UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
WASHINGTON,
D.C. 20549
FORM
10-K
or
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 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 for 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 (§232.405 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. ☐
If
securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant
included in the filing reflect the correction of an error to previously issued financial statements. ☐
Indicate
by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation
received by any of the registrant’s executive officers during the relevant recovery period pursuant to § 240.10D-1(b). ☐
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 $42.8 million as of June 28, 2024. 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 no
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 11, 2025, the registrant had 5,350,356 shares of common stock outstanding.
DOCUMENTS
INCORPORATED BY REFERENCE
Portions of the definitive proxy statement relating to the annual meeting of shareholders to be held on June 4, 2025 are incorporated by reference into Part III of this annual report.
TABLE
OF CONTENTS
Page
PART I
Item 1. Business 4
Item 1A. Risk Factors 23
Item 1B. Unresolved Staff Comments 52
Item 1C. Cybersecurity 52
Item 2. Properties 52
Item 3. Legal Proceedings 52
Item 4. Mine Safety Disclosures 52
PART II
Item 6. [Reserved] 53
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 63
Item 8. Financial Statements and Supplementary Data 64
Item 9A. Controls and Procedures 92
Item 9B. Other Information 92
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 92
PART III
Item 10. Directors, Executive Officers and Corporate Governance 93
Item 11. Executive Compensation 93
Item 14. Principal Accountant Fees and Services 93
PART IV
Item 15. Exhibits and Financial Statement Schedules 94
FORWARD-LOOKING
STATEMENTS
THIS
ANNUAL REPORT ON FORM 10-K (THE “ANNUAL REPORT”), 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 (the “SECURITIES ACT”), AND
SECTION 21E OF THE SECURITIES EXCHANGE ACT OF 1934, AS AMENDED (the “EXCHANGE ACT”), 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, global political changes, particularly the transition in the U.S. presidential administration, and their impact on
the pharmaceutical industry, 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 ANNUAL REPORT. 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. 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;
● our ability to monetize non-core product candidates;
● significant competition in our industry;
● our intellectual property position;
● loss of key members of management;
● failure to successfully execute our strategy;
● 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 apply only as of the date made and are expressly
qualified in their entirety by the cautionary statements included in this Annual Report. We undertake no obligation to publicly
update or revise any forward-looking statements to reflect subsequent events or circumstances, except as otherwise required by law.
PART
I
ITEM 1. BUSINESS
General
Lipocine
Inc. (“Lipocine” or the “Company”) is incorporated under the laws of the State of Delaware.
We
are a biopharmaceutical company focused on leveraging our proprietary Lip’ral platform to develop differentiated products through
the oral delivery of previously difficult to deliver molecules. 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 of our product candidate, TLANDO®, an oral treatment
indicated for testosterone replacement therapy (“testosterone replacement therapy” or “TRT”) in adult males
for conditions associated with a deficiency or absence of endogenous testosterone (primary or hypogonadotropic hypogonadism)
comprised of testosterone undecanoate (“testosterone undecanoate” or “TU”). On January 12, 2024, we entered
into a license agreement (the “Verity License Agreement”) with Gordon Silver Limited (“GSL”) and Verity
Pharmaceuticals, Inc. (“Verity” or our “Licensee”), pursuant to which we granted to Verity an exclusive,
royalty-bearing, sublicensable right and license to commercialize TLANDO for TRT in the U.S. and Canada (the “Licensed Verity
Territory”). Any post-marketing studies required by the United States Food and Drug Administration (“FDA”) will
also be the responsibility of our Licensee, Verity. On January 31, 2024, our license agreement with former licensee (the “Antares License Agreement”), Antares
Pharma, Inc. (“Antares”), was terminated and the transition of the U.S. commercial rights for TLANDO from Antares to
Verity was completed on February 1, 2024, for the distribution, marketing and sale of TLANDO. The Verity License Agreement also
provides Verity with a license to develop and commercialize LPCN 1111 (also referred to as TLANDO XR), the Company’s potential
next generation, once daily oral product candidate for testosterone replacement therapy comprised of testosterone tridecanoate
(“TT”), in the U.S. and Canada.
In
September 2024, we entered into a distribution and license agreement (the “SPC License Agreement”) for the development and
commercialization of TLANDO, an oral TRT with SPC Korea Limited (“SPC”), pursuant to which the Company granted to SPC a non-transferable,
exclusive, royalty-bearing license to commercialize our TLANDO product for TRT in South Korea (the “SPC Territory”). In October
2024, we entered into a distribution and supply agreement (the “Pharmalink Distribution Agreement”) with Pharmalink granting
a non-transferable, exclusive, license to commercialize our TLANDO product in the field specific to the Gulf Cooperation Council (“GCC”)
countries, including Saudi Arabia, Kuwait, the United Arab Emirates, Qatar, Bahrain, and Oman (the “Pharmalink
Territory”).
Additional
clinical development pipeline candidates include: LPCN 1154 for postpartum depression (“PPD”); LPCN 2101 for epilepsy;
LPCN 2203 for essential tremor and LPCN 2401 for improved body composition in obesity management. In addition to our clinical
development product candidates, we have assets for which we expect to seek partnerships to enable further development including
TLANDO for territories outside of the United States, South Korea, and the GCC, LPCN 1148 comprising a novel prodrug of testosterone
and testosterone laurate (“testosterone
laurate” or “TL”), for the management of cirrhosis, LPCN 1144, an oral prodrug of androgen
receptor modulator for the treatment of metabolic dysfunction-associated steatohepatitis (“MASH”), formerly referred to
as non-cirrhotic non-alcoholic steatohepatitis (“MASH”), which has completed Phase 2 testing; and LPCN 1107, potentially
the first oral hydroxy progesterone caproate (“HPC”) product indicated for the prevention of recurrent PTB, which has completed a dose finding clinical study in pregnant women and has been granted orphan drug
designation by the FDA.
The
following chart summarizes the status of our product candidate development programs:
Corporate
Strategy
Our
goal is to become a leading biopharmaceutical company focused on leveraging our proprietary Lip’ral drug delivery technology platform
to develop differentiated products through oral delivery of previously difficult to deliver molecules. The key components of our strategy
are to:
Advance
LPCN 1154 and other CNS product candidates. We intend to focus on the development of endogenous neuroactive steroids (“NASs”)
which have broad applicability in treating various CNS conditions where we can leverage our technology platform to develop highly differentiated
oral therapeutics. Our priority is on the development of LPCN 1154, a fast-acting oral antidepressant for PPD with potential for outpatient use.
Support
our Licensees, Verity, SPC, and Pharmalink, in commercialization of our licensed oral TRT product. We believe the TRT market
needs a differentiated, convenient oral option. We have exclusively licensed rights to TLANDO to Verity for commercialization of TLANDO
in the Licensed Verity Territory, to SPC for commercialization in the SPC Territory, and to Pharmalink in the Pharmalink Territory (together,
the “Currently Licensed TLANDO Territories”). We plan to support Verity’s, SPC’s and Pharmalink’s
efforts to effectively enable the availability of TLANDO to patients in a timely manner, in addition to receiving milestone payments,
royalty payments, and/or payments for product sales associated with TLANDO commercialization as agreed to in the Verity License Agreement,
the SPC License Agreement and the Pharmalink Distribution Agreement.
Develop
partnership(s) to continue the advancement of pipeline assets. We continuously strive to prioritize our resources in seeking
partnerships of our pipeline assets. We are currently exploring partnerships for our liver programs LPCN 1144, our candidate for
treatment of MASH and LPCN 1148 for the management of cirrhosis including prevention of the recurrence of overt
hepatic encephalopathy (“overt hepatic encephalopathy” or “OHE”); LPCN 2401 for improved body composition in
obesity management as adjunct therapy as an adjunct therapy to or as a monotherapy post cessation of incretin mimetics use; and LPCN
1107, our candidate for prevention of pre-term birth. We are also exploring the possibility of licensing LPCN 1021 (known as TLANDO
in the United States) to third parties outside of the Currently Licensed TLANDO Territories, although no additional licensing
agreements have been entered into by the Company in any other territories.
Our
Pipeline Product Candidates
Our
pipeline of clinical development candidates includes LPCN 1154 for PPD, LPCN 2101 for epilepsy, LPCN 2203 for essential tremor, and LPCN
2401 as an aid for improved body composition in obesity management. We will continue to explore other product development candidates
targeting CNS indications with a significant unmet need. We will also continue efforts to enter into partnership arrangements for the
continued development and/or marketing of LPCN 1144, LPCN 1148, LPCN 2401, LPCN 1107 as well as for the TRT Assets outside of the Currently
Licensed TLANDO Territories.
Our
products are based on our proprietary Lip’ral drug delivery technology platform. Lip’ral-based TLANDO was approved by the
FDA in March 2022. Lip’ral technology is a patented technology based on lipidic compositions which form an optimal dispersed phase
in the gastrointestinal environment for improved absorption of insoluble drugs. The drug loaded dispersed phase presents the solubilized
drug efficiently at the absorption site (gastrointestinal tract membrane) thus improving the absorption process and making the drug less
dependent on physiological variables such as dilution, gastro-intestinal pH and food effects for absorption. Lip’ral-based formulation
enables improved solubilization and higher drug-loading capacity, which can lead to improved bioavailability, reduced dose, faster and
more consistent absorption, reduced variability, reduced sensitivity to food effects, improved patient compliance, and targeted lymphatic
delivery where appropriate.
TRT
Franchise – TLANDO and LPCN 1111 (TLANDO XR)
TLANDO:
An Oral Product for Testosterone Replacement Therapy
As
previously described, under the Verity License Agreement, in January 2024, we granted to Verity an exclusive, royalty-bearing,
sublicensable right and license to develop and commercialize TLANDO, our product for TRT, in the U.S. and Canada effective February 1,
2024. TLANDO received FDA approval on March 28, 2022. Any FDA requirement to conduct certain post-marketing studies will be the responsibility
of Verity. In addition, in September 2024, we granted SPC an exclusive, royalty-bearing license to commercialize TLANDO in South
Korea and in October 2024 we granted Pharmalink an exclusive license to commercialize TLANDO in the GCC countries.
Proof-of-concept
for TLANDO was initially established in 2006, and TLANDO was subsequently 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 of TLANDO. Such royalties are limited to $1 million in the first
two calendar years following product launch, after which period there is no cap on royalties and no maximum aggregate amount. If generic
versions of any such product are introduced, then royalties are reduced by 50%. TLANDO was commercially launched on June 7, 2022. During
the years ended December 31, 2024 and 2023, we incurred royalty expense of approximately $24,000 and $34,000, respectively.
Since
TLANDO received full FDA approval, under the terms of the Verity License Agreement, Verity will need to assess the safety and
effectiveness of TLANDO in pediatric patients, as required by the Pediatric Research Equity Act. The FDA may also require certain post-marketing
studies to be conducted which will also be the responsibility of Verity. Similarly, SPC and Pharmalink are responsible for obtaining
any regulatory/marketing approvals for TLANDO required for the SPC Territory and the Pharmalink Territory, respectively.
Upon
execution of the Verity License Agreement, Verity paid us an initial payment of $2.5 million which was received on signing of
the License Agreement and $5 million which was received on February 1, 2024. Verity also made an additional payment of $2.5 million
to us on December 30, 2024, and is required to make an additional payment of $1 million to us before January 1, 2026. We are also eligible
to receive milestone payments of up to $259 million in the aggregate, depending on the achievement of certain sales milestones in a single
calendar year and/or development milestones with respect to products licensed by Verity under the Verity License Agreement. In
addition, we will receive tiered royalty payments at rates ranging from 12% up to 18% of net sales of all products licensed under the
Verity License Agreement in the Licensed Verity Territory.
SPC
paid us a non-refundable, non-creditable upfront fee in October 2024. The Company also received an additional payment for a non-refundable,
non-creditable prepayment in consideration for TLANDO product inventory, and is eligible to receive additional payments for various marketing
authorization and sales milestones, and the Company will supply TLANDO to SPC and receive a supply price. In addition, we will receive
royalties on net sales in South Korea under the SPC License Agreement.
Upon
execution of the Pharmalink Distribution Agreement, Pharmalink paid a non-refundable, non-creditable upfront fee. Under the
Pharmalink Distribution Agreement, we could receive additional payments in regulatory authorization milestones and we will supply
TLANDO to Pharmalink at an agreed transfer price. Our ex-U.S. commercialization partners are planning to file marketing approval
applications in Canada, the GCC countries, and South Korea in 2025.
We
are exploring the possibility of licensing LPCN 1021 (known as TLANDO in the United States) to third parties outside the Currently Licensed
TLANDO Territories, although no licensing agreement has been entered into by the Company in any other territories. If and when an agreement
is made with a partner, such an arrangement would likely be partially contingent upon obtaining local regulatory approval. 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 terms
favorable to us.
LPCN
1111: A Next-Generation Long-Acting Oral Product Candidate for TRT
As
previously described, under the terms of the Verity License Agreement, we have licensed the development and commercialization rights
to LPCN 1111 (TLANDO XR) in the Licensed Verity Territory to Verity. We will continue to explore the possibility of partnering
LPCN 1111 with third parties outside of the Licensed Verity Territory, although no additional partnering agreement has been entered into
by the Company. No assurance can be given that any license agreement outside of the Licensed Verity Territory will be completed, or,
if an agreement is completed, that such an agreement would be on terms favorable to us.
LPCN
1111 is a next-generation, novel ester prodrug of testosterone comprised of testosterone tridecanoate which uses our 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. All future development and commercialization of LPCN 1111 in the Licensed Verity Territory will be the
responsibility of Verity.
Oral
Programs for CNS Disorders
Some
preferred endogenous or naturally occurring NAS present in the central nervous system act as positive allosteric modulators (“PAMs”)
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.
In
October 2024, we announced positive data from our qEEG study of our oral brexanolone with results indicating robust central nervous system
activity of oral brexanolone, with concentration- and time-dependent post-dose changes in qEEG as follows:
●
Quantitative Electroencephalogram (“qEEG”) in healthy subjects administered single doses of oral brexanolone, a neuroactive
steroid, confirmed GABAA modulation
●
Rapid and durable CNS target engagement confirms effective oral delivery of bioidentical brexanolone
●
Promising results support continued development of oral brexanolone for the treatment of neuropsychiatric disorders
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 deemed to be not orally bioavailable. As a novel drug class, NASs have received considerable
attention because of their potential to treat various neuropsychiatric conditions including depression, movement disorders, epilepsy,
anxiety, and neurodegenerative diseases. We have conducted Phase 1 pharmacokinetic (“PK”) studies for each of our three lead
NAS candidates which have demonstrated promising PK results, safety, and tolerability and we are evaluating additional undisclosed CNS-focused
candidates.
LPCN
1154: Product Candidate for PPD
Our
most advanced NAS candidate is LPCN 1154, a non-invasive, rapid onset, oral formulation of the neuroactive steroid brexanolone which
we are developing for the treatment of PPD. We have completed clinical oral PK studies including a pilot food effect study and a pilot
PK bridge study. In addition, as a prelude to a LPCN 1154 pivotal study, a multi-dose study was done confirming the dosing regimen for
the PK bridge study using the scaled up “to be marketed” formulation required for New Drug Application (“NDA”)
filing. In June 2024, we announced results from the PK bridge study which demonstrated LPCN 1154 meets bioequivalence with comparator,
IV brexanolone, meeting standard bioequivalence criteria and Ctrough criteria. LPCN 1154 treatment was well-tolerated with
no sedation nor somnolence events observed in the pivotal study.
After
completing PK studies and labeling studies such as a food effect study and PK profiling in women with PPD, we met with the FDA in
the first quarter of 2025. In the meeting, we were advised that the FDA believes, in addition to the previously completed PK bridge
data, an efficacy and safety study of oral LPCN 1154 in the target population will be required for 505(b)(2) NDA
submission. Based on observed comparable exposure of LPCN 1154 and the
reference drug in the PK bridge study, we are initiating a phase 3 safety and efficacy study with expected first patient dosed in the second quarter of 2025.
We are exploring the possibility of partnering with a third party for the development and/or marketing of LPCN 1154,
although no partnering agreement has been entered into by the Company. No assurance can be given that any partnering agreement will be
completed, or, if an agreement is completed, that such an agreement would be on terms favorable to us.
PPD
PPD,
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 one in eight mothers suffers from PPD in the United States alone; this equates to approximately 600,000 women being
affected by PPD annually.
Disease
Overview - PPD
Associated
Risk Factors
Unmet
Medical Need
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 and require weeks for
onset of efficacy; therefore, a need for an oral treatment option with a faster onset of action remains a significant unmet need in treating
PPD, especially in mothers with moderate to severe depression prone to harmful actions.
Injectable
brexanolone (ZulressoTM, SAGE Therapeutics) became the first FDA-approved treatment for postpartum depression. However,
numerous factors limited the utilization of injectable brexanolone such as method of administration, cost, and safety concerns, and
SAGE Therapeutics discontinued Zulresso in October 2024. In addition to approval for Zulresso, SAGE Therapeutics received FDA
approval for zuranolone (brand name ZURZUVAETM) in August 2023 and ZURZUVAE was launched commercially in December 2023.
Zuranolone, a synthetic neuroactive steroid derivative, is an oral, once daily 14-day treatment for postpartum depression and is the
first oral medication approved by the FDA for the treatment of postpartum depression. Per label, besides long terminal half-life of
approximately 19.7 to 24.6 hours and dosage modifications needed for concomitant use with CYP3A4 modulators, warnings and
precautions include CNS depressant effects, impaired ability to drive or engage in other potentially hazardous activities and
embryo-fetal toxicity.
We
believe LPCN 1154 targets the unmet need for robust, rapid relief of PPD symptoms with a 48-hour dosing duration through a convenient
oral therapy candidate comprising bioidentical NASs with good tolerability.
LPCN
2101: NAS for Epilepsy
We
are currently evaluating an additional NAS candidate, LPCN 2101, for women with epilepsy (“WWE”). We have completed pre-clinical
and Phase 1 studies for LPCN 2101 which demonstrated promising PK results, safety and tolerability. In July 2022 our IND was accepted
by the FDA for LPCN 2101 for adults with epilepsy and we plan to initiate a Phase 2 IND opening proof-of-concept study to evaluate the
safety, tolerability, and efficacy of LPCN 2101, subject to resource prioritization.
Disease
Overview – Epilepsy
Epilepsy
is defined by the 1) occurrence of at least two unprovoked seizures more than 24 hours apart, 2) occurrence of one unprovoked seizure
and a probability of further seizures occurring over the next 10 years, and/or 3) diagnosis of an epilepsy syndrome. Patients with epilepsy
have increased risk of mortality due to direct effects of seizures (e.g., status epilepticus, car accidents) and indirect effects of
seizures (e.g., suicide, cardiovascular effects.)
Epilepsy
is a disorder of the brain that causes seizures, affecting the physical, mental, and social well-being of persons, and is associated
with a 2 to 3 times greater mortality rate compared with the general population. About 60-65% of epilepsy is idiopathic and about 30%
of patients are refractory (i.e., epilepsy not well managed with currently available Anti-Seizure Medications (“ASMs”). Epilepsy
is the most common neurological disorder during pregnancy.
It
is estimated that approximately 900,000 child-bearing (“CB”) age women suffer from active epilepsy in the U.S. Women of CB
age with epilepsy face many additional challenges due to hormonal influences on seizure activity and endocrine function throughout the
different phases of their reproductive cycles. Elevated estrogen or decreased progesterone levels can exacerbate seizure frequency. Often,
these women experience hormonal and endogenous NAS imbalances, coupled with fluctuations in the blood levels of ASMs that impact control
of seizures, efficacy of oral contraceptives, any coexisting anxiety and/or depression and any associated sleep impairment. Epileptic
patients are 5-20 times more likely to develop depression.
Clinical
segmentation can be categorized by epilepsy type, comorbidities and patient subgroups. Categorization of focal epilepsy, generalized
epilepsy, combined focal and generalized epilepsy, and unknown epilepsy can guide the choice of ASM. Special patient subgroups, including
WWE of CB age and elderly patients, require special care and management of epilepsy. Comorbidities such as depression and anxiety may
be co-treated with therapies that do not aggravate seizures and have no drug interaction with the ASM used for epilepsy. While lowest
effective dose and monotherapy are preferred, management of patients with epilepsy is focused on controlling seizures, avoiding adverse
events, and maintaining quality of life. Despite a wide range of ASMs available, about 30% of all people with epilepsy still fail to
respond to treatment effectively. Women with epilepsy face specific challenges throughout their lifespan because of seizures, ASMs, and
hormonal fluctuations.
Women
with epilepsy were once counseled to avoid pregnancy, but epilepsy is no longer considered a contraindication to pregnancy. Caregivers
for WWE in the preconception phase either intending to start a family (planning pregnancy) or using contraception to prevent an unplanned
pregnancy face significant challenges to balance seizure control efficacy with the selection and dosage of ASMs and ASM-related risks
such as, among other risks, fetal-neonatal toxicity, contraception failure, and psychiatric side effects.
Several
ASMs are known to have teratogenic effects on the developing fetus (converging evidence from registry studies indicates that teratogenic
risks are highest with valproate, followed by carbamazepine and topiramate). Other commonly prescribed ASMs, including older generation
agents, such as phenobarbital and phenytoin, have been associated with higher risks as compared with lamotrigine, levetiracetam, clonazepam
and gabapentin (Vajda et al., 2014; Voinescu and Pennell, 2015). Moreover, risks associated with ASMs are considerable early in pregnancy;
therefore, it is necessary that WWE of CB age undergo counseling, monitoring, and adjustment to the most appropriate ASM prior to becoming
pregnant. It is preferable that WWE of CB age discuss seizure control with their doctor for at least 6 months before conception and,
if possible, cease ASM therapy or use the lowest effective dose of a single anticonvulsant according to the type of epilepsy and the
fetal toxicity of the ASM. Anxiety, depression, lack of adherence to ASM, and/or contraception failure may be experienced by women who
are worried about unplanned pregnancy or are late in confirming pregnancy, planned or unplanned. ASMs can reduce the efficacy of oral
contraceptives, compounding this problem.
Complex,
multidirectional interactions between female hormones, seizures, and ASMs exist. Most hormones act as NASs and can thus modulate brain
excitability. Any changes in endogenous or exogenous hormone levels can affect the occurrence of seizures, either directly or via PK
interactions that modify the plasma levels of ASMs (Harden, 2008). The PK interactions between oral contraceptives and ASMs are bidirectional
(Johnston and Crawford, 2014). The efficacy of hormonal contraception may be diminished for women taking CYP-P450 enzyme inducing ASMs.
Epilepsy is not a medical condition in which contraceptives are contraindicated. Contraceptive failure, possibly related to ASMs, may
be responsible for up to 1 in 4 unplanned pregnancies in WWE (~12.5% of all WWE pregnancies), versus a rate of 1% in healthy women.
Unmet
need to treat WWE in CB age
It
is estimated that approximately 900,000 CB age women suffer from active epilepsy in the U.S. Women of CB age with epilepsy face many
additional challenges such as hormonal influences on seizure activity and endocrine function throughout the different phases of their
reproductive cycles, and approximately 30% of patients with epilepsy cannot efficiently control their seizures with available ASMs, making
consideration of newer pharmacological treatment development options important.
Managing
uncontrolled seizures in WWE of CB age is the primary aim during preconception, pregnancy, and postpartum phases. Therefore, uncompromised
ASM efficacy with acceptable variability and less or no drug-drug interactions achieved with lowest possible monotherapy dose to address
fetal toxicity concerns remain highly unmet needs. Moreover, control of seizures including prevention of breakthrough seizures is critical
when planning for pregnancy and also during pregnancy, as it can also lead to undesired falls or auto-accidents and compromise freedom
to drive.
Select
ASMs have the potential to induce contraception failures, reproductive hormone imbalance, anxiety, and depression. There remains an unmet
need for an ASM without the aforementioned downsides, with no to low fetal-neonatal toxicity and without any breast-feeding concerns,
as well as the potential to treat associated comorbidities.
While
over 30 molecules have been approved for the treatment of epilepsy in the U.S., no epilepsy drug has been specifically approved for WWE
of CB age. We believe our endogenous NASs as GABAA PAMs, while targeting the goal of seizure control, also have the potential
for additional benefits in psychiatric disorders comorbidities (e.g., anxiety and/or depression) and sleep impairment. Moreover, these
oral endogenous NASs could potentially address some of the fetal toxicity concerns related to unplanned or planned pregnancy in WWE.
(1)
LPCN
2203: Oral Product for Management of Essential Tremor
LPCN
2203 is an oral candidate for management of essential tremor (“ET”) comprising a bioidentical GABAA modulating
NAS. We have successfully completed oral pharmacokinetics with bioidentical GABAA modulating NAS and are planning to submit
a protocol for a proof-of-concept phase 2 study for ET to the FDA.
Disease
Overview - Essential Tremor
Essential
Tremor is one of the most common movement disorders in the United States, affecting an estimated 7 million in the U.S. For ET patients,
uncontrollable shaking of the hands, head, voice, or legs creates difficulty eating, dressing, writing, and pursuing other day-to-day
tasks. The etiology of ET is largely unknown, but reduced GABAA receptor levels and decreased GABAergic activity have been
observed in ET.
While
ET is often associated with aging populations, ET can begin much earlier in life, with a progressive disease course that can eventually
necessitate a care partner. Social anxiety and depressive symptoms can manifest in patients with ET as tremor severity increases, and
may negatively impact a patient’s ability to work and engage in hobbies. In an interview study of ET patients and care partners,
the most common impacts on activities of daily living are pouring liquids and writing/typing (100%) and grooming/hygiene, drinking, dressing,
eating, and reading (80-85%). Overall, 90% of participants noted the emotional impact of ET, with 75% reporting tremor-related worry
or anxiety.
The
only FDA approved pharmacological treatment for ET was approved more than 50 years ago, and the majority of patients with ET experience
a sub-optimal response with standard-of-care treatments, highlighting numerous and compelling unmet needs in care such as daytime efficacy
and improved tolerability, a PRN (pro re nata) or “as needed” option, and a superior benefit-to-risk profile. (1) (2)
(1)
Ref: Louis ED, Ottman R. Tremor Other Kyperkinet Mov (NY). 2014;4:259.
(2)
Ref: Gerbasi et.al. Patient experiences in essential tremor: Mapping functional impacts to existing measures using qualitative research.
MDS 2023.
Other
Pipeline Candidates
We
continue to pursue opportunities for partnering and/or development arrangements for the continued development and/or marketing of LPCN
2401, LPCN 1148, LPCN 1144, and LPCN 1107. We do not currently anticipate conducting any further significant development activities
with respect to these products and product candidates without the participation of a partner. There can be no guarantee that we will
be able to identify or enter into partnering arrangements on terms that are beneficial to us or at all. Even if we do enter into partnering
arrangements, such arrangements may not be sufficient to successfully develop and commercialize these products.
LPCN
2401: For Improved Body Composition in Obesity Management
LPCN
2401 is targeted to be a once daily oral formulation comprising a proprietary anabolic androgen receptor agonist, and LPCN 2401+E is
a proprietary anabolic androgen receptor agonist co-formulated with Vitamin E, an antioxidant metabolic modifier. LPCN 2401 is expected
to have a favorable benefit to risk profile as a non-invasive option for use as an adjunct to GLP-1 receptor agonist chronic weight management
therapies and/or as a monotherapy post cessation of GLP-1 receptor agonist chronic weight management therapies with demonstrated benefits
to the liver.
LPCN
2401 has potential for use as an adjunct to incretin mimetics (GLP-1/GIP agonists) including amplification of GLP-1 insulinotropic actions
which is supported by studies demonstrating the role of androgen receptor agonist in regulation of GLP-1 through:
●
Enhancement of GLP-1-mediated insulin release from β cells through genomic- and non-genomic mechanisms
●
Increase in GLP-1 Receptor Expression in diabetics and non-diabetics
●
Promoting proliferation of β cells and improving insulin sensitivity
Target
benefits of LPCN 2401 in combination with GLP-1 agonists include improved body composition with quality weight loss while attenuating
lean mass loss, a serious unmet need, in addition to quality fat loss through appreciable abdominal fat loss. Moreover, as an adjunct
to incretin mimetics, LPCN 2401 may increase weight loss, particularly in diabetics, through increased expression activity of GLP1R and
increased effectiveness of GIP1 therapies secondary to actions at GLP1R (glucose lowering). LPCN 2401 could also be potentially used
as monotherapy post discontinuation of GLP-1 agonist to manage weight/fat regain and durability of diabetes remission.
Data
from preclinical and clinical studies support the potential of LPCN 2401 and LPCN 2401+E in improving body composition. In April 2024,
Lipocine announced results from a multi-center prospective, blinded Phase 2 study, which demonstrated placebo-adjusted increase in lean
mass of 4.4%, decrease in fat mass of 6.7%, reduction in trunk fat mass of 2.5%, and increased bone mineral content of 2.8% with LPCN
2401+E in a population consistent with FDA guidance for developing products for weight management. LPCN 2401 was well tolerated with
minimal GI or androgenic adverse events and no reports of muscle spasms. The 2025 FDA draft guidance (https://www.fda.gov/media/71252/download)
on Obesity and Overweight: Developing Drugs and Biological Products for Weight Reduction defines obesity as a chronic disease characterized
by excess adiposity and defines weight reduction as a long-term reduction in excess adiposity (body fat) but states the primary endpoint
for a weight-reduction drug should be mean percent change in weight. FDA also invited sponsors to consult with FDA to discuss
efficacy claims related to change in body composition as this was beyond the scope of the guidance document. Areas for discussion would
include the appropriate population and selection of endpoint that measures how a patient feels, functions, or survives.
As
an adjunct therapy to incretin mimetics, LPCN 2401 has the potential to attenuate fat/weight rebound, ameliorate loss of muscle mass,
improve muscle quality and functionality, amplify fat mass loss with improved body composition, maintain weight, prevent “fat overshoot,”
attenuate fat/weight rebound, and accelerate muscle rebound post incretin mimetic discontinuation. In pre-IND written responses (November
2024), FDA’s recommendations were consistent with the 2025 draft guidance. Specifically, FDA recommended we identify the appropriate
patient population for treatment, ‘such as those with demonstrated impairments in muscle function after weight loss intervention,’
and an approvable endpoint would be one that measures how a patient feels, functions, or survives. FDA also recognized that Lipocine’s
proposed indication and population (including women) would be distinct to those for whom testosterone therapy is currently approved (testosterone
replacement in men with low T not due to aging). We may explore the possibility of partnering LPCN 2401 with a third party, although
no partnering agreement has been entered into by us. 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 terms favorable to us.
Disease
and Market Overview – Obesity Management
Approximately
74% of U.S. adults aged 20 and older are either obese or overweight, and an estimated 30% of the U.S. adult population has a BMI ≥
30 kg/m2. Obesity is a chronic, relapsing health risk defined by excess body fat. Excess body fat increases the risk of death
and major comorbidities such as type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease, osteoarthritis of the knee, sleep
apnea, and some cancers1. About 30% of overweight (BMI ≥ 25 kg/m2) adults2 have type 2 diabetes,
50%3 have dyslipidemia, and 67%4 have hypertension. It is estimated that the total GLP-1 users in the U.S. may
reach 30 million (around 9% of the overall population) by 20305. Among older adults aged 60 and over prevalence of: obesity
(BMI ≥ 30 kg/m2) is ~43%).6
Sarcopenic
obesity (SO) is defined as the coexistence of excess fat mass and reduced skeletal muscle mass. The rates of sarcopenic obesity
increase with age.7 Reportedly, ~54% of adults with obesity have sarcopenia (low muscle mass.) 8
The
causes of SO are multifactorial and can include sedentary lifestyle, hormonal changes, chronic diseases, inflammation, insulin resistance,
and nutritional deficiencies. SO is associated with several clinical complications: frailty, fractures, cardiovascular diseases, cancer,
mental health, and an increased risk of hospitalization and mortality.9
The
rapid weight loss observed with the currently approved chronic weight management GLP-1 receptor agonist medications includes unwanted
lean mass loss, up to 40% of the patient’s total weight lost. Moreover, discontinuation of these therapies frequently results in
a rapid regain in weight. Loss of lean mass has multiple negative health implications including weakness/fatigue and lowered metabolism
which can cause a regain in fat mass, declines in neuromuscular function, potential effects on emotion and psychological states, and
increased risk of injury.
Elderly
obese and SO patients are most vulnerable to lean mass loss with GLP-1 receptor agonist use due to pre-existing low muscle mass that
is compounded with high magnitude and rate of muscle mass loss with GLP use.10 Recent reports suggest ~4% loss in lean mass
with ~43% with compromised functionality (loss of ≥10% Stair Climb Power ) in elderly obese patients upon just 16 weeks of semaglutide
treatment.10
Several
recent studies showed that body composition, especially lean body mass (muscle) may play an independent role in survival of patients
with diseases such as cancer and cardiovascular diseases.11 Therefore, a focus on body composition in obesity management to
sustainably lose fat mass while maintaining lean mass should be an essential goal.
There
is a significant unmet need for an oral, efficacious, muscle preserving/gaining option for chronic obesity/weight management that ameliorates
the loss of lean mass associated with GLP-1/GIP agonist treatment, resulting in a higher quality weight loss and improved functionality,
especially in elderly obese and sarcopenic obese patients. Moreover, there is a need for a chronic long-term pharmacotherapy option to
maintain weight upon cessation of incretin mimetic therapy, prevent fat/weight rebound “overshoot” and minimize lag in muscle
recovery to prevent collateral fattening as well as improve the durability of any achieved diabetes remission while on GLP-1.
(1)
Ref: Caterson and Hubbard et al. 2004; Calle and Thun et al. 1999
(2)
https://news.harvard.edu/gazette/story/2012/03/the-big-setup/
(3)
https://www.ncbi.nlm.nih.gov/books/NBK305895/
(4)
https://pmc.ncbi.nlm.nih.gov/articles/PMC6316192/#sec3-nutrients-10-01976
(5)
https://www.jpmorgan.com/insights/global-research/current-events/obesity-drugs
(6)
Ref: Flynn et al. Morgan Stanley, February 27, 2024 https://www.cdc.gov/nchs/products/databriefs/db360.htm
(7)
J. Gerontol. A Biol. Sci. Med. Sci 72, 1445–1451 (2017)
(8)
Prev Chronic Dis 2020;17:200167
(9)
J Am Med Dir Assoc. 2011 May;12(4):249-56
(10)
Veru press release on January 27, 2025. https://ir.verupharma.com/news-events/press-releases/detail/225/veru-announces-positive-topline-data-from-phase-2b-quality
(11)
DH Lee and EL Giovannucci, Exp Biol Med. 2018
LPCN
1148: Oral Product Candidate for the Management of Cirrhosis