI-PDFF, and showed improvement of liver
injury markers with no observed tolerability issues.
Liver
biopsies were performed at baseline (“BL”) and after 36 weeks of treatment (“EOS”). Prespecified biopsy analyses
included NASH Clinical Research Network (“CRN”) scoring as well as a continuous paired (“Paired Technique”) and
digital technique (“Digital Technique-Fibronest”). All biopsy analyses were performed on the same slides and the reads for
the three techniques were done independently. Analysis sets included the NASH Resolution Set (all subjects that have BL and EOS biopsy
with NASH at BL [NAS ≥4 with lobular inflammation score ≥ 1 and hepatocyte ballooning score ≥1 at BL] (n=37)), the Biopsy Set
(all subjects with baseline and EOS biopsies (n=44)), and the Safety Set (all randomized subjects (n=56)).
Both
LPCN 1144 treatment arms met with statistical significance the pre-specified accelerated approval regulatory endpoint of NASH resolution
with no worsening of fibrosis based on NASH CRN scoring. Additionally, both treatment arms showed substantial improvement of the observed
NASH activity in steatosis, inflammation, and ballooning.
Key
results from the LiFT clinical study are presented in the following tables and figures:
In
both treatment arms, substantial reductions in markers of liver injury compared to placebo were observed post four weeks of treatment
and were sustained through EOS. Using all available Safety Set data, ALT decreased up to a mean of 23.4 U/L at EOS from all group mean
baseline of 51.5 U/L and AST decreased up to a mean of 13.3 U/L at EOS from all group mean baseline of 31.9 U/L.
Positive
effects in appendicular lean mass and whole-body fat mass, an indicator overall tissue quality, based on dual-energy X-ray absorptiometry
scans were noted in both LPCN 1144 treatment arms.
Finding
on liver injury marker and positive effects on body composition can be seen in the following table:
During
the 36 weeks of treatment, LPCN 1144 was well tolerated with an overall safety profile comparable to placebo.
In
November 2021, the FDA granted Fast Track Designation
to LPCN 1144 as a treatment for non-cirrhotic NASH. The Fast Track program is designed to accelerate the development and expedite the
review of products, such as LPCN 1144, which are intended to treat serious diseases and for which there is an unmet medical need.
We
had a written only response from FDA for a LPCN 1144 Type C meeting with the FDA in January 2022 to discuss the development path
forward with LPCN 1144. The FDA acknowledged that the NDA submission of LPCN 1144 would be via 505(b)2 regulatory pathway
and agreed that no additional non-clinical studies are needed to support an NDA submission. The FDA recommended to request
an end of phase 2 (EOP2) meeting. The FDA acknowledged that in the LiFT study subjects achieved improvements in
key components associated with NASH histopathology after 36-weeks of treatment with LPCN 1144 in adult males and agreed that the proposed
multicomponent primary surrogate endpoint is acceptable for seeking approval under the accelerated approval pathway. The FDA also
recommended either conducting a separate dose–ranging study prior to phase 3 or evaluating multiple doses in phase 3. The FDA
agreed that the proposed primary multicomponent surrogate endpoint, NASH resolution with no worsening of fibrosis, is acceptable
for seeking approval under the accelerated approval pathway and the FDA recommended a phase 3 trial with a study
duration of 72 weeks. The FDA has requested that Lipocine submit an updated Phase 3 protocol for FDA
feedback on the study design and our next step will be to request an end-of-phase 2 (EOP2) meeting to discuss the phase 3 and confirmatory
trial designs, including the plan for reading liver histopathology.
We are exploring the possibility
of licensing LPCN 1144 to a third party, although no licensing agreement has been entered into by the Company. No assurance can be given
that any license agreement will be completed, or, if an agreement is completed, that such an agreement would be on acceptable terms.
TLANDO: An Oral Product Candidate for Testosterone
Replacement Therapy
As previously described, under
the Antares License Agreement, we granted to Antares an exclusive, royalty-bearing, sublicensable right and license to develop and commercialize,
upon final approval of TLANDO from the FDA, our TLANDO product for TRT in the U.S. Prior to entering into the Antares License Agreement
on December 8, 2020, we received tentative approval from the FDA regarding our NDA filed in February 2020 for TLANDO as a TRT in adult
males for conditions associated with a deficiency of endogenous testosterone, also known as hypogonadism. In granting tentative approval,
the FDA concluded that TLANDO has met all required quality, safety and efficacy standards necessary for approval. However, TLANDO has
not received final approval and is not eligible for final approval to market in the U.S. until the expiration of the exclusivity period
previously granted to Clarus with respect to Jatenzo®, which expires on March 27,
2022. The FDA has affirmed to Antares the acceptance of the resubmission of the NDA for TLANDO. The FDA has designated the NDA as a Class
1 resubmission with a two-month review goal period and set a target action date of March 28, 2022, under the PDUFA. Any FDA requirement
to conduct certain post-marketing studies will also be the responsibility of our licensee, Antares.
Proof-of-concept for TLANDO
was initially established in 2006, and subsequently TLANDO was licensed in 2009 to Solvay Pharmaceuticals, Inc. which was then acquired
by Abbott Products, Inc. (“Abbott”). Following a portfolio review associated with the spin-off of AbbVie Inc. by Abbott in
2011, the rights to TLANDO were reacquired by us. All obligations under the prior license agreement have been completed except that Lipocine
will owe Abbott a perpetual 1% royalty on net sales. Such royalties are limited to $1 million in the first two calendar years following
product launch, after which period there is not a cap on royalties and no maximum aggregate amount. If generic versions of any such product
are introduced, then royalties are reduced by 50%.
Under the Pediatric Research
Equity Act (“PREA”), if TLANDO receives full approval, under the terms of the Antares Licensing Agreement, Antares will need
to address the PREA requirement to assess the safety and effectiveness of TLANDO in pediatric patients. The FDA may also require certain
post-marketing studies to be conducted which will also be the responsibility of our licensee, Antares.
Upon execution of the Antares
License Agreement, Antares paid to us an initial payment of $11.0 million. Antares will also make additional payments of $5.0 million
to us on each of January 1, 2025, and January 1, 2026, provided that certain conditions are satisfied. We are also eligible to receive
milestone payments of up to $160.0 million in the aggregate, depending on the achievement of certain sales milestones in a single calendar
year with respect to all products licensed by Antares under the Antares License Agreement. In addition, upon commercialization, we will
receive tiered royalty payments at rates ranging from percentages in the mid-teens to up to 20% of net sales of TLANDO in the United
States, subject to certain minimum royalty obligations. Further, on October 14, 2021, we assigned our Manufacturing Agreement, dated
August 27, 2013, by and between the Company and Encap Drug Delivery (the “Manufacturing Agreement”) to Antares as part of
the Antares License Agreement.
LPCN 1111: A Next-Generation Long-Acting Oral
Product Candidate for TRT
LPCN 1111: is a next-generation,
novel ester prodrug of testosterone comprised of testosterone tridecanoate (TT) which uses the proprietary delivery technology to enhance
solubility and improve systemic absorption. We completed a Phase 2b dose finding study in hypogonadal men in the third quarter of 2016.
The primary objectives of the Phase 2b clinical study were to determine the starting Phase 3 dose of LPCN 1111 along with safety and
tolerability of LPCN 1111 and its metabolites following oral administration of single and multiple doses in hypogonadal men. Good dose-response
relationship was observed over the tested dose range in the Phase 2b study. Additionally, the target Phase 3 dose met primary and secondary
end points. Overall, LPCN 1111 was well tolerated with no drug-related severe or serious adverse events reported in the Phase 2b study.
In February 2018 we had a
meeting with the FDA to discuss these pre-clinical results and to discuss the Phase 3 clinical study and path forward for LPCN 1111.
Based on the results of the FDA meeting and additional pre-clinical studies conducted after the FDA meeting, we have proposed a Phase
3 protocol for LPCN 1111 and have solicited FDA feedback. Based on initial FDA feedback, we expect the Phase 3 clinical trial design
to follow the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (“ICH”)
guidelines and will include at least a three-month efficacy treatment period and a one-year safety component for approximately 100 subjects.
We are currently seeking further clarification from FDA with respect to the total subject LPCN 1111 exposure information needed for an
NDA filing. We continue to refine the Phase 3 protocol and plan to request FDA approval of the protocol once it is finalized. Additionally,
the FDA previously requested that a food effect and a phlebotomy study be completed, and that ambulatory blood pressure monitoring (“ABPM”)
be included as part of the Phase 3 clinical study. We are currently transferring the manufacturing of LPCN 1111 to a third-party contract
manufacturer and scaling up the formulation after which we anticipate the next steps in developing LPCN 1111 may be to conduct a food
effect/phlebotomy study with LPCN 1111. Under the terms of the Antares License Agreement, Antares has been granted an option to license
LPCN 1111, exercisable on or before March 31, 2022, for further development and, should LPCN 1111 receive FDA approval, commercialization.
If Antares exercises its option to license LPCN 1111, we will be entitled to an additional payment of $4.0 million, as well as development
milestone payments of up to $35.0 million in the aggregate and tiered royalty payments at rates ranging from percentages in the mid-teens
to 20% of net sales of LPCN 1111 in the United States.
LPCN 1107: An Oral Product Candidate for the
Prevention of Preterm Birth
We believe LPCN 1107 has
the potential to become the first oral hydroxyprogesterone
caproate (“HPC”) product indicated for the reduction of risk of PTB (delivery less than 37 weeks) in women with singleton
pregnancy who have a history of singleton spontaneous PTB. Prevention of PTB is a significant unmet need as approximately 11.7% of all
U.S. pregnancies result in PTB, a leading cause of neonatal mortality and morbidity.
Current Status
We have completed a multi-dose
PK dose selection study in pregnant women. The objective of the multi-dose PK selection study was to assess HPC blood levels in order
to identify the appropriate LPCN 1107 Phase 3 dose. The multi-dose PK dose selection study was an open-label, four-period, four-treatment,
randomized, single and multiple dose PK study in pregnant women with three dose levels of LPCN 1107 and the IM HPC (Makena®). The
study enrolled 12 healthy pregnant women (average age of 27 years) with a gestational age of approximately 16 to 19 weeks. Subjects received
three dose levels of LPCN 1107 (400 mg BID, 600 mg BID, or 800 mg BID) in a randomized, crossover manner during the first three treatment
periods and then received five weekly injections of HPC during the fourth treatment period. During each of the LPCN 1107 treatment periods,
subjects received a single dose of LPCN 1107 on Day 1 followed by twice daily administration from Day 2 to Day 8. Following completion
of the three LPCN 1107 treatment periods and a washout period, all subjects received five weekly injections of HPC. Results from this
study demonstrated that average steady state HPC levels (Cavg0-24) were comparable or higher for all three LPCN 1107 doses than for injectable
HPC. Additionally, HPC levels as a function of daily dose were linear for the three LPCN 1107 doses. Also, unlike the injectable HPC,
steady state exposure was achieved for all three LPCN 1107 doses within seven days.
A traditional PK/PD based
Phase 2 clinical study in the intended patient population is not expected to be required prior to entering into Phase 3. Therefore, based
on the results of our multi-dose PK study we had an End-of-Phase 2 meeting and subsequent guidance meetings with the FDA to define a
pivotal Phase 2b/3 development plan for LPCN 1107. However, these discussions will need to be updated based on recent developments with
Covis’ Makena®. We plan to resume our interactions with the FDA to discuss our pivotal clinical trial design and better understand
next steps to advance LPCN 1107 after completion of our on-going food-effect study.
We are exploring the possibility
of licensing LPCN 1107 to a third party, although no licensing agreement has been entered into by the Company. No assurance can be given
that any license agreement will be completed, or, if an agreement is completed, that such an agreement would be on acceptable terms.
The FDA has granted orphan
drug designation to LPCN 1107 based on a major contribution to patient care. Orphan designation qualifies Lipocine for various development
incentives, including tax credits for qualified clinical testing, and a waiver of the prescription drug user fee when we file our NDA.
Recent Competition Update
On
October 5, 2020, the FDA’s Center for Drug Evaluation and Research (“CDER”) proposed that Makena be withdrawn
from the market because the PROLONG trial failed to verify the clinical benefit of Makena and concluded that the available evidence does
not show Makena is effective for its approved use.
CDER
issued AMAG Pharmaceuticals, the NDA holder at the time, a Notice of Opportunity for Hearing to withdraw approval of Makena, for
which AMAG Pharmaceuticals responded by requesting a hearing and providing detail on the company’s position, recognizing clinicians’
decade-long use of Makena’s treatment and the public health implications of withdrawing approval. The FDA Commissioner has recently
granted Covis a public hearing although the date of that hearing is not publicly known. During this time, Makena and the approved generics
of Makena will remain on the market until the FDA makes a final decision about these products.
Currently,
Makena and the approved generics of Makena are the only products approved for the prevention of recurrent preterm birth.
The
FDA also indicated that it intends to hold a meeting with experts in obstetrics, neonatal care, and clinical trial design to discuss
how to facilitate development of effective and safe therapies to treat preterm birth.
Oral
NAS Programs for CNS Disorders
Some
preferred endogenous or naturally occurring NAS present in central nervous system (CNS) act as positive allosteric modulators (PAM) of
the GABAA receptor, the major biological target of the inhibitory neurotransmitter γ-aminobutyric acid (GABAA).
To improve oral delivery of these modulators, several synthetic NAS derivatives of endogenous GABAA receptor PAMs, have been
developed for therapeutic use in the past few decades.
We
believe through utilization of our proprietary technology we may have the ability to enable effective oral delivery of endogenous GABAA
receptor PAMs which historically had been challenging to deliver orally as they were deemed to be not orally bioavailable. We believe
these endogenous GABAA receptor PAMs provide opportunity as a differentiated NAS for treatment of various CNS disorders via
the preferred and convenient oral route.
LPCN
1154: Product Candidate for PPD
We
are currently evaluating LPCN 1154 comprising an endogenous NAS for PPD. FDA has cleared LPCN 1154 IND (investigational new drug) application
to conduct a phase 2 study in PPD. We have completed a PK study with LPCN 1154 post oral administration in which appreciable levels were
observed with dose proportionality. We plan to conduct further PK analyses and a food effect PK study.
PPD
PPD
(Postpartum depression), a type of major depressive disorder with onset either during pregnancy or within four weeks of delivery, refers
to depression persisting up to 12 months after childbirth. PPD can be clinically segmented by the severity of symptoms and presence of
a comorbidity, including epilepsy. Approximately 1 in 9 mothers suffers from PPD in the United States alone; this equates to approximately
500,000 women affected by PPD annually.
Disease
Overview - PPD
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PPD
is distinct from the “baby blues,” a condition that affects up to 70% of all new mother’s experience; “baby
blues” tend to be short-lived emotional conditions that do not interfere with daily activities |
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Symptoms
of PPD include hallmarks of major depression, including, but not limited to, sadness, depressed mood, loss of interest, change in
appetite, insomnia, sleeping too much, fatigue, difficulty thinking/concentrating, excessive crying, fear of harming the baby/oneself,
and/or thoughts of death or suicide |
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During
pregnancy, levels of endogenous NAS increase considerably along with levels of progesterone; however, they drop sharply postpartum.
It has been hypothesized that the rapid perinatal decrease in circulating levels of endogenous NASs may be involved in the development
of PPD. The first and only approved treatment option for PPD is an injectable containing endogenous NAS. |
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Depression
may persist long after child delivery. Additionally, approximately 40% women relapse in subsequent pregnancies or on other occasions |
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Psychiatric
comorbidities are common in patients with epilepsy. Patients with epilepsy are at high risk for major depressive disorders and PPD.
Reported PPD rates are higher among women with epilepsy than the general population. |
Associated
Risk Factors
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Genetic:
family history and/or previous experience of depression or other mood disorders |
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Physiological:
rapid changes in sex hormones, stress hormones, and thyroid hormone levels during and after delivery |
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Environmental:
stressful life events, changes in relationships at home and at work, and/or lack of familial support |
Unmet
medical need
Approximately,
1 in 9 moms suffers from PPD in the United States alone, which equates to approximately 500,000 women affected by PPD annually. We believe
there is considerable unmet need within women with PPD due to lack of convenient and fast-acting oral therapies. Selective Serotonin
Reuptake Inhibitors (SSRIs) have been the traditional first-line choice for women with severe PPD requiring weeks for onset of efficacy;
therefore, a need for a faster onset of action remains a significant unmet need in treating PPD, especially in women with epilepsy risk
wherein psychiatric comorbidity is common and PPD rates are higher than the general population.
Injectable
brexanolone (ZulressoTM, Sage Therapeutics) became the first FDA-approved treatment for postpartum depression. However, numerous factors
limit the utilization of injectable brexanolone such as method of administration, cost, and safety concerns. Administration of injectable
brexanolone requires a 60-hour continuous infusion in a supervised medical setting, a demanding ask for a mother with a newborn. Besides
associated privacy concerns and social stigma, hospitalization may also require separation of the mother and child for a few days, which
may be difficult to the already strained mother-infant bond and may present breast feeding challenges. Moreover, the pharmacotherapy
costs coupled with hospitalization/childcare costs limits its accessibility and affordability to women most in need of the therapy. Finally,
due to concerns about the safety of injectable ZulressoTM including excessive sedation or loss of consciousness, Zulresso has a Black
Box Warning in its label and is only available through a restricted distribution program (REMS), and sites need significant time to become
treatment ready.
We
believe the need for a convenient, at-home treatment with faster onset of action which could offer privacy and affordability, independent
of socio-economic status, for women with PPD is a significant unmet need. LPCN 1154 targets this unmet need with affordable NAS.
LPCN
2101: NAS for epilepsy
We
are currently evaluating an additional NAS candidate, LPCN 2101, for women with epilepsy (“WWE”). We have completed a pre-clinical study for LPCN 2101. We plan
to file an IND with the U.S. FDA for LPCN 2101 to conduct a proof-of-concept study for the evaluation of safety, tolerability, and efficacy
in adult female subjects of childbearing age diagnosed with epilepsy.
Research
and Development
As
disclosed in our development pipeline, we continue to build a diversified multi-asset pipeline of novel therapies. In 2021 and 2020,
we spent $7.7 million and $9.7 million, respectively, on research and development.
Competition
Cirrhosis
Market Overview
Decompensated
cirrhosis patients with sarcopenia exhibit significantly shorter overall survival than those without sarcopenia. There are no therapies
specifically approved for sarcopenia or decompensated cirrhosis. Currently, the only curative therapy for decompensated cirrhosis
is liver transplant; however, liver transplantation is very costly, limited by the supply of available donors, and has a high risk of
post-operative complications.
Xifaxan
(rifaximin) is the only FDA-approved medicine indicated for the reduction in risk of overt hepatic encephalopathy (HE) recurrence in
adults, a decompensation event typically associated with liver cirrhosis.
Currently, there are no FDA approved drugs to treat
secondary sarcopenia in decompensated cirrhosis beyond treatment of the underlying conditions. Lipocine is the only clinical-stage
company pursuing treatment for subjects with decompensated cirrhosis with sarcopenia, however there are candidates known to
be under development for cirrhosis related indication(s).
GB
1211 (by Galecto), an oral galectin-3 inhibitor for advanced liver cirrhosis targeted for directly addressing fibrosis, is in phase 2
development being assessed in patients with moderate-to-severe cirrhosis (Child-Pugh classes B and C) and is anticipated to read out
in the second half of 2022.
AXA-1665
(by Axcella Health), an orally active mixture of 8 amino acids in specific ratios designed to maximize anabolic activity and minimize
ammonia genesis, is in a Phase 2 study in the secondary prevention of overt HE with a projected completion date of March 2023. While
AXA-1665’s studies have so far enrolled non-sarcopenic patients, Axcella could pursue cirrhotic sarcopenia with AXA-1665.
Reformulated
Rifaximin SSD (by BAUSCH health) is in a phase 3 study for Reduction of Early Decompensation in Cirrhosis with time to first occurrence
of hepatic encephalopathy as the Primary endpoint. Reportedly, a new drug application (NDA) planned to be submitted 2026.
NASH Market Overview
There are currently no medications
approved for the treatment of NASH. However, various therapeutics are used off-label for the treatment of NASH, including vitamin E (an
antioxidant), insulin sensitizers (e.g., metformin, pioglitazone), antihyperlipidemic agents (e.g., gemfibrozil), pentoxifylline and
ursodeoxycholic acid. There are several product candidates in Phase 3 or earlier clinical or preclinical development for the treatment
of NASH, including FGF21 stimulants such as BIO89-100 (89bio), Efruxifermin (EFX; Akero Therapeutics), Pegbelfermin (Bristol Myers
Squibb/Ambrx Inc.); FGF19 Analog:Aldafermin (NGM Biopharmaceuticals); FXR Agonists: Tropifexor (Novartis), EDP-305 (Enata Pharmaceuticals),
PXL007/EYP001 (Poxel/Enyo Pharma:) Glucagon-like Peptide-1 (GLP-1) Agonist: Semaglutide (Novo Nordisk); Peroxisome Proliferator-activated
Receptor (PPAR) Regulator: Lanifibranor (Inventiva);THR-β
Agonis:t VK2809 (Viking Therapeutics), and Resmetirom (Madrigal Pharmaceuticals).
Additional pharmaceutical
and biotechnology companies with product candidates in development for the treatment of NASH include AstraZeneca plc, Boehringer Ingelheim
GmbH, Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., CymaBay Therapeutics, Inc., Durect Corporation, Galectin Therapeutics
Inc., Galmed Pharmaceuticals Ltd., Immuron Ltd., Ionis Pharmaceuticals, Inc., Islet Sciences, Inc., Madrigal Pharmaceuticals, Inc., MediciNova,
Inc., MiNA Therapeutics, NGM Biopharmaceuticals, Inc., Novo Nordisk A/S, NuSirt Sciences Inc., Viking Therapeutics, Inc. and Zydus Pharmaceuticals
(USA) Inc.
Testosterone Replacement Therapy Market Overview
The gel-based testosterone
replacement products that are currently available include AbbVie’s AndroGel®, Lilly’s Axiron® Topical Solution and
Endo’s Testim® and Fortesta® along with their respective authorized generics as well as the equivalent generic versions
of each. Transdermal patches include Allergan’s Androderm®. Intramuscular forms of testosterone also exist although commercialized
mostly in generic forms by multiple companies and in branded form as Aveed® by Endo. Additionally, Endo markets the buccal testosterone
replacement therapy Striant® and the Testopel® implantable testosterone pellets, which it acquired from Auxillium in 2015. Antares
Pharma, Inc. markets a sub-cutaneous weekly auto-injector testosterone therapy, Xyoste®. Acerus Pharmaceuticals markets an intranasal
testosterone therapy, NATESTO®. Finally, Clarus markets an oral TRT, JATENZO®, which received approval in March 2019.
Currently, intramuscular injections
have the highest market share in the testosterone replacement market in terms of annual prescriptions. While gels are also a
widely used form of TRT, there is a risk of transference; additionally, the gels are messy to apply and have significant compliance issues
leading to high rates of discontinuance among patients. Additionally, certain intramuscular injections have the potential to cause pulmonary
embolisms as well as cause injection site reactions, scarring, pain and risk of infection in patients. We believe a safe and effective
oral therapy could potentially increase patient convenience and compliance, while eliminating the testosterone transference risk associated
with gels and injection site reaction of injectables.
The
FDA has granted a therapeutic equivalence rating of AB to “generic” versions of approved products which have been approved
via a 505(b)(2) NDA. In July 2014, FDA granted the AB rating to Perrigo’s 1% testosterone gel drug product (NDA 203098) approved
in January 2013, and a BX rating to Teva’s 1% gel drug product (NDA 202763) approved in February 2012. Each are versions of AbbVie’s
AndroGel 1.0% and employed 505(b)(2) submissions citing AndroGel as their reference listed drugs. Teva’s version was found to be
bioinequivalent to AndroGel, hence the BX rating. Upsher-Smith Laboratories also received approval for a version of Endo’s Testim
(Vogelxo™; NDA 204399) in June 2014 using the same pathway. In January of 2015, the FDA determined that Vogelxo™ is therapeutically
equivalent to Testim and received an AB rating. In August 2015, the FDA granted AB rating to Perrigo’s 1.62% testosterone gel drug
product (NDA 204268) which also received FDA approval in August 2015. Lilly and Acrux’s Axiron had patent expiry in February 2017.
On July 6, 2017, Acrux confirmed that a generic version of Axiron® Topical Solution, 30 mg/1.5 mL (Testosterone Topical Solution,
30 mg/1.5 mL) has been launched in the United States by Perrigo Company plc. Acrux also confirmed the availability of an authorized generic
version of Axiron in the United States, through a marketing and distribution agreement between Lilly and Company and a leading authorized
generics company
Other
TRT Therapies in Development
Recently
there has been increased interest in developing oral TRT’s therapies as well as testosterone therapies which are not considered
testosterone replacement and as such will need to achieve efficacy endpoints in addition to endpoints related to serum testosterone levels
that are required for testosterone replacement therapies.
Marius
is developing an oral TU as a testosterone replacement therapy for the treatment of hypogonadism in men as well as in the treatment of
Constitutional Delay of Growth and Puberty in adolescent boys (14-17 years of age). Marinus submitted a NDA to the FDA in January 2021
for its product, Kyzatrex™, its novel oral TU soft gelatin capsule for the treatment of hypogonadism in adult men. According to
Marius, it was assigned a PDUFA date of October 31, 2021, for KYZATREX®. However, no updates have been provided by Marius post the
October 31, 2021, PDUFA date for KYZATREX®.
We
believe there remains a significant unmet need in TRT for a once-a-day convenient oral option. LPCN 1111 is targeted to meet this unmet
need.
Hydroxyprogesterone
caproate, or HPC, Preterm Birth, or PTB, Market Overview
PTB
is defined as delivery before 37 weeks of gestation. The only approved therapy for prevention of PTB in women with a prior history of
at least one preterm birth (approximately 180,000 pregnancies annually) is a weekly intramuscular injection of HPC, marketed by
Covis under the brand name Makena®. The FDA granted a 7-year orphan drug exclusivity to Makena in February 2011 because the product
is intended to treat “rare diseases or conditions” defined as a condition that affects fewer than 200,000 persons in the
United States; exclusivity expired in February 2018. Generic versions of the intramuscular injection of Makena became available
during 2018. In order to protect market share, Covis also developed a subcutaneous auto-injector for Makena that received FDA approval
on February 14, 2018. Treatment with Makena is initiated in pregnant women between week 16 and week 20 of pregnancy and is continued
until up to delivery or week 37, whichever is earlier. The intramuscular injection is administered by a healthcare provider using a 21-gauge
needle into the gluteus muscle, alternating sides each week. The intramuscular injections are associated with significant pain, discomfort
and associated injection site reactions. The subcutaneous auto-injector for Makena eliminates the need to travel weekly to a healthcare
provider to have the injection administered. Covis has disclosed that the completed confirmatory trial for Makena did not demonstrate
a statistically significant difference between the treatment and placebo arms for the co-primary endpoints of reducing the risk of recurrent
preterm birth or improving neonatal mortality and morbidity. On October 29, 2019 a Meeting of the Bone, Reproductive and Urologic Drugs
Advisory Committee (“BRUDAC”) was held to consider the trial’s findings and the sNDA in the context of AMAG Pharmaceuticals’
confirmatory study obligation. While the committee discussed multiple questions, in a mixed vote on the key question, nine advisory committee
members voted to recommend that the FDA pursue withdrawal of approval for Makena and seven committee members voted to leave the product
on the market under accelerated approval and require a new confirmatory trial. Among the clinicians on the advisory committee, five of
the six who practice obstetrics voted to keep Makena on the market and generate more data. On October 5, 2020, the FDA’s CDER proposed
that Makena be withdrawn from the market because the PROLONG trial failed to verify the clinical benefit of Makena and concluded that
the available evidence does not show Makena is effective for its approved use.
CDER
issued AMAG, the NDA holder at the time, a NOOH to withdraw approval of Makena, for which AMAG Pharmaceuticals responded by requesting
a hearing and providing detail on the company’s position, recognizing clinicians’ decade-long use of Makena’s treatment
and the public health implications of withdrawing approval. The FDA Commissioner granted a hearing, and the process is expected to take
months. During this time, Makena and the approved generics of Makena will remain on the market until the FDA makes a final decision about
these products.
Neuroactive Steroids Market overview
The unique potential mechanism
of action (MOA) of NAS presents an opportunity to treat variety of CNS disorders. Accordingly, multiple NAS as GABAA receptor
PAMs are in active development for varied indications. Some companies engaged in development include SAGE Therapeutics, Inc., Marinus
Pharmaceuticals, Praxis Precision Medicines, and Eliem Therapeutics.
Postpartum Depression
Sage Therapeutics is currently
marketing an injectable version of an endogenous neuroactive steroid, brexanolone, under tradename of ZULRESSO, as first and only FDA
approved product (approval on 03/19/2019) for treatment in postpartum depression (PPD).
SAGE therapeutics is also
currently developing an oral synthetic derivative of an endogenous NAS, SAGE-217 (Zuranolone), a GABAA receptor PAM, and is
in phase 3 development for postpartum depression. Zuranolone (oral) received Breakthrough Therapy Designation for the treatment of MDD
in February 2018.
Marinus Pharmaceuticals has
also reported clinical development of Ganaxolone, a synthetic GABAA receptor PAM in PPD that been studied in two Phase 2 trials,
one investigating IV +/- oral administration (Magnolia part 1 and 2) and one oral administration (Amaryllis). Additional assets of the
same MOA are indicated for MDD (PRAX-114 and ETX-155) but could be pivoted to a PPD indication.
Intellectual
Property
Drug
Delivery Technologies for Lipophilic Drug Substances
Our
patent portfolio is directed to various types of compositions and methods for delivery of lipophilic drugs, which are drugs that are
soluble in lipids. Our licensed product, TLANDO, is an oral formulation of the lipophilic prodrug TU, utilizing our proprietary technology
for improved delivery of lipophilic therapeutic agents. As of March 7, 2022, our intellectual property patent portfolio
is as follows:
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15
issued patents in the US related to Oral TU with 2029-2030 expiration dates; |
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1
issued patent in the US related to Oral TU with 2031 expiration date; |
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4
U.S. patent applications related to Oral TU with potential expiration dates, if issued, in 2029; |
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5
U.S. patent applications related to Oral TU with potential expiration dates, if issued, in 2030; |
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6
U.S. patent applications related to Oral TU with potential expiration dates, if issued, in 2035-2040; |
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3
issued U.S. patents related to LPCN 1111 with expiration dates in 2035-2037; |
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5
U.S. patent applications related to LPCN 1111, with potential expiration dates, if issued, in 2029-2037; |
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7
U.S. patents related to LPCN 1107 with expiration dates in 2031; |
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3
U.S. patent applications related to LPCN 1107 with potential expiration dates, if issued, in 2031-2036; |
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1
issued patent related to Oral TU in the following countries: India, Mexico, Japan, Canada and Australia that expires in 2030; |
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1
issued patent related to Oral TU in the following countries: Australia, Canada and Japan that expires in 2024; |
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1 issued
patent related to Oral TU in in the following countries: Australia, Canada, and New Zealand that expires in 2026; |
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1 issued patent related to Oral TU in the following
country: Canada that expires in 2034 |
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1 patent
application related to Oral TU in the following countries: Europe, Brazil, and Hong Kong, that if issue, will expire in
2030; |
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1
patent application related to Oral TU in the following countries: China and Russia, that if issue, will expire in 2035; |
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1
patent application related to Oral TU in the following countries: Europe and Japan, that if issue, will expire in 2037; |
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1
patent application related to LPCN 1111 in the following countries: Europe and Japan, that if issue, will expire in 2037; |
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1
issued patents or applications related to LPCN 1111 in the following countries: Argentina, Australia, Brazil, Canada, China,
Europe, Israel, India, Japan, South Korea, Mexico, New Zealand, Russia, Uruguay, Paraguay, Venezuela, and South Africa, that expires
or will expire, if issued, in 2030; |
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1
patent application related to LPCN 1111 in the following countries: Australia, Brazil, Canada, China, Europe, India, Indonesia,
Israel, Japan, Mexico, New Zealand, Russia, South Korea and South Africa, that, if issued, will expire in 2035; |
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1
issued patent or application related to LPCN 1107 in the following countries: Australia, Brazil, Canada, China, Europe, Israel, India,
Japan, South Korea, Mexico, New Zealand, Russia, and South Africa that expires, or will expire if issued, in 2032; |
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1
patent application related to LPCN 1107 in the following countries: Australia, Brazil, China, Europe, Indonesia, Israel, Japan, Mexico,
New Zealand, Philippines and South Africa that will expire, if issued in 2036; |
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6
U.S. Patent applications related to LPCN 1144/1148 and one Patent Cooperation Treaty (“PCT”) application; and |
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A
U.S. patent related to progesterone formulations that expires in 2031. |
We
also hold license rights in fields other than cough and cold, to 2 U.S. patents and 1 U.S. application (and related foreign patents
and applications) that we previously assigned to Spriaso LLC, which could be possibly used with future product candidates.
Additionally,
we have 6 U.S. patents that we plan to list in the FDA Orange Book for TLANDO that are expected to expire in 2029 and 2030. If we or
our licensee are marketing the TLANDO product at the time the patents expire and have no other issued U.S. patents covering the product,
then we will lose certain advantages that come with FDA Orange Book listing of patents and will no longer be able to prevent others in
the U.S. from practicing the inventions claimed by the 6 patents.
We
expect to file new patent applications in the future in an attempt to further cover to various aspects of our products and product development.
See
Item 3 – Legal Proceedings, for a discussion of intellectual property related legal proceedings.
Government
Regulation
The
Regulatory Process for Drug Development
The
production and manufacture of our product candidates and our research and development activities are subject to regulation by various
governmental authorities around the world. In the United States, drugs and products are subject to regulation by the FDA. There are other
comparable agencies in Europe and other parts of the world. Regulations govern, among other things, the research, development, testing,
manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval
monitoring and reporting, marketing and export and import of products. Applicable law requires licensing and registration of manufacturing
and contract research facilities, carefully controlled research and testing of products, governmental review and/or approval of results
prior to marketing therapeutic products. Additionally, adherence to good laboratory practices, or GLP, good clinical practices, or GCP,
during clinical testing and current good manufacturing practices, or cGMP, during production is required. The system of new drug approval
in the United States is generally considered to be the most rigorous in the world and is described in further detail below under “United
States Pharmaceutical Product Development Process.”
United
States Pharmaceutical Product Development Process
In
the United States, the FDA regulates pharmaceutical products under the Federal Food, Drug and Cosmetic Act and implementing regulations.
The testing, production, sale, and promotion of pharmaceutical products are also subject to other federal, state and local statutes and
regulations. 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 United
States requirements at any time during the product development process, approval process or after approval, may subject an applicant
to administrative or judicial sanctions. FDA sanctions could include refusal to approve pending applications, withdrawal of an approval,
a clinical hold, warning letters, product recalls, 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.
It
takes many years for a typical experimental drug to go from concept to approval. The process required by the FDA before a pharmaceutical
product may be marketed in the United States generally includes the following:
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Completion of preclinical
laboratory tests and animal studies. The latter often conducted according to GLPs or other applicable regulations, as well as synthesis
and drug formulation development leading ultimately to clinical drug supplies manufactured according to cGMPs; |
| |
|
| |
● |
Submission to the FDA of
an IND, which must be submitted to the FDA and become effective before human clinical trials may begin in the United States; |
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|
| |
● |
Performance of adequate and
well-controlled human clinical trials according to the FDA’s current GCPs, to establish the safety and efficacy of the proposed
pharmaceutical product for its intended use; |
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|
| |
● |
Submission to the FDA of
an NDA for a new pharmaceutical product; |
| |
● | Satisfactory
completion of an FDA inspection of the manufacturing facility or facilities where the pharmaceutical
product is produced to assess compliance with the FDA’s cGMP to assure that the facilities,
methods and controls are adequate to preserve the pharmaceutical product’s identity,
strength, quality and purity; |
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| |
| |
● |
Potential FDA audit of the
preclinical and clinical trial sites that generated the data in support of the NDA; and |
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|
|
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● |
FDA review and approval of
the NDA. |
The
lengthy process of seeking required approvals and the continuing need for compliance with applicable statutes and regulations require
the expenditure of substantial resources and FDA approval is inherently uncertain.
Preclinical
Studies: Prior to preclinical studies, a research phase takes place which involves demonstration of target and function, design,
screening and synthesis of agonists or antagonists. Preclinical studies include laboratory evaluations of product chemistry, toxicity
and formulation, as well as animal studies to evaluate efficacy and activity, toxic effects, PKs and metabolism of the pharmaceutical
product candidate and to provide evidence of the safety, bioavailability and activity of the pharmaceutical product candidate in animals.
The conduct of the preclinical safety evaluations must comply with federal regulations and requirements including GLPs. The results of
the formal IND-enabling preclinical studies, together with manufacturing information, analytical data, any available clinical data or
literature as well as the comprehensive descriptions of proposed human clinical studies, are then submitted as part of the IND application
to the FDA.
The
IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA places the IND on a clinical hold within that 30-day
time period. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. The
FDA may also impose clinical holds on a pharmaceutical product candidate at any time before or during clinical trials due to safety concerns
or non-compliance. Accordingly, we cannot be certain that submission of an IND will result in the FDA allowing clinical trials to begin,
or that, once begun, issues will not arise that suspend or terminate such clinical trial.
Clinical
Trials: Clinical trials involve the administration of the pharmaceutical product candidate to healthy volunteers or patients under
the supervision of qualified investigators, generally physicians not employed by the sponsor. Clinical trials are conducted under protocols
detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and
the parameters to be used to monitor subject safety. Each protocol must be submitted to the FDA if conducted under a U.S. IND. Clinical
trials must be conducted in accordance with the FDA’s GCP requirements. Further, each clinical trial must be reviewed and approved
by an independent institutional review board, or IRB, or ethics committee at or servicing each institution at which the clinical trial
will be conducted. An IRB or ethics committee is charged with protecting the welfare and rights of trial participants and considers such
items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated
benefits. The IRB or ethics committee also approves the informed consent form that must be provided to each clinical trial subject or
his or her legal representative and must monitor the clinical trial until completed.
Human
clinical trials are typically conducted in three sequential phases that may overlap or be combined:
Phase
1 Clinical Trials: Phase 1 clinical trials are usually first-in-man trials, take approximately one to two years to complete and are
generally conducted on a small number of healthy human subjects to evaluate the drug’s activity, schedule and dose, PKs and pharmacodynamics.
However, in the case of life-threatening diseases, such as cancer, the initial Phase 1 testing may be done in patients with the disease.
These trials typically take longer to complete and may provide insights into drug activity.
Phase
2 Clinical Trials: Phase 2 clinical trials can take approximately one to three years to complete and are carried out on a relatively
small to moderate number of patients (as compared to Phase 3) in a specific indication. The pharmaceutical product is evaluated to preliminarily
assess efficacy, to identify possible adverse effects and safety risks, and to determine optimal dose, regimens, PKs, pharmacodynamics
and dose response relationships. This phase also provides additional safety data and serves to identify possible common short-term side
effects and risks in a larger group of patients. Phase 2 clinical trials sometimes include randomization of patients.
Phase
3 Clinical Trials: Phase 3 clinical trials take approximately two to five years to complete and involve tests on a much larger population
of patients (several hundred to several thousand patients) suffering from the targeted condition or disease. These studies usually include
randomization of patients and blinding of both patients and investigators at geographically dispersed test sites (multi-center trials).
These trials are undertaken to further evaluate dosage, clinical efficacy and safety and are intended to establish the overall risk/benefit
ratio of the product and provide an adequate basis for product labeling. Generally, two adequate and well-controlled Phase 3 clinical
trials are required by the FDA for approval of an NDA or foreign authorities for approval of marketing applications.
Post-approval
studies, or Phase 4 clinical trials, may be conducted after initial marketing approval. These studies are used to gain additional experience
from the treatment of patients in the intended therapeutic indication and may be required by the FDA as a condition of approval.
Progress
reports detailing the results of the clinical trials must be submitted at least annually to the FDA, and written IND safety reports must
be submitted to the FDA and the investigators for serious and unexpected adverse events or for any finding from tests in laboratory animals
that suggests a significant risk for human subjects. Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within
any specified period, if at all. The FDA or the sponsor or, if used, its data safety and monitoring board may suspend a clinical trial
at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health
risk. Similarly, an IRB or ethics committee can suspend or terminate approval of a clinical trial at its institution if the clinical
trial is not being conducted in accordance with the IRB’s or ethics committee’s requirements or if the pharmaceutical product
has been associated with unexpected serious harm to patients.
Concurrent
with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry
and physical characteristics of the pharmaceutical product, as well as finalize a process for manufacturing the product in commercial
quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches
of the pharmaceutical product candidate and, among other things, must develop methods for testing the identity, strength, quality and
purity of the final pharmaceutical product. Additionally, appropriate packaging must be selected and tested, and stability studies must
be conducted to demonstrate that the pharmaceutical product candidate does not undergo unacceptable deterioration over its shelf life.
U.S.
Pharmaceutical Review and Approval Process
New
Drug Application: Upon completion of pivotal Phase 3 clinical studies, the sponsor assembles all the product development, preclinical
and clinical data along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the pharmaceutical
product, proposed labeling and other relevant information, and submits it to the FDA as part of an NDA. The submission or application
is then reviewed by the regulatory body for approval to market the product. This process typically takes eight months to one year to
complete. The FDA may refuse to approve an NDA if the applicable regulatory criteria are not satisfied or may require additional clinical
data or other data and information. Even if such data and information is submitted, the FDA may ultimately decide that the NDA does not
satisfy the criteria for approval. If a product receives regulatory approval, the approval may be limited to specific diseases and dosages
or the indications for use may otherwise be limited, which could restrict the commercial value of the product. Further, the FDA may require
that certain contraindications, warnings or precautions be included in the product labeling.
Orphan
Drug Designation
Under
the Orphan Drug Act, the FDA may grant orphan drug designation to drugs 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, or more than 200,000 individuals in the United
States and for which there is no reasonable expectation that the cost of developing and making available in the United States a drug
for this type of disease or condition will be recovered from sales in the United States for that drug. 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 drug designation does not convey any advantage in or shorten the duration of the
regulatory review and approval process.
If
a product that has orphan drug designation subsequently receives the first FDA approval for the disease for which it has such designation,
the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications to market the
same drug for the same indication, except in very limited circumstances, for seven years. Orphan drug exclusivity, however, could also
block the approval of one of our products for seven years if a competitor obtains approval of the same drug as defined by the FDA or
if our drug candidate is determined to be contained within the competitor’s product for the same indication or disease.
Post-Approval
Requirements
Any
pharmaceutical products for which we receive FDA approvals are subject to continuing regulation by the FDA, including, among other things,
record-keeping requirements, reporting of adverse experiences with the product, providing the FDA with updated safety and efficacy information,
product sampling and distribution requirements, complying with certain electronic records and signature requirements and complying with
the FDA promotion and advertising requirements, which include, among others, standards for direct-to-consumer advertising, prohibitions
on promoting pharmaceutical products for uses or in patient populations that are not described in the pharmaceutical product’s
approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities and promotional activities
involving the internet. Failure to comply with the FDA requirements can have negative consequences, including adverse publicity, enforcement
letters from the FDA, mandated corrective advertising or communications with doctors and civil or criminal penalties.
The
FDA also may require post-marketing testing, known as Phase 4 testing, risk evaluation and mitigation strategies and surveillance to
monitor the effects of an approved product or place conditions on an approval that could restrict the distribution or use of the product.
21st
Century Cures Act
The
21st Century Cures Act (Public Law No. 144-255) was enacted on December 13, 2016. This sweeping legislation makes significant
changes to the way that FDA approves new drugs and medical devices. Among other things, the legislation calls on FDA to consider new
types of data, such as patient experience data, in its drug approval process. The legislation also permits drug manufacturers to utilize
new types of clinical trial designs in order to collect data in the drug approval process. The intent of many of the statute’s
provisions are to speed the approval of new drugs and medical devices. Whether the 21st Century Cures Act realizes these goals
will depend on the adoption of new FDA regulations, policy guidance and FDA approval practices, many of which the agency has not yet
proposed or issued.
Other
Healthcare Laws and Compliance Requirements
In
the United States, our activities are potentially subject to regulation by various federal, state and local authorities in addition to
the FDA, including, but not limited, to the Centers for Medicare and Medicaid Services and other divisions of the United States government,
including the U.S. Federal Communications Commission, the Department of Health and Human Services, the U.S. Department of Justice and
individual U.S. Attorney offices within the Department of Justice, and state and local governments. For example, if a drug product is
reimbursed by Medicare, Medicaid, or other federal or state healthcare programs, our Company, including our sales, marketing and scientific/educational
grant programs, among others, must comply with federal healthcare laws, including, but not limited to, the federal Anti-Kickback Statute,
false claims laws, civil monetary penalties laws, healthcare fraud and false statement provisions and data privacy and security provisions
under the Health Insurance Portability and Accountability Act, or HIPAA, the Physician Payment Sunshine Act, and any analogous state
laws. If a drug product is reimbursed by Medicare or Medicaid, pricing and rebate programs must comply with, as applicable, the Medicaid
rebate requirements of the Omnibus Budget Reconciliation Act of 1990 (“OBRA”), and the Medicare Prescription Drug Improvement
and Modernization Act of 2003. Among other things, OBRA requires drug manufacturers to pay rebates on prescription drugs to state Medicaid
programs and empowers states to negotiate rebates on pharmaceutical prices, which may result in prices for our future products that will
likely be lower than the prices we might otherwise obtain. Additionally, the Patient Protection and Affordable Care Act as amended by
the Health Care and Education Reconciliation Act of 2010 (collectively, “ACA”) substantially changes the way healthcare is
financed by both governmental and private insurers. Among other cost containment measures, ACA establishes: an annual, nondeductible
fee on any entity that manufactures or imports certain branded prescription drugs and biologic agents; a new Medicare Part D coverage
gap discount program; and a new formula that increases the rebates a manufacturer must pay under the Medicaid Drug Rebate Program. There
may continue to be additional proposals relating to the reform of the U.S. healthcare system, in the future, some of which could further
limit coverage and reimbursement of drug products. If drug products are made available to authorized users of the Federal Supply Schedule
of the General Services Administration, additional laws and requirements may apply.
Additionally,
to the extent that any of our products are sold in a foreign country, we may be subject to similar foreign laws and regulations, which
may include, for instance, applicable post-marketing requirements, including fraud and abuse, privacy and transparency laws.
Pharmaceutical
Coverage, Pricing and Reimbursement
In
the United States and markets in other countries, sales of any products for which we receive regulatory approval for commercial sale
will depend in part on the availability of coverage and adequate reimbursement from third-party payers, including government health administrative
authorities, managed care providers, private health insurers and other organizations. In the United States, private health insurers and
other third-party payers often provide reimbursement for products and services based on the level at which the government (through the
Medicare or Medicaid programs) provides reimbursement for such treatments. Third-party payers are increasingly examining the medical
necessity and cost-effectiveness of medical products and services in addition to their safety and efficacy and, accordingly, significant
uncertainty exists as to the coverage and reimbursement status of newly approved therapeutics. In particular, in the United States, the
European Union and other potentially significant markets for our product candidates, government authorities and third-party payers are
increasingly attempting to limit or regulate the price of medical products and services, particularly for new and innovative products
and therapies, which has resulted in lower average selling prices. Further, the increased emphasis on managed healthcare in the United
States and on country and regional pricing and reimbursement controls in the European Union will put additional pressure on product pricing,
reimbursement and usage, which may adversely affect our future product sales and results of operations. These pressures can arise from
rules and practices of insurers and managed care organizations, judicial decisions and governmental laws and regulations related to Medicare,
Medicaid and healthcare reform, pharmaceutical reimbursement policies and pricing in general. As a result, coverage and adequate third-party
reimbursement may not be available for our products to enable us to realize an appropriate return on our investment in research and product
development.
The
market for our product candidates for which we may receive regulatory approval will depend significantly on access to third-party payers’
drug formularies or lists of medications for which third-party payers provide coverage and reimbursement. The industry competition to
be included in such formularies often leads to downward pricing pressures on pharmaceutical companies. Also, third-party payers may refuse
to include a particular branded drug in their formularies or may otherwise restrict patient access to a branded drug when a less-costly
generic equivalent or other alternative is available. In addition, because each third-party payer individually approves coverage and
reimbursement levels, obtaining coverage and adequate reimbursement is a time-consuming and costly process. We would be required to provide
scientific and clinical support for the use of any product to each third-party payer separately with no assurance that approval would
be obtained, and we may need to conduct expensive pharmacoeconomic studies in order to demonstrate the cost-effectiveness of our products.
This process could delay the market acceptance of any of our product candidates for which we may receive approval and could have a negative
effect on our future revenues and operating results. We cannot be certain that our product candidates will be considered cost-effective.
If we are unable to obtain coverage and adequate payment levels for our product candidates from third-party payers, physicians may limit
how much or under what circumstances they will prescribe or administer them, and patients may decline to purchase them. This in turn
could affect our ability to successfully commercialize our products and impact our profitability, results of operations, financial condition,
and future success.
The
United States Orphan Drug Act encourages the development of orphan drugs, which are intended to treat “rare diseases or conditions”
within the meaning of this Act (i.e., those that affect fewer than 200,000 persons in the United States). The provisions of the Act are
intended to stimulate the research, development and approval of products that treat rare diseases. Orphan Drug Designation provides a
sponsor with several potential benefits: (1) sponsors may be granted seven years of marketing exclusivity after approval of the orphan-designated
indication for the drug product; (2) sponsors are granted U.S. tax incentives for clinical research; (3) the FDA’s office of orphan
products development coordinates research study design assistance for sponsors of drugs for rare diseases; and (4) grant funding can
be obtained to defray costs of qualified clinical testing.
Priority
Review
Priority
Review is a designation for an NDA after it has been submitted to the FDA for review. Reviews for NDAs are designated as either “Standard”
or “Priority.” A Standard designation sets the target date for completing all aspects of a review and the FDA taking an action
on 90% of applications (i.e., approve or not approve) at 12 months after the date it was submitted for drugs considered new molecular
entities and at 10 months after the date it was submitted for drugs considered non-new molecular entities. A Priority designation sets
the target date for the FDA action on 90% of applications at eight months after submission submitted for drugs considered new molecular
entities and at 6 months after submission for drugs considered non-new molecular entities. A Priority designation is intended for those
products that address unmet medical needs.
Accelerated
Approval
Accelerated
Approval or Subpart H Approval is a program described in the NDA regulations that is intended to make promising products for life threatening
diseases available on the basis of evidence of effect on a surrogate endpoint prior to formal demonstration of patient benefit. A surrogate
marker is a measurement intended to substitute for the clinical measurement of interest, usually prolongation of survival in oncology
that is considered likely to predict patient benefit. The approval that is granted may be considered a provisional approval with a written
commitment to complete clinical studies that formally demonstrate patient benefit.
Related
Party Transaction
On
July 23, 2013, we entered into assignment/license and services agreements with Spriaso, an entity that is majority-owned by Mahesh V.
Patel, Gordhan Patel, John W. Higuchi, Dr. William I. Higuchi, and their affiliates. Mahesh V. Patel is our President and Chief Executive
Officer and Chairman of our Board of Directors. Mr. Higuchi is a member of our Board of Directors and Gordhan Patel and Dr. Higuchi,
former Board members, were each members of our Board of Directors at the date the license and agreements were entered into.
Under
the assignment agreement, we assigned and transferred to Spriaso all of our rights, title and interest in our intellectual property for
the cough and cold field. In addition, Spriaso was assigned all rights and obligations under our product development agreement with a
co-development partner. In exchange, we would be entitled to receive a potential cash royalty of 20% of the net proceeds received by
Spriaso, up to a maximum of $10 million. Spriaso also granted back to us an exclusive license to such intellectual property to develop
products outside of the cough and cold field. The assignment agreement will expire upon the expiration of all of Spriaso’s payment
obligations thereunder and the expiration of all of the licensed patents thereunder. Spriaso has the right to terminate the assignment
agreement with 30 days written notice. We have the right to terminate the assignment agreement upon the complete liquidation or dissolution
of Spriaso, unless the assignment agreement is assigned to an affiliate or successor of Spriaso.
Under
the services agreement, we agreed to provide facilities and up to 10% of the services of certain employees to Spriaso for a period of
time. The agreement to provide services expired in 2021; however, it may be extended upon written agreement of Spriaso and us.
Additionally, Spriaso filed its first NDA in 2014, and as an affiliated entity of Lipocine, it used up the one-time waiver of user fees
for a small business submitting its first human drug application to FDA.
Employees
As
of December 31, 2021, we had 13 full time employees and we also utilize the services of consultants on a regular basis. Eight employees
are engaged in drug development activities and five are in general and administration functions and all of our employees work out of
our Salt Lake City facility. The Company continually evaluates the business need and opportunity
and balances in house expertise and capacity with outsourced expertise and capacity. Currently, we outsource substantial clinical trial
work to clinical research organizations and certain drug manufacturing to contract manufacturers. None of our employees are represented
by labor unions or covered by collective bargaining agreements and we consider our relations with our employees to be good.
We
strive toward having a diverse team of employees and are committed to equality, inclusion and workplace diversity.
Available
Information
Our
website address is www.lipocine.com. We make available free of charge on the Investor Relations portion of our website, ir.lipocine.com,
our annual reports 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 Securities Exchange Act of 1934 as soon as reasonably practicable after we electronically
file such material with, or furnish it to, the Securities and Exchange Commission. The SEC maintains an internet website that contains
reports, proxy and information statements, and other information that we file electronically, which can be found at http://www.sec.gov.
We
have identified the following risks and uncertainties that may have a material adverse effect on our business, financial condition, results
of operations and future growth prospects. Our business could be harmed by any of these risks. The risks and uncertainties described
below are not the only ones we face. The trading price of our common stock could decline due to any of these risks, and you may lose
all or part of your investment. In assessing these risks, you should also refer to the other information contained in this Annual Report
on Form 10-K, including our consolidated financial statements and related notes.
Risk
Factors Summary
Our
business operations are subject to numerous risks, factors and uncertainties, including those outside of our control, that could cause
our actual results to be harmed, including risks regarding the following:
Risks
Relating to Our Business and Industry
| |
● |
the
timelines of our clinical trials; |
| |
● |
the early stage of development of LPCN 1148, LPCN 1114, LPCN 1111, LPCN
1107 and neuro active steroids; |
| |
● |
the early stage of development of our research and development programs
and processes and the risk of competition; |
| |
● |
the regulation requirements for our product candidates; |
| |
● |
the
regulatory approval, success, and commercialization of our licensed product candidate, TLANDO; |
| |
● |
the
possibility that T-replacement therapies could be found to create, or could be perceived to create, health risks; |
| |
● |
any
possible failure to obtain adequate healthcare reimbursement for our products; |
| |
● |
competition
in the TRT market, including the entrance of generic T-gels into the market; |
| |
● |
our
licensee’s ability to commercialize TLANDO may be limited; |
| |
● |
successful
commercialization of our product candidates internally or through collaborators; |
| |
● |
the
possibility that we may never receive regulatory approval to market our products outside the United States; |
| |
● |
the
stringent government regulations concerning the clinical testing of our products; |
| |
● |
the
market’s acceptance of our products; |
| |
● |
physicians
and patients using other products may not switch to our product; |
| |
● |
the
possibility that regulatory agencies could find that we have improperly promoted off-label uses; |
| |
● |
any
possible failure to comply with federal and state healthcare laws; |
| |
● |
the
ongoing outbreak of coronavirus around the world; |
| |
● |
our
ability to retain our chief executive officer and other key executives and to attract, retain and motivate qualified personnel; |
| |
● |
difficulties
in managing the growth of the Company; |
| |
● |
re-importation
of drugs from foreign countries into the United States by our competitors; |
| |
● |
any
product liability claims; |
| |
● |
any
failure to comply with the Controlled Substances Act; |
| |
● |
the
defense and resolution of any litigation; |
| |
● |
cyber
security risks; |
Risks
Related to Our Dependence on Third Parties
| |
● |
our
reliance on third-party contractors and service providers for the execution of some aspects of our development programs; |
| |
● |
our
reliance on contract research organizations or other third parties to assist us in conducting clinical trials; |
| |
● |
our
reliance on suppliers for the active and inactive ingredients for our products; |
| |
● |
our
ability to establish successful collaborations for our products; |
Risks
Related to Ownership of Our Common Stock
| |
● |
our
stock price’s reaction to the results and timing of clinical trials, regulatory and other decisions; |
| |
● |
the
effectiveness of our internal control over financial reporting; |
| |
● |
the
cost and expense to comply with the requirements of being a public company; |
| |
● |
the
volatility of our share price; |
| |
● |
fluctuations
in the value of our warrants outstanding from the November 2019 Offering; |
| |
● |
the
possibility of delisting of our securities from the Nasdaq Capital Market; |
| |
● |
anti-takeover
provisions in our amended and restated certificate of incorporation and our amended and restated bylaws, as well as provisions of
Delaware law and our stockholder rights plan; |
| |
● |
the
right of the holders of the common warrants issued in the November 2019 Offering to receive the Black Scholes value of the warrants
in the event of a fundamental transaction; |
| |
● |
our
decision not to pay dividends on our common stock; |
| |
● |
our
management and directors’ ability to exert influence over our affairs; |
| |
● |
volatility
in the trading price of our common stock; |
| |
● |
any
failure of securities or industry analysts to publish accurate research about our business; |
Risks
Relating to Our Financial Position and Capital Requirements
| |
● |
our
need for and ability to obtain substantial additional capital in the future; |
| |
● |
the
covenants in our loan agreement or our failure to comply with such covenants; |
| |
● |
our
ability to generate sufficient cash flow to satisfy our significant debt service obligations; |
| |
● |
potential
dilution to our existing stockholders from raising any additional capital; |
| |
● |
our
inability to predict when we will generate product revenues or achieve profitability; |
| |
● |
our
incurrence of significant operating losses; |
| |
● |
any
fluctuation in our operating results; |
| |
● |
limited
shares available for issuance to raise capital; |
Risks
Relating to Our Intellectual Property
| |
● |
our
ability to protect our intellectual property; |
| |
● |
our
ability to obtain additional protection under the Drug Price Competition and Patent Term Restoration Act; |
| |
● |
the
possibility of incurring substantial costs as a result of litigation or other proceedings relating to patent and other intellectual
property rights, or our inability to protect our rights to our products and technology; |
| |
● |
the
cost and expense, and any unfavorable outcomes, resulting from any claims for infringing intellectual property rights of third parties; |
| |
● |
the
fact that we do not have patent protection for our product candidates in a significant number of countries; |
| |
● |
our
ability to comply with various procedural, document submission, fee payment and other requirements imposed by governmental patent
agencies; and |
| |
● |
the
possibility that we may be subject to claims that our employees have wrongfully used or disclosed alleged trade secrets of their
former employers. |
Risks
Relating to Our Business and Industry
The
timelines of our clinical trials may be impacted by numerous factors and any delays may adversely affect our ability to execute our current
business strategy.
Our
expectations regarding the success of our product candidates, including our clinical candidates and lead compounds, and our business
are based on projections which may not be realized for many scientific, business or other reasons. We therefore cannot assure investors
that we will be able to adhere to our current schedule. We set goals that forecast the accomplishment of objectives material to our success:
selecting clinical candidates, product candidates, failures in research, the inability to identify or advance lead compounds, identifying
target patient groups or clinical candidates, the timing and completion of clinical trials, and anticipated regulatory approval. The
actual timing of these events can vary dramatically due to factors such as slow enrollment of subjects in studies, uncertainties in scale-up,
manufacturing and formulation of our compounds, failures in research, the inability to identify clinical candidates, failures in our
clinical trials, requirements for additional clinical trials and uncertainties inherent in the regulatory approval process and regulatory
submissions. Decisions by our partners or collaborators may also affect our timelines and delays in achieving manufacturing capacity.
The length of time necessary to complete clinical trials and to submit an application for marketing approval by applicable regulatory
authorities may also vary significantly based on the type, complexity and novelty of the product candidate involved, as well as other
factors.
LPCN
1148 is in a very early stage of development and is currently undergoing phase 2 clinical evaluation in a proof-of-concept study
for management of liver cirrhosis in male patients and while there are no therapies specifically approved by the FDA for sarcopenia
or cirrhosis beyond treatment of underlying conditions, there are candidates know to be under development for cirrhosis related indication(s).
LPCN
1148 is in a very early stage of development and consequently the risk that we may fail to commercialize LPCN 1148 and related products
is high. This development program is susceptible
to technical failures in ongoing and future clinical studies, regulatory hurdles for further testing and/or meeting FDAs needs for NDA
filing or approval. The results of the current phase 2 clinical evaluation may not support continued development or regulatory approval.
While we believe there is a potential to gain Orphan Drug Designation for an indication or condition in male liver cirrhosis, the
FDA may not grant such designation which could adversely impact development or the commercial potential of LPCN 1148.
LPCN
1144 is in a very early stage of development and may not be further developed for a variety of reasons.
LPCN
1144 is in a very early stage of development and consequently the risk that we fail to commercialize LPCN 1144 and related products is
high. In particular, we have only recently announced topline primary and key secondary endpoint results from our Phase 2 LiFT
clinical study.
Although
our results from the LiFT clinical study results were positive for NASH resolution with no worsening of fibrosis, these results
may not be indicative of ultimate success in a larger Phase 2/3 clinical study with required FDA endpoints and populations needed for
regulatory approval of LPCN 1144 for the treatment of NASH.
In
addition, a number of companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical
trials, even after achieving positive results in early-stage development. The FDA currently insists on histopathology endpoint for diagnosis
and assessment of efficacy in a pivotal trial. Accordingly, our results from our LiFT study may not be predictive of the results
we may obtain from further studies and trials.
Several
factors could significantly affect the prospects for LPCN 1144, including factors relating to the regulatory approval, competitive landscape
and clinical development challenges for LPCN 1144. The anticipated Phase 3 programs for an NDA filing for LPCN 1144 will be very long
and resource intensive.
LPCN 1111 is in a very early stage of development
and may not be further developed for a variety of reasons.
LPCN 1111 is in a very early
stage of development. We have completed a Phase 2a and Phase 2b study in hypogonadal men. Future studies may not have clinical results
that support continued develop and/or a path towards regulatory approval and commercialization.
In addition, the active ingredient
in LPCN 1111 has only been manufactured on a small scale. Scaling up into larger batches could be challenging and our ability to procure
adequate material in a timely manner to further develop LPCN 1111 is uncertain. We also may not be able to engage a manufacturer who
can supply adequate quantities of the drug substance in compliance with cGMP.
Several
factors could significantly affect the prospects for LPCN 1111, including Antares’ option to license LPCN 1111 (TLANDO XR) as such
option is available to them under the Antares License Agreement, and factors relating to the regulatory approval and clinical development
challenges for LPCN 1111 discussed above. The anticipated phase 3 program for an NDA filing for LPCN 1111, however, could be very long
and expensive.
LPCN
1107 is in a very early stage of development and may not be further developed for a variety of reasons.
LPCN
1107 is in a very early stage of development and consequently the risk that we fail to commercialize LPCN 1107 and related products is
high. In particular, we have only conducted three phase 1 clinical studies with this product candidate. Two of the studies were in healthy
pregnant women and one was in healthy women. Although these studies demonstrated oral absorption of LPCN 1107 is possible, we may not
be able to match Cavg blood levels shown with the intramuscular injection comparator product over a longer duration. Furthermore, our
completed phase 1 clinical studies may not be predictive of safety concerns that may arise in pregnant women or demonstrate that LPCN
1107 has an adequate safety profile to warrant further development. The FDA may also require further preclinical studies. All of these
factors can impact the timing of and our ability to continue development of LPCN 1107.
In
addition, a number of companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical
trials, even after achieving positive results in early-stage development. Accordingly, our results from our Phase 1a, our Phase 1b and
our multi-dose PK dose selection studies may not be predictive of the results we may obtain from further studies and trials.
A
traditional PK/PD based phase 2 clinical study in the intended patient population may not be required prior to entering into Phase 3.
Therefore, based on the results of our multi-dose PK study results, we had an end-of-phase 2 meeting with the FDA in the second quarter
of 2016, as well as subsequent guidance meetings to agree on a pivotal Phase 2b/3 development plan for LPCN 1107. However, these discussions
will need to be updated based on recent developments with Covis’ Makena®. We plan to resume our interactions with the FDA to
discuss our pivotal Phase 2b/3 clinical trial design and better understand next steps to advance LPCN 1107 after completion of our ongoing
food effect study. Once the pivotal Phase 2b/3 clinical trial is started, the anticipated Phase 2b/3 program for an NDA filing for LPCN
1107 will be very long and expensive.
The
FDA has concluded that Makena, based on Makena’s failed definitive PROLONG study, a competing product with the same active ingredient
and similar target indication, is ineffective and has proposed that it be withdrawn from the market, but the final decision is still
pending. It is entirely possible that any pivotal study may require a placebo-controlled trial design. Therefore, given the uncertainly
of the status of the current standard of care, Makena and its generics, Lipocine may face significant challenges in patient recruitment
for a placebo-controlled trial, be faced with significant resource investment to conduct additional trials, and face potential perceived
risk of efficacy failure in a pivotal study resulting in no further development of LPCN 1107.
LPCN 1154 and LPCN 2101 a very early stage
of development and may not be further developed for a variety of reasons.
Our oral NAS comprising programs
(LPCN 1154 and LPCN 2101) are in a very early stage of development and consequently the risk that we may fail to commercialize LPCN 1154,
LPCN 2101, and related products is high. We have not conducted clinical studies of these programs and the ultimate regulatory or technical
success of each of the neuroactive steroids under investigation in these programs is uncertain. The current limited pre-clinical results
we have observed may not be replicated in larger studies, future PK phase 2, or pivotal studies with a potential “to be marketed
formulation”. We may not be able get IND clearance in a timely manner or may be unable to further test in-clinic due to other regulatory
hurdles.
In addition, our oral NAS
product candidates may not be effective in treating PPD or WWE or may not have differentiation from competitive products on the market
or in development. We may expend significant resources before determining that these programs are not viable candidates for regulatory
approval and commercialization.
Our
research and development programs and processes are at an early stage of development, which makes it difficult to evaluate our business
and prospects or predict if or when we will successfully commercialize our product candidates.
Our
operations to date have primarily been limited to conducting research and development activities under license and collaboration agreements.
Our current portfolio consists of product candidates at various clinical stages of development in addition to our out-licensed product
TLANDO. We have never marketed or commercialized a drug product. Consequently, any predictions about our future performance may not be
as accurate as they could be if we were further along our commercialization path. In addition, as a pre-commercial stage business, we
may encounter unforeseen expenses, difficulties, complications, delays and other unknown factors.
Our
clinical product candidates are at an early stage of development and will require significant further investment and regulatory approvals
prior to marketing and commercialization. As such, our product development processes for oral neuro active steroids, LPCN 1148, LPCN
1111, LPCN 1144, and LPCN 1107 are very risky and uncertain, and our product candidates may fail to advance beyond the current study.
Even if we obtain required financing, we cannot ensure successful product development or that we will obtain regulatory approval or successfully
commercialize any of our product candidates and generate product revenues.
All
of our clinical candidates will be subject to extensive regulation which can be costly and time consuming, cause delays or prevent approval
of the products for commercialization.
Our
clinical development of oral neuro active steroids, LPCN 1148, LPCN 1111, LPCN 1144, and LPCN 1107 and any future product candidates
is subject to extensive regulations by the FDA. Product development is a very lengthy and expensive process and can vary significantly
based upon the product candidate’s novelty and complexity. Regulations are subject to change and regulatory agencies have significant
discretion in the approval process.
Numerous
statutes and regulations govern human testing and the manufacture and sale of human therapeutic products in the United States. Such legislation
and regulation bears upon, among other things, the approval of protocols and human testing, the approval of manufacturing facilities,
safety of the product candidates, testing procedures and controlled research, review and approval of manufacturing, preclinical and clinical
data prior to marketing approval including adherence to cGMP during production and storage as well as regulation of marketing activities
including advertising and labeling.
In
order to obtain regulatory clearance for the commercial sale of any of our product candidates, we must demonstrate through preclinical
studies and clinical trials that the potential product is safe and efficacious for use in humans for each target indication. Obtaining
approval of any of our product candidates is an extensive, lengthy, expensive and uncertain process, and the FDA may delay, limit or
deny approval for many reasons, including:
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we
may not be able to demonstrate that the product candidate is safe and effective to the satisfaction of the FDA; |
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the
results of our clinical trials may not meet the level of statistical or clinical significance required by the FDA for marketing approval; |
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the
FDA may disagree with the number, design, size, conduct or implementation of our clinical trials; |
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the
contract research organization that we retain to manage our clinical trials may take actions outside of our control that materially
adversely impact our clinical trials; |
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the
FDA may not find the data from preclinical studies and clinical trials sufficient to demonstrate that a particular product candidate’s
clinical and other benefits outweigh its safety risks; |
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the
FDA may disagree with our interpretation of data from our preclinical studies and clinical trials or may require that we conduct
additional trials; |
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the
FDA may not accept data generated at our clinical trial sites; |
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if
our NDA once submitted is reviewed by an Advisory Committee, the FDA may have difficulties scheduling an Advisory Committee meeting
in a timely manner or the Advisory Committee may recommend against approval of our application or may recommend that the FDA require,
as a condition of approval, additional preclinical studies or clinical trials, limitations on approved labeling or distribution and
use restrictions; |
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the
FDA may require development of a REMS as a condition of approval; |
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the
FDA may require longer or additional duration of stability data on the clinical lots prior to initiation of further clinical trials; |
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the
FDA may identify deficiencies in the formulation or stability of our product candidates or products, or relating to our manufacturing
processes or facilities, or in the processes and facilities of the contract manufacturing organization (“CMO”), our suppliers,
or other third parties that may be utilized in the production supply chain of our products; and |
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with
respect to TLANDO and LPCN 1111, the FDA may not grant a three-year exclusivity as the active is a Testosterone prodrug. |
Preclinical
and clinical data are often susceptible to varying interpretations and analyses, and many companies that have believed their product
candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain FDA approval for their
products.
No
assurance can be given that current regulations relating to regulatory approval will not change or become more stringent. The FDA may
also require that we amend clinical trial protocols and/or run additional trials in order to provide additional information regarding
the safety, efficacy or equivalency of any compound for which we seek regulatory approval. Moreover, any regulatory approval of a drug
which is eventually obtained may entail limitations on the indicated uses for which that drug may be marketed. Furthermore, product approvals
may be withdrawn or limited in some way if problems occur following initial marketing or if compliance with regulatory standards is not
maintained. The FDA could become more risk averse to any side effects or set higher standards of safety and efficacy prior to reviewing
or approving a product. This could result in a product not being approved
We
are substantially dependent on the success of our licensed product candidate, TLANDO, for which we received tentative approval
from the FDA and which may not receive final regulatory approval or be successfully commercialized.
TLANDO
is currently our only product candidate that has completed Phase 3 clinical trials. In October 2021, we entered into the Antares License
Agreement with Antares, pursuant to which we granted Antares an exclusive, royalty-bearing, sublicensable right and license to develop
and commercialize, upon final approval of TLANDO from the FDA, our TLANDO product with respect to TRT in the U.S. None of our other products
have been approved for sale. Therefore, at this stage, our ability to realize revenue depends on TLANDO’s successful regulatory approval and commercialization, if final approval is obtained. The commercial success of TLANDO depends almost entirely on
Antares’ commercialization efforts and we have very limited ability to influence Antares’ efforts, including the amount and
timing of resources they devote, if any, to the commercialization of TLANDO.
On
December 8, 2020, the FDA informed us that it granted tentative approval to TLANDO for testosterone replacement therapy in adult males
indicated for conditions associated with a deficiency or absence of endogenous testosterone: primary
hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired). In granting tentative approval, the
FDA concluded that TLANDO has met all required quality, safety and efficacy standards necessary for approval, but TLANDO has not received
final approval and is not eligible for final approval and marketing in the U.S. until the expiration of the exclusivity period previously
granted to Clarus with respect to JATENZO®, which expires on March 27, 2022. Antares will not be able to market TLANDO in the U.S.
until that time. Any delay in receiving final FDA approval could adversely affect Antares’s commercialization efforts and ability
to compete with other TRT products and have a material adverse effect on our business.
Under
the PREA, if TLANDO receives full approval, our licensing partner, Antares, will need to address the PREA requirement to assess the safety
and effectiveness of TLANDO in pediatric patients. The FDA has also required us to conduct certain post-marketing studies including:
(i) conduct an appropriately designed label comprehension and knowledge study that assesses patient understanding of key risk messages
in the Medication Guide for TLANDO and (ii) conduct an appropriately designed one-year trial to evaluate development of adrenal insufficiency
with chronic TLANDO therapy. The timetables for these post-marketing requirements will be established at the time of full approval of
TLANDO. Antares will be responsible for any required studies after approval of TLANDO.
Even
if final regulatory approval of TLANDO is obtained, the success of TLANDO, and our ability to realize royalty revenue, will depend on
the commercialization efforts of Antares. If Antares is not able to successfully commercialize TLANDO, we may not realize any royalty
revenue under the Antares License Agreement and our business could be adversely affected.
In
the event that we seek regulatory approval of TLANDO outside the United States, such markets have requirements for approval of drug candidates
with which we must comply prior to marketing. Obtaining regulatory approval for marketing of TLANDO in one country does not ensure we
will be able to obtain regulatory approval in other countries but a failure or delay in obtaining regulatory approval in one country
may have a negative effect on the regulatory process in other countries.
Any
regulatory approval of TLANDO, once obtained, including the FDA’s tentative approval, may be withdrawn. Ultimately, the failure
to obtain and maintain regulatory approvals would prevent TLANDO from being marketed and would have a material adverse effect on our
business.
If
T-replacement therapies are found, or are perceived, to create health risks, our ability to realize any revenue from TLANDO and
LPCN 1111 could be materially adversely affected, and our business could be harmed. Even if our TLANDO and our LPCN
1111 are approved, physicians and patients may be deterred from prescribing and using T-replacement therapies, which could depress
demand for TLANDO and LPCN 1111 and compromise the successful commercialization of TLANDO and LPCN 1111, if final approval
is obtained.
Certain
publications have suggested potential health risks associated with T-replacement therapy, such as increased cardiovascular disease risk,
including increased risk of heart attack or stroke, fluid retention, sleep apnea, breast tenderness or enlargement, increased red blood
cells, development of clinical prostate disease, including prostate cancer, and the suppression of sperm production. These potential
health risks are described in various articles, including the following publications:
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a
2014 publication in PLOS ONE, which found that, compared to the one year prior to beginning T-replacement therapy, the risk of heart
attack doubled 90 days after the start of T deficiency treatment in older men regardless of their history of heart disease and was
two to three times higher in men younger than 65 with a history of heart disease; |
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a
2013 publication in the Journal of the American Medical Association, which reported that hypogonadal men receiving T-replacement
therapy developed a 30% increase in the risk of stroke, heart attack and death; and |
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a
2013 publication in BMC Medicine, which concluded that exogenous T increased the risk of cardiovascular-related events, particularly
in trials not funded by the pharmaceutical industry. |
Prompted
by these events, the FDA announced on January 31, 2014, that it will investigate the risk of stroke, heart attack, and death in men taking
FDA-approved testosterone products and that the FDA would hold a T-class Advisory Committee meeting on September 17, 2014, to discuss
this topic further. The FDA has also asked health care professionals and patients to report side effects involving prescription testosterone
products to the agency.
Following
the FDA’s announcement, the Endocrine Society, a professional medical organization, released a statement in February 2014 in support
of further studies regarding the risks and benefits of FDA-approved T-replacement products for men with age-related T deficiency. Specifically,
the Endocrine Society noted that large-scale randomized controlled trials are needed to determine the risks and benefits of T-replacement
therapy in older men. In addition, the Endocrine Society recommended that patients should be informed of the potential cardiovascular
risks in middle-aged and older men associated with T-replacement therapies. Also following the FDA’s announcement, Public Citizen,
a consumer advocacy organization, petitioned the FDA to add a “black box” warning about the increased risks of heart attacks
and other cardiovascular dangers to the product labels of all T-replacement therapies. In addition, this petition urged the FDA to delay
its decision date on approving Aveed, a long-acting T-injectable developed by Endo, which was subsequently approved by the FDA in March
2014. In July 2014, the FDA responded to the Public Citizen petition and denied the petition. Additionally, in June 2014 the FDA announced
that it would require the manufacturers of testosterone drugs to update the warning label to include blood clots including deep vein
thrombosis and pulmonary embolism.
At
the T-class Advisory Committee meeting held on September 17, 2014, the Advisory Committee discussed (i) the identification of the appropriate
patient population for whom T-replacement therapy should be indicated and (ii) the potential risk of major adverse cardiovascular events,
defined as non-fatal stroke, non-fatal myocardial infarction and cardiovascular death associated with T-replacement therapy. At the meeting,
16 of the 21 members of the Advisory Committee voted that the FDA should require sponsors of testosterone products to conduct a post
marketing study (e.g. observational study or controlled clinical trial) to further assess the potential cardiovascular risk. Further,
12 of these voted that such post marketing study be required only if the T-replacement therapy is also approved for age-related hypogonadism.
The
Advisory Committee also held a meeting on September 18, 2014, to evaluate the safety and efficacy of JATENZO® (previously Rextoro),
an oral TU submitted to the FDA by Clarus for the proposed indication of T-replacement therapy. 18 of the 21 members of the Advisory
Committee voted that the overall benefit/risk profile of JATENZO® was not acceptable to support approval for T-replacement therapy.
The Advisory Committee agreed that an oral TU as a T-replacement therapy is promising and that it would be of great value to patients
to have an oral treatment option, but they did not believe the current JATENZO® data supported approval.
On
March 3, 2015, the FDA issued a safety announcement addressing the Advisory Committee’s recommendations and communicated its expectations
related to label revisions and additional clinical requirements.
The
FDA’s safety assessment recommended the following label modifications/restrictions in the indicated population for T-replacement
therapy:
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limiting
use of T-replacement products to men who have low testosterone caused by certain medical conditions; |
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prior
to initiating use of T-replacement products, confirm diagnosis of hypogonadism by ensuring that serum testosterone has been measured
in the morning on at least two separate days and that these concentrations are below the normal range; |
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adding
cautionary language stating that the safety and efficacy of TRT products with age-related hypogonadism have not been established;
and |
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adding
cautionary language stating that some studies have shown an increased risk of myocardial infarction and stroke associated with use
of T-replacement products. |
Additionally,
the FDA stated that it will require manufacturers of approved T-replacement products to conduct a well-designed clinical trial
to more clearly address the question of whether an increased risk of heart attack or stroke exists among users of T-replacement products.
The FDA encouraged manufacturers to work together on conducting a clinical trial, although the FDA will allow manufacturers to work separately
if they so choose.
On
December 8, 2020, the FDA tentatively approved TLANDO. As part of their approval, the FDA has required us to include certain warnings
and precautions in our labeling for TLANDO, including a “black box warning,” including warnings relating to blood pressure
increases and an indication that the safety and efficacy of TLANDO in males less than 18 years has not been established. These warnings
may deter physicians and patients from using TLANDO after it has received final approval, which could adversely affect our business.
The
FDA has also required us to conduct certain post-marketing studies to (i) assess patient understanding of key risks relating to TLANDO
and (ii) evaluate development of adrenal insufficiency with chronic TLANDO therapy. Antares is responsible for conducting these post-marketing
studies. Negative outcomes from such studies could adversely affect the ability of Antares to successfully commercialize TLANDO, which
would adversely affect our ability to realize royalty revenue under the Antares License Agreement.
If
we fail to obtain adequate healthcare reimbursement for our products, our revenue-generating ability will be diminished and there is
no assurance that the anticipated market for our products will be sustained.
We
believe that there could be many different applications for products successfully derived from our technologies and that the anticipated
market for products under development could continue to expand. However, due to competition from existing or new products, potential
changes to the class TRT label by the FDA and the yet to be established commercial viability of our products, no assurance can be given
that these beliefs will prove to be correct. Physicians, patients, formularies, payors or the medical community in general may not accept
or utilize any products that we or our collaborative partners may develop. Other drugs may be approved during our clinical testing which
could change the accepted treatments for the disease targeted and make our compound obsolete.
Our
ability to commercialize our products with success may depend, in part, on the extent to which coverage and adequate reimbursement to
patients for the cost of such products and related treatment will be available from governmental health administration authorities, private
health coverage insurers and other organizations, as well as the ability of private payors to pay for or afford our drugs. Adequate third-party
coverage may not be available to patients to allow us to maintain price levels sufficient for us to realize an appropriate return on
our investment in product development.
Coverage
and adequate reimbursement from governmental healthcare programs, such as Medicare and Medicaid, and commercial payers can be critical
to new product acceptance. Coverage decisions may depend upon clinical and economic standards that disfavor new drug products when more
established or lower cost therapeutic alternatives are already available or subsequently become available. Additionally, current manufacturers
of drug products may have agreements with payors that may limit the ability of new products to get on formulary or require a step edit
with an existing product before reimbursement or a new product will occur. Even if we obtain coverage for our products, the resulting
reimbursement payment rates might not be adequate or may require co-payments that patients find unacceptably high. Patients are less
likely to use our products unless coverage is provided and reimbursement is adequate to cover a significant portion of the cost of our
products. Payers may require a more arduous prior authorization process as a condition to payment for TRT therapy. This could adversely
affect the market for TRT products.
In
the United States and in many other countries, pricing and/or profitability of some or all prescription pharmaceuticals and biopharmaceuticals
are subject to varying degrees of government control. Healthcare reform and controls on healthcare spending may limit the price we charge
for any products and the amounts thereof that we can sell. In particular, in the United States, the federal government and private insurers
have changed and have considered ways to change, the manner in which healthcare services are provided. In March 2010, ACA became law
in the United States. ACA substantially changes the way healthcare is financed by both governmental and private insurers and significantly
affects the healthcare industry. The provisions of ACA of importance to our potential product candidates include the following:
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an
annual, nondeductible fee on any entity that manufactures or imports certain branded prescription drugs and biologic agents; |
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an
increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program; |
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expansion
of healthcare fraud and abuse laws, including the False Claims Act and the Anti-Kickback Statute, new government investigative powers,
and enhanced penalties for noncompliance; |
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a
new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% point-of-sale discounts off negotiated
prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s
outpatient drugs to be covered under Medicare Part D; |
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extension
of manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed
care organizations; |
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expansion
of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals
beginning in 2014 and by adding new mandatory eligibility categories for certain individuals with specified income levels, thereby
potentially increasing manufacturers’ Medicaid rebate liability; |
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expansion
of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program; |
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new
requirements to report annually certain financial arrangements with physicians, certain other healthcare professionals, and teaching
hospitals; |
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a
new requirement to annually report drug samples that manufacturers and distributors provide to licensed practitioners, pharmacies
of hospitals and other healthcare entities; and |
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a
new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness
research, along with funding for such research. |
In
addition, other legislative changes have been proposed and adopted since ACA was enacted. On August 2, 2011, the Budget Control Act of
2011, created, among other things, measures for spending reductions by Congress. A Joint Select Committee on Deficit Reduction, tasked
with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required
goals, thereby triggering the legislation’s automatic reduction to several government programs. This includes aggregate reductions
to Medicare payments to providers of up to 2% per fiscal year, starting in 2013. On January 2, 2013, President Obama signed into law
the American Taxpayer Relief Act of 2012, which, among other things, reduced Medicare payments to several providers and increased the
statute of limitations period for the government to recover overpayments to providers from three to five years. The Medicare Access and
CHIP Reauthorization Act of 2015 was signed into law on April 16, 2015 and implemented the most significant change in Medicare reimbursement
since the ACA was enacted. This 2015 law authorizes a new Medicare pay –for-performance reimbursement system for physicians, which
will reward physicians for performance on metrics related to quality of care, resource use, meaningful use of electronic medical records,
and clinical practice improvement activities. The Bipartisan Budget Act was enacted on November 2, 2015, and among provisions, restricts
the types of facilities that may receive hospital reimbursement under Medicare. These new laws may result in additional reductions in
Medicare and other healthcare funding, which could have a material adverse effect on our customers and accordingly, our financial operations.
We
anticipate that ACA will result in additional downward pressure on the reimbursement we may receive for any approved and covered product
and could seriously harm our business. Any reduction in reimbursement from Medicare and other government programs may result in a similar
reduction in payments from private payers. In the future, the U.S. government may institute further controls and different reimbursement
schemes and limits on Medicare and Medicaid spending or reimbursement that may affect the payments we could collect from sales of any
products in the United States.
The
Department of Health and Human Services Office of Inspector General issued final regulations on November 30, 2020 to eliminate safe harbor
protection under the anti-kickback statute for drug price reductions that pharmaceutical manufacturers pay to Medicare and Medicaid plan
sponsors and their pharmacy benefit managers. The proposal reflects a clear intent to substantially alter many of the current drug discount
and services compensation practices among pharmaceutical manufacturers and Medicare and Medicaid managed care organizations and their
pharmacy benefit managers. The proposal also reflects a skepticism that current drug discount and compensation practices among manufacturers
and pharmacy benefit managers are sufficiently transparent to health plans to ensure that all appropriate cost reductions and value is
passed through to health plans and reflected in lower health plans costs and lower premiums for beneficiaries. The Biden Administration
has delayed the effective date of this rule until January 1, 2023, and a lawsuit initiated by the Pharmaceutical Care Management Administration
has challenged this final rule. If the regulation becomes effective, it could result in lower prices for pharmaceutical products in general.
The
Centers for Medicare and Medicaid Services issued an interim final rule on November 20, 2020, that would tie prices for certain drugs
under Medicare Part B to the lowest price for those drugs available in certain countries that are members of the Organization for Economic
Co-operation and Development. This “most favored nation” drug pricing rule is also the subject of lawsuits, and a federal
court has placed an injunction on the implementation of the rule. This rule, if finalized, could also result in lower prices for pharmaceutical
products in general.
The
Biden Administration will have the opportunity to address these regulations as well as drug pricing, health care access, and other health
care reform issues. Any further legislative or administrative action to reduce reimbursement or health benefits to beneficiaries under
the Medicare or Medicaid program could affect the payment we could collect from sale of any product in the United States.
There
is substantial competition in the TRT market, which may result in others discovering, developing or commercializing products before or
more successfully than us or our licensing partner.
We
expect to face significant competition for any of our product candidates, if approved. In particular, once final approval is obtained,
TLANDO would compete in the T-replacement therapies market, which is competitive and currently dominated by the sale of T-gels and T-injectables.
Receipt of future potential payments under our licensing agreement will depend, in large part, on our licensing partner’s ability
to obtain an adequate share of the market. Potential competitors in North America, Europe and elsewhere include major pharmaceutical
companies, specialty pharmaceutical companies, biotechnology firms, universities and other research institutions and government agencies.
Other pharmaceutical companies may develop oral T-replacement therapies that compete with TLANDO. For example, because TU is not a patented
compound and is commercially available to third parties, it is possible that competitors may design methods of TU administration that
would be outside the scope of the claims of either our issued patents or our patent applications. This would enable their products to
effectively compete with TLANDO, which could have a negative effect on potential payments under our licensing agreement.
The
following T-replacement therapies currently on the market in the United States would compete with TLANDO:
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Oral-T,
such as Jatenzo; |
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T-gels,
such as AndroGel (marketed by Abbvie) and Perrigo’s AB-rated 1% generic of AndroGel, Teva’s 1% generic of AndroGel, Testim
and its generics (marketed by Endo Health Solutions, or Endo), and Fortesta and its generics (marketed by Endo); |
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T-injectables,
including a subcutaneous auto-injector, XYOSTED, marketed by Antares Pharma, Inc.; |
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Branded,
longer-acting injectables, such as Aveed (marketed
by Endo); |
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T-nasals,
such as Natesto (marketed by Acerus); |
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methyl-T,
such as Methitest (marketed by Impax) and Testred (marketed by Valeant); |
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transdermal
patches, such as Androderm (marketed by Allergan); |
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buccal
patches, such as Striant (marketed by Endo); |
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generic
testosterone enanthate intra-muscular injectables; |
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generic and generic T-gels; and |
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subcutaneous
injectable pellets, such as Testopel (marketed by Endo). |
On
March 27, 2019, Clarus’ product JATENZO®, an oral TU product, was approved by the FDA and also received three years of marketing
exclusivity. On February 10, 2020, Clarus announced that JATENZO® has been launched and is commercially available. Based on the FDA’s
tentative approval of TLANDO, the marketing of TLANDO cannot begin until after March 27, 2022, the expiration of the exclusivity period
granted to Clarus with respect to JATENZO®.
We
are also aware of other pharmaceutical companies that have T-replacement therapies or testosterone therapies in development that may
be approved for marketing in the United States or outside of the United States.
Based
on publicly available information, we believe that several other T-replacement therapies that would be competitive with TLANDO are in
varying stages of development, some of which may be approved, marketed and/or commercialized prior to TLANDO. These therapies include
T-gels, oral-T, an aromatase inhibitor, a new class of drugs called Selective Androgen Receptor Modulators and hydroalcoholic gel formulations
of DHT.
In
light of the competitive landscape above, TLANDO will not be the only oral TRT to market, which may significantly affect the market acceptance
and commercial success of TLANDO.
Furthermore,
many of our potential competitors have substantially greater financial, technical, and human resources than we do and significantly greater
experience in the discovery and development of drug candidates, obtaining FDA and other marketing approvals of products and the commercialization
of those products. Accordingly, our competitors may be more successful than we may be in obtaining FDA approval for drugs and achieving
widespread market acceptance. Our competitors’ drugs may be more effective, or more effectively marketed and sold, than our products
and may render our products obsolete or non-competitive before we can recover the expenses of developing and commercializing them. We
anticipate that we will face intense and increasing competition as new drugs enter the market and advanced technologies become available.
Failure to successfully compete in this market would materially and negatively impact our business and operations.
Even
if TLANDO is approved by the FDA, our licensee’s ability to commercialize TLANDO may be limited.
Our
licensee partner’s ability to commercialize TLANDO, should it receive final approval, is uncertain. Our licensee’s ability
to commercially launch TLANDO is contingent upon numerous factors including, among other things, receipt of final FDA approval, the completion
of post-marketing studies, the availability of commercial launch supplies, the impact of COVID-19, commercial acceptance by patients,
the medical community, and third-party payors, and the resources that our licensee devotes to the commercialization of TLANDO.
If our licensee is unable to successfully launch TLANDO commercially at scale, our business and operations could be adversely affected.
We
will not be able to successfully commercialize our product candidates without establishing sales, marketing and market access capabilities
internally or through collaborators.
We
currently do not have a sales, marketing and market access staff. If and when any of our product candidates are commercialized, we may
not be able to find suitable sales and marketing staff and collaborators for our product candidates. The outside collaborators we work
with, including Antares under the Antares License Agreement with respect to TLANDO, may not be adequate or successful and any collaborators
could terminate or materially reduce the effort they direct to our products. The development of collaborations or an internal sales force
and marketing, market access and sales capability will require significant capital, management resources and time. The cost of establishing
such a sales force may exceed any potential product revenues and our marketing, market access and sales efforts may be unsuccessful.
If we are unable to develop an internal marketing, market access and sales capability or if we are unable to enter into a marketing and
sales arrangement with a third party on acceptable terms, we may be unable to successfully commercialize our product candidates.
Even
if we receive marketing approval in the United States, we may never receive regulatory approval to market our products outside the United
States, which could reduce the size of our potential markets and have a material adverse impact on our business.
In
order to market any products outside of the United States, we must establish and comply with numerous and varying regulatory requirements
of other countries regarding safety and efficacy.
Approval
procedures vary among countries and can involve additional product candidate testing and additional administrative review periods. The
time required to obtain approvals in other countries might differ from that required to obtain FDA approval. The marketing approval process
in other countries may include all of the risks detailed above regarding FDA approval in the United States as well as other risks. In
particular, in many countries outside of the United States, products must receive pricing and reimbursement approval before the product
can be commercialized. This can result in substantial delays in such countries. Marketing approval in one country does not ensure marketing
approval in another, but a failure or delay in obtaining marketing approval in one country may have a negative effect on the regulatory
process in others. Failure to obtain marketing approval in other countries or any delay or setback in obtaining such approval would impair
our ability to market our products in such foreign markets. Any such impairment would reduce the size of our potential markets, which
could have an adverse impact on our business, results of operations and prospects.
We
are subject to stringent government regulations concerning the clinical testing of our products and will continue to be subject to government
regulation of any product that receives regulatory approval.
Numerous
statutes and regulations govern human testing and the manufacture and sale of human therapeutic products in the United States and other
countries where we intend to market our products. Such legislation and regulation bears upon, among other things, the approval of clinical
study protocols and human testing of our products, the approval of manufacturing facilities, testing procedures and controlled research,
the review and approval of manufacturing, preclinical and clinical data prior to marketing approval, including adherence to cGMP during
production and storage, and marketing activities including advertising and labeling.
Clinical
trials may be delayed or suspended at any time by us or by the FDA or by other similar regulatory authorities if it is determined at
any time that patients may be or are being exposed to unacceptable health risks, including the risk of death, or if compounds are not
manufactured under acceptable cGMP conditions or with acceptable quality. Current regulations relating to regulatory approval may change
or become more stringent. The agencies may also require additional clinical trials to be run in order to provide additional information
regarding the safety, efficacy or equivalency of any compound for which we seek regulatory approval. Moreover, any regulatory approval
of a drug which is eventually obtained may entail limitations on the indicated uses for which that drug may be marketed. Furthermore,
product approvals may be withdrawn or limited in some way if problems occur following initial marketing or if compliance with regulatory
standards is not maintained. Regulatory agencies could become more risk adverse to any side effects or set higher standards of safety
and efficacy prior to reviewing or approving a product. This could result in a product not being approved.
If
we, or any future marketing collaborators or CMOs, fail to comply with applicable regulatory requirements, we may be subject to sanctions
including fines, product recalls or seizures and related publicity requirements, injunctions, total or partial suspension of production,
civil penalties, suspension or withdrawals of previously granted regulatory approvals, warning or untitled letters, refusal to approve
pending applications for marketing approval of new products or of supplements to approved applications, import or export bans or restrictions,
and criminal prosecution and penalties. Any of these penalties could delay or prevent the promotion, marketing or sale of our products.
The
successful commercialization of our product candidates and ability to generate significant revenue will depend on achieving market acceptance.
Even
if our product candidates are successfully developed and receive regulatory approval, they may not gain market acceptance among physicians,
patients, healthcare payers such as private insurers or governments and other funding parties and the medical community. The degree of
market acceptance for our products, if approved, will depend on a number of factors, including:
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relative convenience and ease of administration, including as compared to alternative treatments and competitive therapies; |
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prevalence and severity of any adverse side effects; |
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limitations
or warnings contained in the labeling approved by the FDA; |
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availability
of alternative treatments, including a number of competitive therapies already approved or expected to be commercially launched in
the near future; |
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distribution
and use restrictions imposed by the FDA or agreed to by us as part of a mandatory REMS or voluntary risk management plan; |
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pricing
and cost effectiveness; |
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the
effectiveness of our or any future collaborators’ sales and marketing strategies; |
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ability to increase awareness of our products through marketing efforts; |
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our
ability to obtain sufficient third-party coverage or reimbursement; and |
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willingness of patients to pay out-of-pocket in the absence of third-party coverage. |
If
our product candidates are approved but do not achieve an adequate level of acceptance by physicians, healthcare payors and patients,
we may not generate sufficient revenue from our products and we may never become or remain profitable. In addition, our efforts to educate
the medical community and third-party payors on the benefits of our products may require significant resources and may never be successful.
Even
if we obtain marketing approval for our products, physicians and patients using existing products may choose not to switch to our products.
Physicians
often show a reluctance to switch their patients from existing drug products even when new and potentially more effective and convenient
treatments enter the market. Also, physicians may be reluctant to switch patients if adequate reimbursement for new products is not available.
In addition, patients often acclimate to the brand or type of drug product that they are currently taking and do not want to switch unless
their physicians recommend switching products or they are required to switch drug treatments due to lack of reimbursement for existing
drug treatments and only if the new product has adequate reimbursement. The existence of either or both of physician or patient reluctance
in switching to our products would have an adverse effect on our operating results and financial condition.
The
FDA and other regulatory agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses. If we are found
to have improperly promoted off-label uses, we may become subject to significant liability.
The
FDA and other regulatory agencies strictly regulate the promotional claims that may be made about prescription products, such as our
product candidates. In particular, a product may not be promoted for uses that are not approved by the FDA or such other regulatory agencies
as reflected in the product’s approved labeling. The FDA may impose further requirements or restrictions on the distribution or
use of our product candidates as part of a REMS plan, such as limiting prescribing to certain physicians or medical centers that have
undergone specialized training, limiting treatment to patients who meet certain safe-use criteria and requiring treated patients to enroll
in a registry. If we receive marketing approval for our product candidates, physicians may nevertheless prescribe our products to their
patients in a manner that is inconsistent with the approved label. If we are found to have promoted such off-label uses, we may become
subject to significant liability, including potential liability under federal civil and criminal false claims acts. 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 or permanent injunctions under which specified
promotional conduct is changed or curtailed.
If
we fail to comply with federal and state healthcare laws, including fraud and abuse and health information privacy and security laws,
we could face substantial penalties and our business, results of operations, financial condition and prospects could be adversely affected.
As
a pharmaceutical company, even though we do not and will not control referrals of healthcare services or bill directly to Medicare, Medicaid
or other third-party payers, certain federal and state healthcare laws and regulations pertaining to fraud and abuse and patients’
rights are and will be applicable to our business. We could be subject to healthcare fraud and abuse and patient privacy regulation by
both the federal government and the states in which we conduct our business. The laws that may affect our ability to operate include:
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the
federal Anti-Kickback Statute, which constrains our marketing practices, educational programs, pricing policies, and relationships
with healthcare providers or other entities, by prohibiting, among other things, soliciting, receiving, offering or paying remuneration,
directly or indirectly, to induce, or in return for, either the referral of an individual or the purchase or recommendation of an
item or service reimbursable under a federal healthcare program, such as the Medicare and Medicaid programs; |
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federal
civil and criminal false claims laws and civil monetary penalty 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 third-party payers that
are false or fraudulent; |
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HIPAA,
which among other things created new federal criminal statutes that prohibit executing a scheme to defraud any healthcare benefit
program or making false statements relating to healthcare matters; |
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the
federal Physician Payments Sunshine Act, which, among other things, requires manufacturers of drugs, devices, biologics and medical
supplies for which payment is available under certain federal healthcare programs to report annually information related to “payments
or other transfers of value” made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors)
and teaching hospitals, and ownership and investment interests held by certain healthcare professionals and their immediate family
members; |
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HIPAA,
as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, and its implementing regulations, which
imposes certain requirements relating to the privacy, security, breach notification, and transmission of individually identifiable
health information; and |
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state
and foreign 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 and foreign 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 HIPAA, thus complicating compliance efforts. |
Because
of the breadth of these laws and the narrowness of available statutory and regulatory exceptions, it is possible that some of our business
activities could be subject to challenge under one or more of such laws. To the extent that any of our product candidates is ultimately
sold in countries other than the United States, we may be subject to similar laws and regulations in those countries. If we or our operations
are found to be in violation of any of the laws described above or any other governmental regulations that apply to us, we may be subject
to penalties, including civil, criminal and administrative penalties, damages, fines, disgorgement, exclusion from participating in government
healthcare programs, contractual damages, reputational harm and the curtailment or restructuring of our operations. Any penalties, damages,
fines, curtailment or restructuring of our operations could materially adversely affect our ability to operate our business and our financial
results. Although compliance programs can mitigate the risk of investigation and prosecution for violations of these laws, the risks
cannot be entirely eliminated. Any action against us for violation of these laws, even if we successfully defend against it, could cause
us to incur significant legal expenses and divert our management’s attention from the operation of our business. Moreover, achieving
and sustaining compliance with applicable federal and state privacy, security and fraud laws may prove costly.
The
Department of Health and Human Services Office of Inspector General proposed new regulations on February 6, 2019 to eliminate safe harbor
protection under the anti-kickback statute for drug price reductions that pharmaceutical manufacturers pay to Medicare and Medicaid plan
sponsors and their pharmacy benefit managers. The proposal reflects a clear intent to substantially alter many of the current drug discount
and services compensation practices among pharmaceutical manufacturers and Medicare and Medicaid managed care organizations and their
pharmacy benefit managers. The proposal also reflects a skepticism that current drug discount and compensation practices among manufacturers
and pharmacy benefit managers are sufficiently transparent to health plans to ensure that all appropriate cost reductions and value is
passed through to health plans and reflected in lower health plans costs and lower premiums for beneficiaries. If the proposal is finalized,
it could result in lower prices for pharmaceutical products in general. The Biden Administration has delayed the effective date of this
rule until January 1, 2023, and a lawsuit initiated by the Pharmaceutical Care Management Administration has challenged this final rule.
If the regulation becomes effective, it could result in lower prices for pharmaceutical products in general.
The
Biden Administration will have the opportunity to address these regulations as well as drug pricing, health care access, and other health
care reform issues. Any further legislative or administrative action to reduce reimbursement or health benefits to beneficiaries under
the Medicare or Medicaid program could affect the payment we could collect from sale of any product in the United States.
The
ongoing outbreak of coronavirus around the world could adversely impact our business and operating results.
In
December 2019, a novel strain of coronavirus, SARS-CoV-2, was reported to have surfaced in Wuhan, China. Since then, SARS-CoV-2, and
the resulting disease COVID-19, has spread to multiple countries, including the United States and all of the primary markets where we
conduct business.
The
duration and extent of COVID-19’s impact on our business may be difficult to assess or predict. The widespread pandemic has resulted,
and may continue to result for an extended period, in significant disruption of global financial markets, reducing our ability to access
capital, which would negatively affect our liquidity. Further, quarantines or government reaction or shutdowns for COVID-19 could disrupt
our operations and harm our business, financial condition and results of operations. Our key personnel and other employees could also
be affected by COVID-19, potentially reducing their availability, and an outbreak such as COVID-19 or the procedures we take to mitigate
its effect on our workforce could reduce the efficiency of our operations or prove insufficient. We may delay or reduce certain capital
spending and certain projects until the travel and logistical impacts of COVID-19 are lifted, which will delay the completion of such
projects.
In
addition, the conduct of clinical trials and studies required to obtain regulatory approvals for our products have been and we expect
may continue to be affected by the COVID-19 pandemic. As hospital resources are prioritized for the COVID-19 outbreak and quarantines
impede patient movement or interrupt healthcare services, clinical studies may continue to be disrupted. If we are unable to successfully
complete our clinical studies, our business and operating results will be harmed. Further, we believe that subject drop-out rates and
the number of subjects that ultimately complete clinical studies could be negatively impacted by COVID-19. Interruptions caused by COVID-19
may also limit our ability to collect data from clinical studies. If we are unable to complete or effectively collect data from clinical
studies, our business and operating results will be harmed.
The
global outbreak of COVID-19 continues to rapidly evolve. The ultimate impact of the COVID-19 outbreak is highly uncertain and subject
to change. We do not yet know the full extent of potential delays or impacts on our business or the global economy as a whole. However,
these effects have harmed our business, financial condition and results of operations in the near term and could have a continuing material
impact on our operations, sales and ability to continue as a going concern.
Our
future success depends on our ability to retain our chief executive officer and other key executives and to attract, retain and motivate
qualified personnel.
We
are highly dependent on Dr. Mahesh V. Patel and the other principal members of our executive team. Employment with our executives and
other employees are “at will”, meaning that there is no mandatory fixed term and their employment with us may be terminated
by us or by them for any or no reason. The loss of the services of any of our executives or other key employees might impede the achievement
of our research, development and commercialization objectives. Recruiting and retaining qualified scientific personnel, and accounting
personnel will also be critical to our success. We may not be able to attract and retain qualified personnel on acceptable terms, or
at all, given the competition among numerous pharmaceutical and biotechnology companies for similar personnel. We also experience competition
for the hiring of scientific personnel from universities and research institutions. Failure to succeed in clinical trials may make it
more challenging to recruit and retain qualified scientific personnel.
In
addition, we rely on consultants and advisors, including scientific and clinical advisors, to assist us in formulating our development
and commercialization strategy. Our consultants and advisors may be employed by employers other than us and may have commitments under
consulting or advisory contracts with other entities that may limit their availability to us.
We
will need to grow our Company, and we may encounter difficulties in managing this growth, which could disrupt our operations.
As
of December 31, 2021, we had 13 employees. To manage our anticipated future growth, we must continue to implement and improve our managerial,
operational and financial systems, expand our facilities and continue to recruit and train additional qualified personnel. Also, our
management may need 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. Due to our limited resources, we may not be able to effectively manage the expansion
of our operations or recruit and train additional qualified personnel. This may result in weaknesses in our infrastructure, and give
rise to operational mistakes, loss of business opportunities, loss of employees and reduced productivity among remaining employees. The
physical expansion of our operations may lead to significant costs and may divert financial resources from other projects. If our management
is unable to effectively manage our future growth, our expenses may increase more than expected, our ability to generate revenue could
be reduced and we may not be able to implement our business strategy. Our future financial performance and our ability to commercialize
our product candidates and compete effectively will depend, in part, on our ability to effectively manage any future growth.
Federal
legislation and actions by state and local governments may permit re-importation of drugs from foreign countries into the United States,
including foreign countries where the drugs are sold at lower prices than in the United States, which could materially adversely affect
our operating results.
Our
licensing partner may face competition for TLANDO, if final approval is received, from lower priced T-replacement therapies from foreign
countries that have placed price controls on pharmaceutical products. The Medicare Prescription Drug Improvement and Modernization Act
of 2003 contains provisions that may change U.S. importation laws and expand pharmacists’ and wholesalers’ ability to import
lower priced versions of an approved drug and competing products from Canada, where there are government price controls. These changes
to U.S. importation laws will not take effect unless and until the Secretary of Health and Human Services certifies that the changes
will pose no additional risk to the public’s health and safety and will result in a significant reduction in the cost of products
to consumers. The Secretary of Health and Human Services has not yet announced any plans to make this required certification.
A
number of federal legislative proposals have been made to implement the changes to the U.S. importation laws without any certification
and to broaden permissible imports in other ways. Even if the changes do not take effect, and other changes are not enacted, imports
from Canada and elsewhere may continue to increase due to market and political forces, and the limited enforcement resources of the FDA,
U.S. Customs and Border Protection and other government agencies. For example, Pub. L. No. 111-83, which was signed into law in October
2009, provides appropriations for the Department of Homeland Security for the 2010 fiscal year, expressly prohibits U.S. Customs and
Border Protection from using funds to prevent individuals from importing from Canada less than a 90-day supply of a prescription drug
for personal use, when the drug otherwise complies with the Federal Food, Drug, and Cosmetic Act. Further, several states and local governments
have implemented importation schemes for their citizens, and, in the absence of federal action to curtail such activities, we expect
other states and local governments to launch importation efforts.
The
importation of foreign products that compete with our products could have an adverse effect on our revenue and profitability.
We
may become subject to the risk of product liability claims.
We
face an inherent risk of product liability as a result of the clinical testing of our product candidates and will face an even greater
risk if we commercialize any products. Human therapeutic products involve the risk of product liability claims and associated adverse
publicity. Currently, the principal risks we face relate to patients in our clinical trials, who may suffer unintended consequences.
Claims might be made by patients, healthcare providers or pharmaceutical companies or others. We may be sued if any product we develop
allegedly causes injury or is found to be otherwise unsuitable during product testing, manufacturing, marketing or sale.
For
example, to our knowledge, HPC has not been administered orally in a published clinical trial in any pregnant woman for the prevention
of PTB. We cannot be certain of the safety profile upon single oral or multiple oral administration of LPCN 1107 to the patient or the
fetus and its long term side effects on the mother as well as the child because (i) oral performance of LPCN 1107 may be substantially
different from efficacy and/or safety standpoint compared to FDA approved and commercialized intramuscular HPC, Makena, and (ii) oral
delivery of HPC could have a very different PK and/or pharmacodynamic profile that has never been experienced with non-oral administration
of HPC, thus having its own significant liability exposure independent of known safety of non-oral HPC in humans.
Any
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 product candidates, if approved. Even successful defense would require significant financial and management
resources. Regardless of the merits or eventual outcome, liability claims may result in:
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to our reputation; |
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withdrawal
of clinical trial participants; |
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initiation
of investigations by regulators; |
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costs
to defend the related litigation; |
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diversion of management’s time and our resources; |
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substantial
monetary awards to trial participants or patients; |
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product
recalls, withdrawals or labeling, marketing or promotional restrictions; |
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inability to commercialize any of our product candidates, if approved. |
We
may not have or be able to obtain or maintain sufficient and affordable insurance coverage, and without sufficient coverage any claim
brought against us could have a materially adverse effect on our business, financial condition or results of operations. We run clinical
trials through investigators that could be negligent through no fault of our own and which could affect patients, cause potential liability
claims against us and result in delayed or stopped clinical trials. We are required in many cases by contractual obligations, to indemnify
collaborators, partners, third party contractors, clinical investigators and institutions. These indemnifications could result in a material
impact due to product liability claims against us and/or these groups. We currently carry $3.0 million in product liability insurance,
which we believe is appropriate for our clinical trials. Although we 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 will 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.
Testosterone
is a Schedule III substance under the Controlled Substances Act and any failure to comply with this Act or its state equivalents would
have a negative impact on our business.
Testosterone
is listed by the U.S. Drug Enforcement Agency, or DEA, as a Schedule III substance under the Controlled Substances Act of 1970. The DEA
classifies substances as Schedule I, II, III, IV or V substances, with Schedule I substances considered to present the highest risk of
substance abuse and Schedule V substances the lowest risk. Scheduled substances are subject to DEA regulations relating to manufacturing,
storage, distribution and physician prescription procedures. For example, all regular Schedule III drug prescriptions must be signed
by a physician and may not be refilled more than six months after the date of the original prescription or more than five times unless
renewed by the physician.
Entities
must register annually with the DEA to manufacture, distribute, dispense, import, export and conduct research using controlled substances.
In addition, the DEA requires entities handling controlled substances to maintain records and file reports, follow specific labeling
and packaging requirements, and provide appropriate security measures to control against diversion of controlled substances. Failure
to follow these requirements can lead to significant civil and/or criminal penalties and possibly even lead to a revocation of a DEA
registration. Individual states also have controlled substances laws. State controlled substances laws often mirror federal law, however
because the states are separate jurisdictions, they may schedule products separately. While some states automatically schedule a drug
when the DEA does so, in other states there must be rulemaking or legislative action, which could delay commercialization.
Products
containing controlled substances may generate public controversy. As a result, these products may have their marketing approvals withdrawn.
State and Federal legislatures and administrative agencies may take additional action to combat a perceived misuse or overuse of such
products.
We
may have to dedicate resources to the defense and resolution of litigation.
Securities
legislation in the United States makes it relatively easy for stockholders to sue. This can lead to frivolous lawsuits which take substantial
time, money, resources and attention or force us to settle such claims rather than seek adequate judicial remedy or dismissal of such
claims. Historically, securities class action litigation has often been brought against a company following a decline in the market price
of its securities. Biotechnology and pharmaceutical companies, including us, have experienced significant stock price volatility in recent
years, increasing the risk of such litigation. As we defend the class action lawsuits or future patent infringement actions should they
be filed, or if we are required to defend additional actions brought by other shareholders, we may be required to pay substantial litigation
costs and managerial attention and financial resources may be diverted from business operations even if the outcome is in our favor.
In addition, while our insurance carrier may cover the costs of settling claims, the Company’s capital resources are critical to
its continued operations, and the payment of litigation settlements and associated legal fees diverts these capital resources away from
our operations, even if such amounts do not have a material impact on our financial statements.
On
November 14, 2019, the Company and certain of its officers were named as defendants in a purported shareholder class action lawsuit,
Solomon Abady v. Lipocine Inc. et al., 2:19-cv-00906-PMW, filed in the United District Court for the District of Utah. The complaint
alleges that the defendants made false and/or misleading statements and/or failed to disclose that our filing of the NDA for TLANDO to
the FDA contained deficiencies and as a result the defendants’ statements about our business and operations were false and misleading
and/or lacked a reasonable basis in violation of federal securities laws. The lawsuit seeks certification as a class action (for a purported
class of purchasers of the Company’s securities from March 27, 2019 through November 8, 2019), compensatory damages in an unspecified
amount, and unspecified equitable or injunctive relief. We have insurance that covers claims of this nature.
Defendants
intend to vigorously defend themselves against these allegations, but doing so may result in substantial litigation costs and managerial
attention and financial resources may be diverted from business operations even if outcome is in favor of our current and former officers
and directors and the Company.
Additionally
on April 2, 2019, we filed a lawsuit against Clarus in the United States District Court in Delaware alleging that Clarus’s JATENZO®
product infringes six of Lipocine’s issued U.S. patents: 9,034,858; 9,205,057; 9,480,690; 9,757,390; 6,569,463; and 6,923,988.
Clarus has answered the complaint and asserted counterclaims of non-infringement and invalidity. We answered Clarus’s counterclaims
on April 29, 2019. On February 11, 2020, we voluntarily dismissed allegations of patent infringement for expired U.S. Patent Nos. 6,569,463
and 6,923,988 in an effort to streamline the issues and associated costs for dispute. The Court held a scheduling conference on August
15, 2019, a claim construction hearing on February 11, 2020 and a summary judgment hearing on January 15, 2021. In May 2021, the Court
granted Clarus’ motion for Summary Judgment, finding the asserted claims of Lipocine’s U.S. patents 9,034,858; 9,205,057;
9,480,690; and 9,757,390 invalid for failure to satisfy the written description requirement of 35 U.S.C. § 112. Clarus still had
remaining claims before the Court. On July 13, 2021, we entered into a Global Agreement with Clarus which resolved all outstanding claims
of this litigation. Under the terms of the settlement, we agreed to pay Clarus $4.0 million, payable as follows: $2.5 million immediately,
$1.0 million on July 13, 2022 and $500,000 on July 13, 2023. The payment of this and other settlement payments diverts capital resources
away from our operations, which may adversely affect our business.
Cyber
security risks and the failure to maintain the integrity of company, employee or guest data could expose us to data loss, litigation
and liability, and our reputation could be significantly harmed.
We
collect and third parties collaborating on our clinical trials collect and retain large volumes of data, including personally identifiable
information regarding clinical trial participants and others, for business purposes, including for regulatory, research and development
and commercialization purposes, and our collaborators’ various information technology systems enter, process, summarize and report
such data. We also maintain personally identifiable information about our employees. The integrity and protection of our Company, employee
and clinical data is critical to our business. We are subject to significant security and privacy regulations, as well as requirements
imposed by government regulation. Maintaining compliance with these evolving regulations and requirements could be difficult and may
increase our expenses. In addition, a penetrated or compromised data system or the intentional, inadvertent or negligent release or disclosure
of data could result in theft, loss or fraudulent or unlawful use of company, employee or clinical data which could harm our reputation,
disrupt our operations, or result in remedial and other costs, fines or lawsuits.
Risks
Related to Our Dependence on Third Parties
We
may enter into license agreements and/or collaborations with third parties for the development and commercialization of our drug candidates.
If those collaborations, including, without limitation, our license arrangement with Antares for the development and commercialization
of TLANDO, are not successful, we may not be able to capitalize on the market potential of these drug candidates and may have to alter
our development and commercialization plans for our products.
Our
drug development programs for our product candidates will require substantial additional cash to fund expenses. We have not yet established
any collaborative arrangements relating to the development or commercialization of LPCN 1111, LPCN 1144, LPCN 1148, LPCN 1107
or our oral NAS. We have entered into the Antares License Agreement for TLANDO with respect to TRT in the U.S. We intend to continue
to develop our other product candidates in the United States without a partner although our ability to advance these product candidates
will depend on our capital resources. However, in order to commercialize our product candidates in the United States, we have partnered
with Antares with respect to TLANDO and we will likely look to establish a partnership or co-promotion arrangement with an established
pharmaceutical company that has a sales force, collaborate on the establishment of an internal sales force or build an internal sales
force on our own with respect to our other product candidates. We may also seek to enter into collaborative arrangements to develop and
commercialize our product candidates outside the United States. We will face significant competition in seeking appropriate collaborators
and these collaborations are complex and time-consuming to negotiate and document. We may not be able to negotiate collaborations on
acceptable terms or in a timely manner, or at all. If that were to occur, we may have to curtail the development or delay commercialization
of our product candidates in certain geographies, reduce the scope of our sales or marketing activities, reduce the scope of our commercialization
plans, or increase our expenditures and undertake development or commercialization activities at our own expense. If we elect to increase
our expenditures to fund development or commercialization activities either inside or outside of the United States on our own, we may
need to obtain additional capital, which may not be available to us on acceptable terms, or at all.
To
the extent we have, and if we do enter into any further such arrangements with any third parties, we will likely have limited control
over the amount and timing of resources that our partners dedicate to the development or commercialization of our product candidates.
On October 14, 2021, we entered into the Antares License Agreement with Antares, pursuant to which we granted to Antares an exclusive,
royalty-bearing, sublicensable right and license to develop and commercialize, upon final approval of TLANDO from the FDA, our TLANDO
product with respect to TRT in the U.S. The Antares License Agreement also provides Antares with an option, exercisable on or before
March 31, 2022, to license TLANDO XR. Consequently, our ability to generate any revenues from TLANDO with respect to TRT in the U.S.
depends on the efforts of Antares to commercialize TLANDO, once final FDA approval is obtained. We have very limited control over the
amount and timing of resources that Antares will dedicate to these efforts.
Our
ability to generate revenues from this and other collaborative arrangements will depend on our collaborators’ abilities and efforts
to successfully perform the functions agreed to with them in these arrangements. License agreements and/or collaborations involving our
drug candidates, such as our agreement with Antares, pose numerous risks to us, including the following:
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partners
have significant discretion in determining the efforts and resources that they will apply to these efforts and may not perform their
obligations as expected; |
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partners
may de-emphasize or not pursue development and commercialization of our drug candidates or may elect not to continue or renew development
or commercialization programs based on clinical trial results, changes in the partners’ strategic focus, including as a result
of a sale or disposition of a business unit or development function, or available funding or external factors such as an acquisition
that diverts resources or creates competing priorities; |
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partners
may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a drug candidate,
repeat or conduct new clinical trials or require a new formulation of a drug candidate for clinical testing; |
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partners
could independently develop, or develop with third parties, products that compete directly or indirectly with our products or drug
candidates if the partners believe that competitive products are more likely to be successfully developed or can be commercialized
under terms that are more economically attractive than ours; |
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partners
may not be able to acquire and maintain supplier and manufacturer relationships necessary to successfully commercialize our products; |
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a
partner with marketing and distribution rights to multiple products may not commit sufficient resources to the marketing and distribution
of our product relative to other products; |
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partners
may not properly obtain, maintain, defend or enforce our intellectual property rights or may use our proprietary information and
intellectual property in such a way as to invite litigation or other intellectual property related proceedings that could jeopardize
or invalidate our proprietary information and intellectual property or expose us to potential litigation or other intellectual property
related proceedings; |
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disputes
may arise between our partners and us that result in the delay or termination of the research, development or commercialization
of our products or drug candidates or that result in costly litigation or arbitration that diverts management attention and resources; |
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agreements
may be terminated and, if terminated, may result in a need for additional capital to pursue further development or commercialization
of the applicable drug candidates; |
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agreements
may not lead to development or commercialization of drug candidates in the most efficient manner or at all; and |
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if
a partner of ours were to be involved in a business combination, the continued pursuit and emphasis on our product development or
commercialization program could be delayed, diminished or terminated. |
If
our license arrangements with Antares, or any future license or collaboration we may enter into, if any, are not successful, our
business, financial condition, results of operations, prospects and development and commercialization efforts may be adversely affected.
Any termination or expiration of the Antares License Agreement, or any future license or collaboration we may enter into, if any, could
adversely affect us financially or harm our business reputation, development and commercialization efforts.
We
rely upon third-party contractors and service providers for the execution of some aspects of our development programs. Failure of these
collaborators to provide services of a suitable quality and within acceptable timeframes may cause the delay or failure of our development
programs.
We
outsource certain functions, tests and services to contract research organizations (“CROs”), medical institutions and collaborators;
and also outsource manufacturing to collaborators and/or contract manufacturers (“CMO’s”). We also rely on third parties
for quality assurance, clinical monitoring, clinical data management and regulatory expertise. We may also engage a CRO to run all aspects
of a clinical trial on our behalf. There is no assurance that such individuals or organizations will be able to provide the functions,
tests, drug supply or services as agreed upon or in a quality fashion. Any failure to do so could cause us to suffer significant delays
in the development of our products or processes.
Due
to our reliance on CROs or other third parties to assist us or who have historically assisted us in conducting clinical trials, we will
be unable to directly control all aspects of our clinical trials.
We
engaged a CRO to conduct our SOAR, DV and DF Phase 3 clinical studies for TLANDO, as well as the ABPM study for TLANDO. Additionally,
we utilized a CRO for the Phase 2 LiFT clinical study for LPCN 1144 and are utilizing a CRO for the on-going Phase 2 clinical
study for LPCN 1148. As a result, we have less direct control over the conduct of our clinical trials, the timing and completion of the
trials and the management of data developed through the trials than if we were relying entirely upon our own staff. Communicating with
outside parties can also be challenging, potentially leading to mistakes as well as difficulties in coordinating activities. Outside
parties, including CROs, may:
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have
staffing difficulties or disruptions; |
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fail
to comply with contractual obligations; |
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experience
regulatory compliance issues; |
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undergo
changes in priorities or may become financially distressed; |
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form
relationships with other entities, some of which may be our competitors; or |
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manufacturing
capacity limitations. |
These
factors may materially adversely affect their willingness or ability to conduct our trials in a manner acceptable to us. We may experience
unexpected cost increases that are beyond our control.
Moreover,
the FDA requires us to comply with GCP’s for conducting, recording, and reporting the results of clinical trials to assure that
data and reported results are credible and accurate and that the rights, integrity and confidentiality of trial participants are protected.
Our reliance on third parties that we do not control does not relieve us of these responsibilities and requirements.
Problems
with the timeliness or quality of the work of a CRO may lead us to seek to terminate the relationship and use an alternative service
provider. However, making this change may be costly and may delay our trials, and contractual restrictions may make such a change difficult
or impossible. If we must replace any CRO that is conducting our clinical trials, our trials may have to be suspended until we find another
CRO that offers comparable services. The time that it takes us to find alternative organizations may cause a delay in the commercialization
of our product candidates or may cause us to incur significant expenses to replicate data that may be lost. Although we do not believe
that any CRO on which we may rely will offer services that are not available elsewhere, it may be difficult to find a replacement organization
that can conduct our trials in an acceptable manner and at an acceptable cost. Any delay in or inability to complete our clinical trials
could significantly compromise our ability to secure regulatory approval of our product candidates and preclude our ability to commercialize
them, thereby limiting or preventing our ability to generate revenue from their sales.
We
and our licensee rely on a single supplier for our supply of testosterone esters, the active pharmaceutical ingredient
of TLANDO, LPCN 1111, LPCN 1148, and LPCN 1144, and the loss of this supplier could harm our business.
We
and our licensee rely on a single third-party supplier for our supply of testosterone esters, the active pharmaceutical ingredient of
TLANDO, LPCN 1111, LPCN 1148, and LPCN 1144. Since there are only a limited number of testosterone esters suppliers in the world, if
this supplier ceases to provide us with testosterone esters, we may be unable to procure testosterone esters on commercially favorable
terms and/or may not be able to obtain testosterone esters in a timely manner. Furthermore, the limited number of suppliers of testosterone
esters may provide such companies with greater opportunity to raise their prices. If we or our licensee are unable to obtain testosterone
esters in a timely manner and/or in sufficient quantities, our ability to develop, and potentially commercialize, LPCN 1111, LPCN 1148,
and LPCN 1144 may be adversely affected. In addition, any increase in price for testosterone esters will likely reduce our potential
gross margins for LPCN 1111, LPCN 1148 and LPCN 1144.
We
rely on limited suppliers for our supply of NAS, the active pharmaceutical ingredient of LPCN 1154 and LPCN 2101 and the loss of these
limited suppliers could harm our business.
We
rely on a limited third-party supplier for our supply NAS, the active pharmaceutical ingredient of LPCN 1154 and LPCN 2101. Since there
are only a limited number of NAS suppliers in the world, if a supplier ceases to provide us with NAS, we may be unable to procure NAS
on developmental or commercially favorable terms. Furthermore, the limited number of suppliers of NAS may provide such suppliers
with a greater opportunity to raise their prices. If we are unable to obtain NAS in a timely manner and/or in sufficient quantities,
our ability to develop NAS may be adversely affected.
If
we do not establish successful collaborations, we may have to alter our development and commercialization plans for our products.
Our
drug development programs for our product candidates will require substantial additional cash to fund expenses. We have not yet established
any collaborative arrangements relating to the development or commercialization of LPCN 1148, LPCN 1114, LPCN 1111, LPCN 1107
or oral neuroactive steroids. We intend to continue to develop our product candidates in the United States without a partner
although our ability to advance these product candidates will depend on our capital resources. However, in order to commercialize our
product candidates in the United States, we will likely look to establish a partnership or co-promotion arrangement with an established
pharmaceutical company that has a sales force, collaborate on the establishment of an internal sales force or build an internal sales
force on our own. We may also seek to enter into collaborative arrangements to develop and commercialize our product candidates outside
the United States. We will face significant competition in seeking appropriate collaborators and these collaborations are complex and
time-consuming to negotiate and document. We may not be able to negotiate collaborations on acceptable terms or in a timely manner, or
at all. If that were to occur, we may have to curtail the development or delay commercialization of our product candidates in certain
geographies, reduce the scope of our sales or marketing activities, reduce the scope of our commercialization plans, or increase our
expenditures and undertake development or commercialization activities at our own expense. If we elect to increase our expenditures to
fund development or commercialization activities either inside or outside of the United States on our own, we may need to obtain additional
capital, which may not be available to us on acceptable terms, or at all.
If
we are successful in entering into collaborative arrangements and any of our collaborative partners does not devote sufficient time and
resources to a collaboration arrangement with us, we may not realize the potential commercial benefits of the arrangement, and our results
of operations may be materially adversely affected. In addition, if any future collaboration partner were to breach or terminate its
arrangements with us, the development and commercialization of our product candidates could be delayed, curtailed or terminated because
we may not have sufficient financial resources or capabilities to continue development and commercialization of our product candidates
on our own in such locations.
Risks
Related to Ownership of Our Common Stock
Our
stock price could decline significantly based on the results and timing of clinical trials, and/or regulatory and other decisions affecting
our product candidates.
Results
of clinical trials and preclinical studies of our current and potential product candidates may not be viewed favorably by us or third
parties, including the FDA or other regulatory authorities, investors, analysts and potential collaborators. The same may be true of
how we design the clinical trials of our product candidates and regulatory decisions affecting those clinical trials. Pharmaceutical
company stock prices have declined significantly when such results and decisions were unfavorable or perceived negatively or when a product
candidate did not otherwise meet expectations. The final results from our clinical development programs may be negative, may not meet
expectations or may be perceived negatively. The designs of our clinical trials (which may change significantly and be more expensive
than currently anticipated depending on our clinical results and regulatory decisions) may also be viewed negatively by third parties.
We may not be successful in completing these clinical trials on our projected timetable, if at all. In addition, we may never achieve
FDA approval for any of our product candidates, which could cause our stock price to decline significantly and have other significant
adverse effects on our business.
If
we do not maintain effective internal controls over financial reporting in the future, the accuracy and timeliness of our financial reporting
may be adversely affected.
The
Sarbanes-Oxley Act requires, among other things, that we assess the effectiveness of our internal control over financial reporting annually
and disclosure controls and procedures quarterly. In particular, we must perform system and process evaluation and testing of our internal
control over financial reporting to allow management to report on the effectiveness of our internal control over financial reporting,
as required by Section 404 of the Sarbanes-Oxley Act. If material weaknesses are identified in the future or we are not able to comply
with the requirements of Section 404 in a timely manner, our reported financial results could be materially misstated, we could receive
an adverse opinion regarding our internal controls over financial reporting from our accounting firm, and we could be subject to investigations
or sanctions by regulatory authorities, which would require additional financial and management resources, and the market price of our
stock could decline.
We
incur significant expenses in order to comply with the requirements of being a public company in the United States.
As
a public company, we incur significantly more legal, accounting and other expenses than as a private company. In addition, the Sarbanes-Oxley
Act of 2002 and rules subsequently implemented by the SEC and U.S. stock exchanges impose numerous requirements on public companies,
including requiring changes in corporate governance practices. Also, the Exchange Act requires, among other things, that we file annual,
quarterly and current reports with respect to our business and operating results. Our management and other personnel will need to devote
a substantial amount of time to compliance with these laws and regulations. These requirements have increased and will continue to increase
our legal, accounting, and financial compliance costs and have made and will continue to make some activities more time consuming and
costly.
Our
share price is expected to be volatile and may be influenced by numerous factors that are beyond our control.
A
low share price and low market valuation may make it difficult to raise sufficient additional cash due to the significant dilution to
current stockholders. Market prices for shares of biotechnology and biopharmaceutical companies such as ours are often volatile. The
market price of our common stock may fluctuate significantly in response to a number of factors, most of which we cannot control, including:
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commercial
launch of TLANDO, if approved; |
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plans
for, progress of and results from clinical trials of our product candidates; |
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the
failure of the FDA to approve our product candidates; |
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regulatory
uncertainty in the TRT class; |
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FDA
Advisory Committee meetings and related recommendations including meetings convened on the TRT class or on similar companies; |
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announcements
by the FDA that may impact on-going clinical studies related to safety or efficacy of TRT products; |
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product
approval and potential FDA required labeling language and/or Phase 4 study commitments; |
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announcements
of new products, technologies, commercial relationships, acquisitions or other events by us or our competitors; |
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our
ability to license our products to third parties; |
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failure
to engage with collaborators or build an internal sales force to commercialize our products should a product candidate receive FDA
approval; |
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the
success or failure of other TRT products or non-testosterone based testosterone therapy products; |
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failure
of our products, if approved, to achieve commercial success; |
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fluctuations
in stock market prices and trading volumes of similar companies; |
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general
market conditions and overall fluctuations in U.S. equity markets; |
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variations
in our quarterly operating results; |
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changes
in our financial guidance or securities analysts’ estimates of our financial performance; |
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changes
in accounting principles; |
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sales
of large blocks of our common stock, including sales by our executive officers, directors and significant stockholders; |
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additions
or departures of key personnel; |
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discussion
of us or our stock price by the press and by online investor communities; |
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our
cash balance; and |
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other
risks and uncertainties described in these risk factors. |
In
recent years, the stock of other biotechnology and biopharmaceutical companies has experienced extreme price fluctuations that have been
unrelated to the operating performance of the affected companies. There can be no assurance that the market price of our shares of common
stock will not experience significant fluctuations in the future, including fluctuations that are unrelated to our performance. These
fluctuations may result due to macroeconomic and world events, national or local events, general perception of the biotechnology industry
or to a lack of liquidity. In addition, other biotechnology companies or our competitors’ programs could have positive or negative
results that impact their stock prices and their results, or stock fluctuations could have a positive or negative impact on our stock
price regardless of whether such impact is direct or not.
Stockholders
may not agree with our business, scientific, clinical, commercial, or financial strategy, including additional dilutive financings, and
may decide to sell their shares or vote against shareholder proposals. Such actions could materially impact our stock price. In addition,
portfolio managers of funds or large investors can change or change their view on us and decide to sell our shares. These actions could
have a material impact on our stock price. In order to complete a financing, or for other business reasons, we may elect to consolidate
our shares of common stock. Investors may not agree with these actions and may sell our shares. We may have little or no ability to impact
or alter such decisions.
The
stock prices of many companies in the biotechnology industry have experienced wide fluctuations that have often been unrelated to the
operating performance of the companies. Following periods of volatility in the market price of a company’s securities, securities
class action litigation often has been initiated against a company. For example, on July 1, 2016, the Company and certain of its officers
were named as defendants in a purported shareholder class action lawsuit, David Lewis v. Lipocine Inc., et al., filed in the United
States District Court for the District of New Jersey. This initial action was followed by additional lawsuits also filed in the District
of New Jersey. David Lewis v Lipocine Inc., et al. was ultimately settled. Additionally on November 14, 2019, the Company and certain
of its officers were named as defendants in a purported shareholder class action lawsuit, Solomon Abady v. Lipocine Inc. et al.,
2:19-cv-00906-PMW, filed in the United District Court for the District of Utah. This initial action was followed by additional lawsuits
also filed in the United States District Court for the District of Utah. These current class action lawsuits and any future class action
litigation that may be initiated against us may result in us incurring substantial costs and our management’s attention may be
diverted from our operations, which could significantly harm our business. In addition, such litigation could lead to increased volatility
in our share price.
The
value of our warrants outstanding from the November 2019 Offering is subject to potentially material increases and decreases based on
fluctuations in the price of our common stock.
In
November 2019, we completed a public offering of common stock and warrants to purchase common stock (the “November 2019 Offering”).
Gross proceeds from the November 2019 Offering were approximately $6.0 million. In the November 2019 Offering, the Company sold (i) 10,450,000
Class A Units, with each Class A Unit consisting of one share of common stock and a common stock warrant to purchase one share of common
stock, and (ii) 1,550,000 Class B Units, with each Class B Unit consisting of one pre-funded warrant to purchase one share of a common
stock and one common stock warrant to purchase one share of common stock at a price of $0.50 per Class A Unit and $0.4999 per Class B
Unit. The pre-funded warrants were issued in lieu of common stock in order to ensure the purchaser did not exceed certain beneficial
ownership limitations. The pre-funded warrants were immediately exercisable at an exercise price of $.0001 per share, subject to adjustment.
Additionally, the common stock warrants were immediately exercisable at an exercise price of $0.50 per share and expire on November 17,
2024.
We
account for the common stock warrants as a derivative instrument, and changes in the fair value of the warrants are included under other
income (expense) in the Company’s statements of operations for each reporting period. As of December 31, 2021, the aggregate fair
value of the warrant liability included in the Company’s consolidated balance sheet was $796,000. We use the Black-Scholes
option pricing model to determine the fair value of the warrants. As a result, the option-pricing model requires the input of several
assumptions, including the stock price volatility, share price and risk-free interest rate. Changes in these assumptions can materially
affect the fair value estimate. While the liability may only result from a change of control at a point in time, we ultimately may incur
amounts significantly different than the carrying value of the liability.
We
may not be able to maintain our listing on the NASDAQ Capital Market, which would adversely affect the price and liquidity of our common
stock.
As
a small capitalization pharmaceutical company, the price of our common shares has been, and is likely to continue to be, highly volatile.
Any announcements concerning us or our competitors, clinical trial results, quarterly variations in operating results, introduction of
new products, delays in the introduction of new products or changes in product pricing policies by us or our competitors, acquisition
or loss of significant customers, partners and suppliers, changes in earnings estimates or our ratings by analysts, regulatory developments,
or fluctuations in the economy or general market conditions, among other factors, could cause the market price of our common shares to
fluctuate substantially. There can be no assurance that the market price of our common shares will not decline below its current price
or that it will not experience significant fluctuations in the future, including fluctuations that are unrelated to our performance.
Currently
our common stock is quoted on the NASDAQ Capital Market under the symbol “LPCN”. We must satisfy certain minimum listing
maintenance requirements to maintain the NASDAQ Capital Market quotation, including certain governance requirements and a series of financial
tests relating to stockholders’ equity or net income or market value, public float, number of market makers and stockholder,
market capitalization, and maintaining a minimum bid price of $1.00 per share. For example, on January 14, 2022, we received
a notice from the Listing Qualifications Department of The NASDAQ Stock Market stating that we are no longer in compliance with
the requirement to have a majority independent board, audit committee and compensation committee for continued listing on
The NASDAQ Capital Market under NASDAQ Listing Rule 5605. In accordance with NASDAQ Listing Rules 5605(b)(1)(A), 5605(c)(4)
and 5605(d)(4) we are entitled to a cure period to regain compliance.
Anti-takeover
provisions in our amended and restated certificate of incorporation and our amended and restated bylaws, as well as provisions of Delaware
law and our stockholder rights plan, might discourage, delay or prevent a change in control of our Company or changes in our Board of
Directors or management and, therefore, depress the trading price of our common stock.
Our
amended and restated certificate of incorporation, amended and restated bylaws and Delaware law contain provisions that may depress the
market price of our common stock by acting to discourage, delay or prevent a merger, acquisition or other change in control that stockholders
may consider favorable, including transactions in which stockholders might otherwise receive a premium for their shares of our common
stock. These provisions may also prevent or frustrate attempts by our stockholders to replace or remove members of our Board of Directors
or our management. Our corporate governance documents include provisions:
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limiting
the ability of our stockholders to call and bring business before special meetings and to take action by written consent in lieu
of a meeting; |
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requiring
advance notice of stockholder proposals for business to be conducted at meetings of our stockholders and for nominations of candidates
for election to our Board of Directors; |
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authorizing
blank check preferred stock, which could be issued with voting, liquidation, dividend and other rights superior to our common stock;
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limiting
the liability of, and providing indemnification to, our directors and officers. |
As
a Delaware corporation, we are also subject to provisions of Delaware law, including Section 203 of the Delaware General Corporation
Law, which limits the ability of stockholders owning in excess of 15% of our outstanding voting stock from engaging in certain business
combinations with us. Any provision of our amended and restated certificate of incorporation, amended and restated bylaws or Delaware
law that has the effect of delaying or deterring a change in control could limit the opportunity for our stockholders to receive a premium
for their shares of our common stock, and could also affect the price that some investors are willing to pay for our common stock.
Additionally,
on November 5, 2021, we adopted an amended and restated stockholder rights plan that would cause substantial dilution to, and substantially
increase the costs paid by, a stockholder who attempts to acquire us on terms not approved by our board. The intent of the stockholder
rights plan is to protect our stockholders’ interests by encouraging anyone seeking control of our Company to negotiate with our
board. However, our stockholder rights plan could make it more difficult for a third party to acquire us without the consent of our board,
even if doing so may be beneficial to our stockholders. This plan may discourage, delay or prevent a tender offer or takeover attempt,
including offers or attempts that could result in a premium over the market price of our common stock. This plan could reduce the price
that stockholders might be willing to pay for shares of our common stock in the future. Furthermore, the anti-takeover provisions of
our stockholder rights plan may entrench management and make it more difficult to replace management even if the stockholders consider
it beneficial to do so.
The
common warrants issued in the November 2019 Offering include a right to receive the Black Scholes value of the warrants in the event
of a fundamental transaction, which payment would be senior to our common stock.
The
common warrants issued in the November 2019 Offering provide that, in the event of a “fundamental transaction,” including,
among other things, a merger or consolidation of the Company or sale of all or substantially all of the Company’s assets, the holders
of such warrants have the option to require the Company to pay to such holders an amount of cash equal to the Black Scholes value of
the warrants. Such amount would be payable prior to any payments to holders of our common stock. The payment of such amount could result
in common stockholders and other warrant holders not receiving any consideration if we were to liquidate, dissolve or wind up, either
voluntarily or involuntarily. In addition, the existence of such right may reduce the value of our common stock, make it harder for us
to sell shares of common stock in offerings in the future, or prevent or delay a change of control.
We
have no current plans to pay dividends on our common stock and investors must look solely to stock appreciation for a return on their
investment in us.
We
do not anticipate paying any cash dividends on our common stock in the foreseeable future. We currently intend to retain all future earnings
to fund the development and growth of our business. Any payment of future dividends will be at the discretion of our board of directors
and will depend on, among other things, our earnings, financial condition, capital requirements, level of indebtedness, statutory and
contractual restrictions applying to the payment of dividends and other considerations that the board of directors deems relevant. Investors
may need to rely on sales of their common stock after price appreciation, which may never occur, as the only way to realize a return
on their investment. Investors seeking cash dividends should not purchase our common stock.
Our
management and directors will be able to exert influence over our affairs.
As
of December 31, 2021, our executive officers and directors beneficially owned approximately 5.3% of our common stock. These stockholders,
if they act together, may be able to influence our management and affairs and all matters requiring stockholder approval, including significant
corporate transactions. This concentration of ownership may have the effect of delaying or preventing a change in control and might affect
the market price of our common stock.
The
market price of our common stock has been volatile over the past year and may continue to be volatile.
The
market price and trading volume of our common stock has been volatile over the past year, and it may continue to be volatile. During
2021, our common stock has traded as low as $0.994 and as high as $2.28 per share. We cannot predict the price at which our common stock
will trade in the future, and it may decline. The price at which our common stock trades may fluctuate significantly and may be influenced
by many factors, including our financial results; developments generally affecting our industry; general economic, industry and market
conditions; the depth and liquidity of the market for our common stock; investor perceptions of our business; reports by industry analysts;
announcements by other market participants, including, among others, investors, our competitors, and our customers; regulatory action
affecting our business; and the impact of other “Risk Factors” discussed herein and in our Annual Report. In addition, changes
in the trading price of our common stock may be inconsistent with our operating results and outlook. The volatility of the market price
of our common stock may adversely affect investors’ ability to purchase or sell shares of our common stock.
If
securities or industry analysts do not publish research or publish inaccurate or unfavorable research about our business, our stock price
could decline.
The
trading market for our common stock will depend in part on the research and reports that securities or industry analysts publish about
us or our business. We currently only have limited securities and industry analysts providing research coverage of our Company and may
never obtain additional research coverage by securities and industry analysts. If no additional securities or industry analysts commence
coverage of our Company or if current securities analyst coverage of our Company ceases, the trading price for our stock could be negatively
impacted. If the analysts downgrade our stock or publish inaccurate or unfavorable research about our business, our stock price would
likely decline. If analysts cease coverage of us or fail to publish reports on us regularly, demand for our stock could decrease, which
could cause our stock price and trading volume to decline.
Risks
Relating to Our Financial Position and Capital Requirements
We
will need substantial additional capital in the future. If additional capital is not available, we will have to delay, reduce or cease
operations.
We
will need to raise additional capital to continue to fund our operations. Our future capital requirements may be substantial and will
depend on many factors including:
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current
and future clinical trials for our product candidates, including for oral neuroactive steroids, LPCN 1148 and LPCN 1144; |
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regulatory
actions of the FDA; |
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the
scope, size, rate of progress, results and costs of completing ongoing clinical trials and development plans with our product candidates; |
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the
cost, timing and outcomes of our efforts to obtain marketing approval for our product candidates in the United States; |
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payments
received under any current or future license agreements, strategic partnerships or collaborations; |
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the
cost of filing, prosecuting and enforcing patent claims; |
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the
costs associated with commercializing our product candidates if we receive marketing approval, including the cost and timing of developing
internal sales and marketing capabilities or entering into strategic collaborations to market and sell our products; |
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the
costs of on-going and future litigation; |
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covenants
in the Securities Purchase Agreements entered into in the February 2020 Offering and the November 2019 Offering restricting our ability
to enter into variable rate transactions; and |
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funding
additional product line expansions. |
We
believe that our existing capital resources, together with interest thereon, will be sufficient to meet our projected operating requirements
through at least March 31, 2023. We have based this estimate on assumptions that may prove to be wrong, and we could utilize our available
capital resources sooner than we currently expect. While we believe we have sufficient liquidity and capital resources to fund our projected
operating requirements through at least March 31, 2023, we will need to raise additional capital at some point through the equity or
debt markets or through out-licensing activities, either before or after March 31, 2023, to support our operations, on-going clinical
study for LPCN 1148, on-going litigation, and compliance with regulatory requirements. If the Company is unsuccessful in raising additional
capital, its ability to continue as a going concern will become a risk. Further, our operating plan may change, and we may need additional
funds to meet operational needs and capital requirements for product development, regulatory compliance, and clinical trial activities
sooner than planned. In addition, our capital resources may be consumed more rapidly if we pursue additional clinical studies for our
oral neuroactive steroids, LPCN 1148, LPCN 1111, LPCN 1144, and LPCN 1107. Conversely, our capital resources could last longer
if we reduce expenses, reduce the number of activities currently contemplated under our operating plan or if we terminate or suspend
on-going clinical studies.
Funding
may not be available to us on favorable terms, or at all. Also, market conditions and the number of authorized shares we have available
may prevent us from accessing the debt and equity capital markets, including sales of our common stock through the ATM Offering (as defined
below). If we are unable to obtain adequate financing when needed, we may have to delay, reduce the scope of or suspend one or more of
our clinical studies, research and development programs or, if any of our product candidates receive approval from the FDA, commercialization
efforts. We may seek to raise any necessary additional capital through a combination of public or private equity offerings, including
the ATM Offering, debt financings, collaborations, strategic alliances, licensing arrangements and other marketing and distribution arrangements.
These arrangements may not be available to us or available on terms favorable to us. To the extent that we raise additional capital through
marketing and distribution arrangements, other collaborations, strategic alliances or licensing arrangements with third parties, we may
have to relinquish valuable rights to our product candidates, future revenue streams, research programs or product candidates or grant
licenses on terms that may not be favorable to us. If we do raise additional capital through public or private equity offerings, the
ownership interest of our existing stockholders will be diluted, and the terms of these securities may include liquidation or other preferences,
warrants or other terms that adversely affect our stockholders’ rights or further complicate raising additional capital in the
future. If we raise additional capital through debt financing, we may be subject to covenants limiting or restricting our ability to
take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends. If we are unable, for any
reason, to raise needed capital, we will have to reduce costs, delay research and development programs, liquidate assets, dispose of
rights, commercialize products or product candidates earlier than planned or on less favorable terms than desired, or reduce or cease
operations.
Our
loan agreement contains covenants which may adversely impact our business; the failure to comply with such covenants could cause our
outstanding debt to become immediately payable.
On
January 5, 2018, we entered into a Loan and Security Agreement (the “Loan and Security Agreement”) with Silicon Valley Bank
(“SVB”) pursuant to which SVB lent us $10.0 million. The principal borrowed under the Loan and Security Agreement bears interest
at a rate equal to the Prime Rate plus one percent per annum, which interest is payable monthly. The loan matures on June 1, 2022. In
addition, as TLANDO was not approved by the FDA by May 31, 2018, we were required to maintain $5.0 million of cash collateral at SVB
until such time as TLANDO’s approval by the FDA. However, on February 16, 2021, we and SVB amended the Loan and Security
Agreement to, among other things, remove the financial trigger and financial trigger release event provisions requiring us to maintain
a minimum cash collateral value and collateral pledge thereof. The Loan Agreement includes a number of restrictive covenants, including
restrictions on incurring additional debt, transactions with affiliates, disposing of property, business combinations or acquisitions,
paying dividends and making other distributions or payments on our capital stock, subject to limited exceptions. Collectively, these
covenants could constrain our ability to grow our business through acquisitions or engage in other transactions. In addition, the Loan
Agreement includes covenants requiring, among other things, that we provide financial statements, comply with all laws, pay all taxes
and maintain insurance. If we are not able to comply with these covenants, the amounts outstanding under the Loan Agreement could become
immediately due and payable and could have a material adverse effect on our liquidity, financial condition, operating results, business,
and prospects and cause the price of our common stock to decline.
We
may be unable to generate sufficient cash flow to satisfy our significant debt service obligations, which would adversely affect our
financial condition and results of operations.
Our
ability to make principal and interest payments on and to refinance our indebtedness will depend on our ability to generate cash in the
future. This, to a certain extent, is subject to general economic, financial, competitive, legislative, regulatory and other factors
that are beyond our control. If our business does not generate sufficient cash flow from operations, in the amounts projected or at all,
or if future borrowings are not available to us under our variable funding notes in amounts sufficient to fund our other liquidity needs,
our financial condition and results of operations may be adversely affected. If we cannot generate sufficient cash flow from operations
to make scheduled principal amortization and interest payments on our debt obligations in the future, we may need to refinance all or
a portion of our indebtedness on or before maturity, sell assets, delay capital expenditures or seek additional equity. If we are unable
to refinance any of our indebtedness on commercially reasonable terms, or at all, or to affect any other action relating to our indebtedness
on satisfactory terms, or at all, our business may be harmed.
Raising
additional capital may cause dilution to our existing stockholders, restrict our operations, or require us to relinquish rights.
We
may seek additional capital through a combination of private and public equity offerings, debt financings collaborations and strategic
and licensing arrangements. To the extent that we raise additional capital through the sale of common stock or securities convertible
or exchangeable into common stock, current stockholders’ ownership interest in the Company will be diluted. In addition, the terms
may include liquidation or other preferences that materially adversely affect their rights as a stockholder. Debt financing, if available,
would increase our fixed payment obligations and may involve agreements that include covenants limiting or restricting our ability to
take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends. If we raise additional
funds through collaboration, strategic alliance and licensing arrangements with third parties, we may have to relinquish valuable rights
to our product candidates, our intellectual property, future revenue streams or grant licenses on terms that are not favorable to us.
We
cannot predict when we will generate product revenues and may never achieve or maintain profitability.
Our
ability to become profitable depends upon our ability to generate revenue from product sales and/or licensing agreements. To date, we
have not generated any revenue from product sales of TLANDO or our other drug candidates in the current pipeline, and we do not know
when, or if, we will generate any revenue from product sales. We do not expect to generate significant revenue unless or until we obtain
marketing approval of, and begin to sell, any of our product candidates. Our ability to generate revenue depends on a number of factors,
including, but not limited to, our ability to:
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obtain
U.S. and foreign marketing approval for our product candidates; |
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commercialize
our product candidates by developing a sales force and/or entering into licensing agreements or collaborations with partners/third
parties, either before or after obtaining marketing approval for our product candidates; and |
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achieve
market acceptance of our product candidates in the medical community and with third-party payors. |
Even
if our product candidates are approved for commercial sale, we expect to incur significant costs as we prepare to commercialize them.
Even if we receive FDA approval for our product candidates, they may not be commercially successful drugs. We may not achieve profitability
soon after generating product sales, if ever. If we are unable to generate product revenue, we will not become profitable and may be
unable to continue operations without continued funding.
Accordingly,
the likelihood of our success must be evaluated in light of many potential challenges and variables associated with an early-stage drug
development company, many of which are outside of our control, and past operating or financial results should not be relied on as an
indication of future results. If one or more of our product candidates is approved for commercial sale and we retain commercial rights,
we anticipate incurring significant costs associated with commercializing any such approved product candidate. Therefore, even if we
are able to generate revenues from the sale of any approved product, we may never become profitable. Because of the numerous risks and
uncertainties associated with pharmaceutical product development, we are unable to predict the timing or amount of expenses and when
we will be able to achieve or maintain profitability, if ever.
We
have incurred significant operating losses in most years since our inception and anticipate that we will incur continued losses for the
foreseeable future.
We
have focused a significant portion of our efforts on developing TLANDO and more recently on our oral neuroactive steroids, LPCN 1148,
and LPCN 1144. We have funded our operations to date through sales of our equity securities, debt, and payments received under our license
and collaboration arrangements. We have incurred losses in most years since our inception. As of December 31, 2021, we had an accumulated
deficit of $172.7 million. Substantially all of our operating losses resulted from costs incurred in connection with our research
and development programs and from general and administrative costs associated with our operations. These losses, combined with expected
future losses, have had and will continue to have an adverse effect on our stockholders’ equity and working capital. We expect
our research and development expenses to significantly increase in connection with clinical trials associated with our oral neuroactive
steroids, LPCN 1148, LPCN 1111, LPCN 1144, and LPCN 1107, if initiated. As a result, we expect to continue to incur significant
operating losses for the foreseeable future as we evaluate further clinical development of our oral neuroactive steroids, LPCN
1148, LPCN 1111, LPCN 1144, and LPCN 1107 and our other programs and continued research efforts. Because of the numerous risks
and uncertainties associated with developing pharmaceutical products, we are unable to predict the extent of any future losses or when
we will become profitable, if at all.
Our
operating results may fluctuate significantly, and any failure to meet financial expectations may disappoint securities analysts or investors
and result in a decline in the price of our securities.
We
have a history of operating losses. Our operating results have fluctuated in the past and are likely to do so in the future. These fluctuations
could cause our share price to decline. Due to fluctuations in our operating results, we believe that period-to-period comparisons of
our results are not indicative of our future performance. It is possible that in some future quarter or quarters, our operating results
will be above or below the expectations of securities analysts or investors. In this case, the price of our securities could decline.
We
have limited shares available for issuance to raise capital to fund our operations and grant stock-based incentive awards to employees,
directors, and consultants. If we are unable to increase the number of shares of common stock available for issuance, our business will
be adversely affected.
Currently,
we have 100,000,000 authorized shares of common stock. As of March 07, 2022, we had 88,290,650 shares of common stock outstanding.
After taking into account the 4,438,013 shares reserved for issuance upon the exercise of outstanding options and 1,934,366 reserved
for issuance upon the exercise of outstanding warrants, as of March 07, 2022, we have a limited number of shares available for
issuance. If we are not able to obtain shareholder approval to increase the number of shares of common stock available for issuance,
including, for example, through an amendment to our certificate of incorporation or a reverse stock split, we will have limited shares
available for issuance to raise capital to fund our operations, make grants of stock-based incentive awards, or take such other actions
requiring available capital stock needed to operate our business. Delays in securing, or the failure to secure, shareholder approval
of such actions, if needed, may prevent us from executing a capital raising transaction, which may have a material adverse effect on
our business and financial condition.
Risks
Relating to Our Intellectual Property
Our
success depends in part on our ability to protect our intellectual property. It is difficult and costly to protect our proprietary rights
and technology, and we may not be able to ensure their protection.
Our
commercial success will depend in large part on obtaining and maintaining patent, trademark and trade secret protection of our product
candidates, their respective formulations, methods used to manufacture them and methods of treatment, as well as successfully defending
these patents against third party challenges. Our ability to stop unauthorized third parties from making, using, selling, offering to
sell, or importing our product candidates, once commercialized, is dependent upon the extent to which we have rights under valid and
enforceable patents or trade secrets that cover these activities.
The
patent positions of pharmaceutical, biopharmaceutical and related companies can be highly uncertain and involve complex legal and factual
questions for which important legal principles remain unresolved. No consistent policy regarding the breadth of claims allowed in patents
in these fields has emerged to date in the United States. There have been changes regarding how patent laws are interpreted, and both
the United States Patent and Trademark Office (“PTO”) and Congress have enacted radical changes to the patent system. We
cannot accurately predict future changes in the interpretation of patent laws or changes to patent laws which might be enacted into law.
Those changes may materially affect our patents, our ability to obtain patents and/or the patents and applications of our collaborators
and licensors. The patent situation in these fields outside the United States is even more uncertain. Changes in either the patent laws
or in interpretations of patent laws in the United States and other countries may diminish the value of our intellectual property or
narrow the scope of our patent protection. Accordingly, we cannot predict the breadth of claims that may be allowed or enforced in the
patents we own or which we license or third-party patents.
The
degree of future protection for our proprietary rights is uncertain because legal means afford only limited protection and may not adequately
protect our rights or permit us to gain or keep a competitive advantage. For example:
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others
may be able to make or use compounds that are the same or similar to the pharmaceutical compounds used in our product candidates
but that are not covered by the claims of our patents; |
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the
Active Pharmaceutical Ingredients (“APIs”) in our licensed product TLANDO and current product candidates LPCN 1144 and
LPCN 1107 are, or may soon become, commercially available in generic drug products, and no patent protection may be available without
regard to formulation or method of use; |
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we
may not be able to detect infringement against our owned or licensed patents, which may be especially difficult for manufacturing
processes or formulation patents; |
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we
might not have been the first to make the inventions covered by our issued patents or pending patent applications or those we license; |
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we
might not have been the first to file patent applications for these inventions; |
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others
may independently develop similar or alternative technologies or duplicate any of our technologies; |
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it
is possible that our pending patent applications or those of our licensor will not result in issued patents; |
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it
is possible that there are dominating patents to any of our product candidates of which we are not aware; |
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it
is possible that there are prior public disclosures that could invalidate our patents, or parts of our patents, of which we are not
aware; |
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it
is possible that others may circumvent our owned or licensed patents; |
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it
is possible that there are unpublished applications or patent applications maintained in secrecy that may later issue with claims
covering our products or technology similar to ours; |
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the
laws of foreign countries may not protect our proprietary rights to the same extent as the laws of the United States; |
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the
claims of our owned or licensed issued patents or patent applications, if and when issued, may not cover our product candidates; |
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our
issued patents or those of our licensor may not provide us with any competitive advantages, or may be narrowed in scope, be held
invalid or unenforceable as a result of legal challenges by third parties; |
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our
licensor or licensees as the case may be, who have access to our patents, may attempt to enforce our owned or licensed patents, which
if unsuccessful, may result in narrower scope of protection of our owned or licensed patents or our owned or licensed patents becoming
invalid or unenforceable; |
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we
may not develop additional proprietary technologies for which we can obtain patent protection; or |
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the
patents of others may have an adverse effect on our business. |
We
also may rely on trade secrets to protect our technology, especially where we do not believe patent protection is appropriate or obtainable.
However, trade secrets are difficult to protect, and we have limited control over the protection of trade secrets used by our collaborators
and suppliers. Although we use reasonable efforts to protect our trade secrets, our employees, consultants, contractors, outside scientific
collaborators and other advisors may unintentionally or willfully disclose our information to competitors. Enforcing a claim that a third
party illegally obtained and is using any of our trade secrets is expensive and time consuming, and the outcome is unpredictable. In
addition, courts outside the United States are sometimes less willing to protect trade secrets. Moreover, our competitors may independently
develop equivalent knowledge, methods, and know-how. If our confidential or proprietary information is divulged to or acquired by third
parties, including our competitors, our competitive position in the marketplace will be harmed and our ability to successfully penetrate
our target markets could be severely compromised.
If
any of our owned or licensed patents are found to be invalid or unenforceable, or if we are otherwise unable to adequately protect our
rights, it could have a material adverse impact on our business and our ability to commercialize or license our technology and products.
Additionally, we currently do not have patent protection for our product candidates in many countries, including large territories such
as India, Russia, and China, and we will be unable to prevent patent infringement in those countries unless we can file patent applications
and obtain patents in those countries that cover our product candidates. Likewise, our United States patents covering certain technology
used in our product candidates, including TLANDO, are expected to expire on various dates from 2023 through 2037. Upon the expiration
of these patents, we will lose the right to exclude others from practicing these inventions to the extent that at those times we have
no additional issued patents to protect our product candidates, including TLANDO. Additionally, if these are our only patents listed
in the FDA Orange Book, should we have an FDA-approved and marketed product at that time, their expiration will mean that we lose certain
advantages that come with Orange Book listing of patents. The expiration of these patents could also have a similar material adverse
effect on our business, results of operations, financial condition and prospects. Moreover, if we are unable to commence or continue
any action relating to the defense of our patents, we may be unable to protect our product candidates.
If
we do not obtain additional protection under the Drug Price Competition and Patent Term Restoration Act and similar foreign legislation
by extending the patent terms and obtaining data exclusivity for our product candidates, our business may be materially harmed.
Depending
upon the timing, duration and specifics of FDA marketing approval of our product candidates, one or more of our U.S. patents may be eligible
for limited patent term restoration under the Drug Price Competition and Patent Term Restoration Act of 1984, referred to as the Hatch-Waxman
Act. The Hatch-Waxman Act permits a patent restoration term of up to five years as compensation for patent term lost during product development
and the FDA regulatory review process. However, we may not be granted an extension because of, for example, failing to apply within applicable
deadlines, failing to apply prior to expiration of relevant patents or competitor’s prior product launch or otherwise failing to
satisfy applicable requirements. Moreover, the applicable time period or the scope of patent protection afforded could be less than we
request. If we are unable to obtain patent term extension or restoration or the term of any such extension is less than we request, our
competitors may obtain approval of competing products following our patent expiration, and our ability to generate revenues could be
materially adversely affected.
We
may incur substantial costs as a result of litigation or other proceedings relating to patent and other intellectual property rights,
and we may be unable to protect our rights to our products and technology.
If
we or our collaborators choose to go to court to stop a third party from using the inventions claimed in our owned or licensed patents,
that third party may ask a court to rule that the patents are invalid and should not be enforced against that third party. These lawsuits
are expensive and would consume time and other resources, including financial resources, even if we were successful in stopping the infringement
of these patents. In addition, there is a risk that a court will decide that these patents are not valid or not enforceable and that
we do not have the right to stop others from using the inventions.
There
is also the risk that, even if the validity of these patents is not challenged or is upheld, the court will refuse to stop the third
party on the ground that such third-party’s activities do not infringe on our owned or licensed patents. In addition, the U.S.
Supreme Court has changed some standards relating to the granting of patents and assessing the validity of patents. As a consequence,
issued patents may be found to contain invalid claims according to the newly revised standards. Some of our owned or licensed patents
may be subject to challenge and subsequent invalidation or significant narrowing of claim scope in a reexamination or other proceeding
before the USPTO, or during litigation, under the revised criteria which make it more difficult to obtain or maintain patents.
While
our in-licensed patents and applications are not currently used in our product candidates, should we develop other product candidates
that are covered by this intellectual property, we will rely on our licensor to file and prosecute patent applications and maintain patents
and otherwise protect the intellectual property we license from them. Our licensor has retained the first right, but not the obligation,
to initiate an infringement proceeding against a third-party infringer of the intellectual property licensed to us, and enforcement of
our in-licensed patents or defense of any claims asserting the invalidity or unenforceability of these patents would also be subject
to the control or cooperation of our licensor. It is possible that our licensor’s defense activities may be less vigorous than
had we conducted the defense ourselves.
We
also license our patent portfolio, including U.S. and foreign patents and patent applications that cover TLANDO and our other product
candidates, to third parties for their respective products and product candidates. Under our agreements with our licensees, we have the
right, but not the obligation, to enforce our current and future licensed patents against infringers of our licensees. In certain cases,
our licensees may have primary enforcement rights and we have the obligation to cooperate. In the event of an enforcement action against
infringers of our licensees, our licensees might not have the interest or resources to successfully preserve the patents, the infringers
may countersue, and as a result our patents may be found invalid or unenforceable or of a narrower scope of coverage and leave us with
no patent protection for TLANDO and our other product candidates.
We
may be subject to a third-party pre-issuance submission of prior art to the PTO, or become involved in opposition, derivation, reexamination,
inter partes review, post-grant review or interference proceedings challenging our owned or licensed patent rights or the patent rights
of others. An adverse determination in any such submission, proceeding or litigation could reduce the scope of, or invalidate, our owned
or licensed patent rights, allow third parties to commercialize our technology or products and compete directly with us, without payment
to us, or result in our inability to manufacture or commercialize products without infringing third party patent rights. In addition,
if the breadth or strength of protection provided by our patents and patent applications is threatened, it could dissuade companies from
collaborating with us to license, develop or commercialize current or future product candidates and impair our ability to raise needed
capital.
If
we are required to defend patent infringement actions brought by other third parties, or if we sue to protect our own patent rights or
otherwise to protect our proprietary information and to prevent its disclosure, we may be required to pay substantial litigation costs
and managerial attention and financial resources may be diverted from business operations even if the outcome is in our favor.
If
we are sued for infringing intellectual property rights of third parties, it will be costly and time consuming, and an unfavorable outcome
in that litigation would have a material adverse effect on our business.
Our
commercial success depends upon our ability and the ability of our collaborators to develop, manufacture, market and sell our product
candidates and use our proprietary technologies without infringing the proprietary rights of third parties. Numerous U.S. and foreign
issued patents and pending patent applications, which are owned by third parties, exist in the fields relating to our product candidates.
As the biotechnology, pharmaceutical, and related industries expand and more patents are issued, the risk increases that others may assert
that our product or product candidates infringe the patent rights of others. Moreover, it is not always clear to industry participants,
including us, which patents cover various types of drugs, products or their formulations or methods of use. Thus, because of the large
number of patents issued and patent applications filed in our fields, there may be a risk that third parties may allege they have patent
rights encompassing our product, product candidates, technology, or methods. For example, on November 2, 2015, Clarus filed a complaint
against us in the United States District Court for the District of Delaware alleging that TLANDO will infringe the Clarus 428 Patent,
and the complaint sought damages, declaratory and injunctive relief. On October 6, 2016, United States District Court of the District
of Delaware granted our motion to dismiss the lawsuit filed by Clarus, because at the time there was no actionable infringement on Clarus’
428 patent.
In
addition, there may be issued patents of third parties of which we are currently unaware, that are infringed or are alleged to be infringed
by our product candidates or proprietary technologies. Because some patent applications in the United States may be maintained in secrecy
until the patents are issued, because patent applications in the United States and many foreign jurisdictions are typically not published
until eighteen months after filing, and because publications in the scientific literature often lag behind actual discoveries, we cannot
be certain that others have not filed patent applications for technology covered by our or our licensor’s issued patents or our
pending applications, or that we were the first to invent the technology. Our competitors may have filed, and may in the future file,
patent applications covering our products or technology similar to ours. Any such patent application may have priority over our owned
or licensed patent applications or patents, which could further require us to obtain rights to issued patents covering such technologies.
If another party has filed a U.S. patent application on inventions similar to those owned or licensed by us, we may have to participate
in an interference proceeding declared by the PTO to determine priority of invention in the United States. If another party has an allowed
reason to question the validity of our owned or licensed U.S. patents, the third party can request that the PTO reexamine the patent
claims, which may result in a loss of scope of some claims or a loss of the entire patent. In addition to potential infringement claims,
interference and reexamination proceedings, we may become a party to patent opposition proceedings in the European Patent Office or post-grant
proceedings in the United States where either our patents are challenged, or we are challenging the patents of others. The costs of these
proceedings could be substantial, and it is possible that such efforts would be unsuccessful, for example if the other party had independently
arrived at the same or similar invention prior to our invention, resulting in a loss of our U.S. patent position with respect to such
inventions. We may be exposed to, or threatened with, future litigation by third parties having patent or other intellectual property
rights alleging that our product candidates and/or proprietary technologies infringe their intellectual property rights. These lawsuits
are costly and could adversely affect our results of operations and divert the attention of managerial and technical personnel. There
is a risk that a court would decide that we or our commercialization partners are infringing the third party’s patents and would
order us or our partners to stop the activities covered by the patents. In addition, there is a risk that a court will order us or our
partners to pay the other party damages for having violated the other party’s patents.
If
a third-party’s patent was found to cover our product candidates, proprietary technologies or their uses, we or our collaborators
could be enjoined by a court and required to pay damages and could be unable to commercialize any one or more of our product candidates
or use our proprietary technologies unless we or they obtained a license to the patent. A license may not be available to us or our collaborators
on acceptable terms, if at all. In addition, during litigation, the patent holder could obtain a preliminary injunction or other equitable
relief which could prohibit us from making, using or selling our products, technologies or methods pending a trial on the merits, which
could be years away.
There
is a substantial amount of litigation involving patent and other intellectual property rights in the biotechnology, pharmaceutical, and
related industries generally. If a third-party claims that we or our collaborators infringe its intellectual property rights, we may
face a number of issues, including, but not limited to:
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infringement
and other intellectual property claims which, regardless of merit, may be expensive and time-consuming to litigate and may divert
our management’s attention from our core business; |
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substantial
damages for infringement, which we may have to pay if a court decides that the product at issue infringes on or violates the third
party’s rights, and if the court finds that the infringement was willful, we could be ordered to pay treble damages and the
patent owner’s attorneys’ fees; |
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a
court prohibiting us from selling or licensing the product unless the third party licenses its product rights to us, which it is
not required to do; |
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if
a license is available from a third party, we may have to pay substantial royalties, upfront fees and/or grant cross-licenses to
intellectual property rights for our products; and |
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redesigning
our products or processes so they do not infringe, which may not be possible or may require substantial monetary expenditures and
time. |
Some
of our competitors may be able to sustain the costs of complex patent litigation more effectively than we can because they have substantially
greater resources. In addition, any uncertainties resulting from the initiation and continuation of any litigation could have a material
adverse effect on our ability to raise the funds necessary to continue our operations or otherwise have a material adverse effect on
our business, results of operations, financial condition, and prospects.
Although
we own worldwide rights to our product candidates, we do not have patent protection for the product candidates in a significant number
of countries, and we will be unable to prevent infringement in those countries.
Our
patent portfolio related to our product candidates includes patents in the United States and other foreign countries. The covered technology
and the scope of coverage varies from country to country. For those countries where we do not have granted patents, we have no ability
to prevent the unauthorized use of our intellectual property, and third parties in those countries may be able to make, use, or sell
products identical to, or substantially similar to our product candidates.
Obtaining
and maintaining our patent protection depends on compliance with various procedural, document submission, fee payment and other requirements
imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.
Periodic
maintenance fees on our owned or licensed patents are due to be paid to the PTO in several stages over the lifetime of the patents. Future
maintenance fees will also need to be paid on other patents which may be issued to us. We have systems in place to remind us to pay these
fees, and we employ outside firms to remind us to pay annuity fees due to foreign patent agencies on our pending foreign patent applications.
We have even less control over our in-licensed patents and applications, for which our licensor retains responsibility. The PTO and various
foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions
during the patent application process. In many cases, an inadvertent lapse can be cured by payment of a late fee or by other means in
accordance with the applicable rules. However, there are situations in which noncompliance can result in abandonment or lapse of the
patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. In such an event,
our competitors might be able to enter the market and this circumstance would have a material adverse effect on our business.
We
also may rely on trade secrets and confidentiality agreements to protect our technology and know-how, especially where we do not believe
patent protection is appropriate or obtainable. However, trade secrets are difficult to protect, and we have limited control over the
protection of trade secrets used by our collaborators and suppliers. Although we use reasonable efforts to protect our trade secrets,
our employees, consultants, contractors, outside scientific collaborators, and other advisors may unintentionally or willfully disclose
our information to competitors. Enforcing a claim that a third party illegally obtained and is using any of our trade secrets is expensive
and time consuming, and the outcome is unpredictable. In addition, courts outside the United States are sometimes less willing to protect
trade secrets. Moreover, our competitors may independently develop equivalent knowledge, methods, and know-how. If our confidential or
proprietary information is divulged to or acquired by third parties, including our competitors, our competitive position in the marketplace
will be harmed and our ability to successfully generate revenues from our product candidates, if approved by the FDA or other regulatory
authorities, could be adversely affected.
We
may be subject to claims that our employees have wrongfully used or disclosed alleged trade secrets of their former employers.
As
is common in the biotechnology, pharmaceutical and related industries, we employ individuals who were previously employed at other biotechnology
or pharmaceutical companies, including our competitors or potential competitors. Although no claims against us are currently pending,
we may be subject to claims that these 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, which would adversely affect our
financial condition.