UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
WASHINGTON,
D.C. 20549
FORM
10-K
☒ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the fiscal
year ended December 31, 2021
or
☐TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from ____ to ____
Commission
File Number: 001-36357
LIPOCINE
INC.
(Exact
name of registrant as specified in its charter)
675 Arapeen Drive, Suite 202, Salt Lake City, Utah 84108
(Address of Principal Executive Offices) (Zip Code)
801-994-7383
(Registrant’s
telephone number, including area code)
Securities
registered pursuant to Section 12(b) of the Act:
Title of Each Class Trading Symbol(s) Name of Each Exchange on Which Registered
Common Stock, par value $0.0001 per share LPCN The NASDAQ Stock Market LLC
Securities
registered pursuant to Section 12(g) of the Act: None
Indicate
by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No☒
Indicate
by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Securities Exchange Act.
Yes ☐ No ☒
Indicate
by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange
Act of 1934 during the preceding 12 months (or such shorter period that the registrant was required to file such reports) and (2) has
been subject to such filing requirements for the past 90 days. Yes: ☒ No ☐
Indicate
by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule
405 of Regulation S-T (§220.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant
was required to submit such files). Yes ☒ No ☐
Indicate
by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting
company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,”
“smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act:
Large accelerated filer ☐
Accelerated filer ☐
Non-accelerated filer ☒
Smaller reporting company ☒
Emerging growth company ☐
If
an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying
with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate
by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness
of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered
public accounting firm that prepared or issued its audit report. ☐
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). Yes ☐ No ☒
Outstanding
Shares
The
aggregate market value of the common stock held by non-affiliates of the registrant was $120.5 million as of June 30, 2021. For purposes
of calculating the aggregate market value of shares of our common stock held by non-affiliates as set forth on the cover page of this
Annual Report on Form 10-K, we have assumed that all outstanding shares are held by non-affiliates, except for shares held by each of
our executive officers, directors and 10% or greater stockholders. However, this assumption should not be deemed to constitute an admission
that all executive officers, directors and 10% or greater stockholders are, in fact, affiliates of our company, or that there are not
other persons who may be deemed to be affiliates of our company. Further information concerning shareholdings of our officers, directors
and principal stockholders is included or incorporated by reference in Part III, Item 12 of this Annual Report on Form 10-K.
As
of March 7, 2022, the registrant had 88,290,650shares of common stock outstanding.
DOCUMENTS
INCORPORATED BY REFERENCE:
Portions
of the registrant’s definitive Proxy Statement for its 2021 Annual Meeting of Stockholders are incorporated by reference into Part
III of this Form 10-K.
TABLE
OF CONTENTS
Page
PART I
Item 1. Business 4
Item 1A. Risk Factors 29
Item 1B. Unresolved Staff Comments 58
Item 2. Properties 58
Item 3. Legal Proceedings 58
Item 4. Mine Safety Disclosures 59
PART II
Item 6. Reserved 60
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 74
Item 8. Financial Statements and Supplementary Data 75
Item 9A. Controls and Procedures 104
Item 9B. Other Information 104
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 104
PART III
Item 10. Directors, Executive Officers and Corporate Governance 105
Item 11. Executive Compensation 105
Item 14. Principal Accountant Fees and Services 105
PART IV
Item 15. Exhibits and Financial Statement Schedules 105
FORWARD-LOOKING
STATEMENTS
THIS
ANNUAL REPORT ON FORM 10-K, IN PARTICULAR “ITEM 7. MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS
OF OPERATION,” AND “ITEM 1. BUSINESS,” CONTAINS FORWARD-LOOKING STATEMENTS WITHIN THE MEANING OF SECTION 27A OF THE
SECURITIES ACT OF 1933, AS AMENDED, AND SECTION 21E OF THE SECURITIES EXCHANGE ACT OF 1934, AS AMENDED, that involve risks and uncertainties.
Forward-looking statements provide current expectations of future events based on certain assumptions and include any statement that
does not directly relate to any historical or current fact. Forward-looking statements may refer to such matters as products, product
benefits, pre-clinical and clinical development timelines, clinical and regulatory expectations and plans, REGULATORY DEVELOPMENTS AND
REQUIREMENTS, THE RECEIPT OF REGULATORY APPROVALS, THE EXPECTATIONS FOR AND RESULTS OF CLINICAL TRIALS, PATIENT ACCEPTANCE OF LIPOCINE’S
PRODUCTS, MANUFACTURING AND COMMERCIALIZATION OF LIPOCINE’S PRODUCTS, anticipated financial performance, future revenues or earnings,
business prospects, projected ventures, new products and services, anticipated market performance, future expectations for liquidity
and capital resources needs and similar matters. Such words as “may”, “will”, “expect”, “continue”,
“estimate”, “project”, “intend”, and “potential” and similar terms and expressions are
intended to identify forward looking statements. Forward-looking statements are not guarantees of future performance and our actual results
may differ significantly from the results discussed in the forward-looking statements. Factors that might cause such differences include,
but are not limited to, those discussed in Part I, Item 1A “Risk Factors” of this Form 10-K. Except as required by applicable
law, we assume no obligation to revise or update any forward-looking statements for any reason.
There
are a number of risks, uncertainties and other important factors that could cause our actual results to differ materially from the forward-looking
statements contained in this Annual Report on Form 10-K. Such risks, uncertainties and other important factors include, among others,
the risks, uncertainties and factors set forth in “Risk Factors,” and the following risks, uncertainties and factors:
● our ongoing and planned clinical trials;
● the effect of the ongoing COVID-19 pandemic on our business;
● significant competition in our industry;
● our intellectual property position;
● loss of key members of management;
● failure to successfully execute our strategy; and
● our failure to maintain effective internal controls.
There
may be other factors that may cause our actual results to differ materially from the forward-looking statements, including factors disclosed
in “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations.”
You should evaluate all forward-looking statements made in this Annual Report on Form 10-K in the context of these risks and uncertainties.
We
caution you that the risks, uncertainties and other factors referred to above may not contain all of the risks, uncertainties and other
factors that are important to you. In addition, we cannot assure you that we will realize the results, benefits or developments that
we expect or anticipate or, even if substantially realized, that they will result in the consequences or affect us or our business in
the way expected. All forward-looking statements in this Annual Report on Form 10-K apply only as of the date made and are expressly
qualified in their entirety by the cautionary statements included in this Annual Report on Form 10-K. We undertake no obligation to publicly
update or revise any forward-looking statements to reflect subsequent events or circumstances.
PART
I
ITEM 1. BUSINESS
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)
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.