LPCN: 1154 Results Illuminate Accelerated Pathway
NASDAQ:LPCN
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1Q:23 Financial and Operational Results
Efforts year to date for Lipocine Inc. (NASDAQ:LPCN) were dominated by the pharmacokinetic (PK) study for LPCN 1154, which is in development for postpartum depression (PPD). The underlying drug in LPCN 1154 is brexanolone, which is approved in an intravenous (IV) formulation for PPD. Results from the study were reported several days after first quarter financial and operational results were released. Lipocine’s recent strategy change to focus on the development of treatments for central nervous system (CNS) disorders, particularly neuroactive steroids, has oriented the company’s efforts towards a narrow portfolio of products and indications including the previously mentioned LPCN 1154 as well as LPCN 1148 and LPCN 2101.
On May 11, 2023 Lipocine (NASDAQ: LPCN) filed its 1Q:23 Form 10-Q and posted its earnings release for the quarter ending March 31, 2023.
Highlights for 2023 include:
➢ First subject dosed in LPCN 1154 PK trial – April 2023
➢ 1:17 reverse stock split – May 12, 2023
➢ Topline results from LPCN 1154 PK trial – May 2023
Lipocine generated revenues of $0.1 million during 1Q:23 and posted a net loss of ($3.9) million, or ($0.74) per share. These results are adjusted for the 1:17 reverse stock split that became effective following the filing of the 1Q:23 10-Q. Reported per share numbers do not adjust for the reverse split that took place on May 12, 2023.
For the quarter ending March 31, 2023 and versus the same period in the prior year:
➢ Revenues were $55,000 compared to nil. The amounts reflect a payment from Spiraso related to a licensing agreement for products in the cough and cold field;
➢ Research & Development expense totaled $3.1 million, rising 65% from $1.9 million. The increase was driven by CRO expense related to LPCN 1148 and LPCN 1154, personnel expense, lab supplies, small equipment and other R&D expenses. Offsets arose from lower LPCN 1111 scale up costs, LPCN 1144 CRO and outside consulting costs and amounts related to ancillary studies for LPCN 1107;
➢ General & Administrative expenses were $1.3 million, up 4% from $1.2 million primarily due to higher strategic advice and planning legal fees, business development consulting fees, director fees and other professional fees. These amounts were offset by lower board recruitment fees and corporate insurance;
➢ Total other net income was $0.5 million related to interest and investment income and a gain on warrant liability;
➢ Net loss was ($3.9) million or ($0.74) per share compared with net loss of ($3.5) million or ($0.67) per share, respectively.
At quarter’s end, marketable securities, cash and equivalents totaled $28.9 million. Cash burn for 1Q:23 was ($3.9) million, matching prior year period amounts. $6,000 of cash was used in financing related to the costs of the at the market (ATM) offering.
Product Candidates
Lipocine’s primary research and development efforts in the CNS pipeline focus on lead candidate LPCN 1154 for post-partum depression (PPD), LPCN 2101 for women with epilepsy and LPCN 1148 for management of decompensated cirrhosis and hepatic encephalopathy.
LPCN 1154
LPCN 1154 recently completed a pilot pharmacokinetic (PK) bridge study and is the most advanced of the company’s active assets. It is attractive as existing administration of the underlying molecule, brexanolone is burdensome and is administered as a continuous intravenous infusion over a period of 60 hours. It is mixed in a sterile solution and delivered through an intravenous catheter. The infusion is started at a low dose and gradually increased over the first 24 hours to the target dose, which is determined based on the patient's weight. During the infusion, the patient's vital signs are closely monitored, and any side effects or adverse reactions are addressed as needed. The time needed to infuse and the requirement that the patient receive the infusion in the hospital create substantial burdens and costs that could be largely alleviated if an oral form is successfully developed.
Lipocine’s PK bridge study results will inform a follow up meeting with the FDA where further discussions are planned to design a pivotal study in order to support a submission via the 505(b)(2) regulatory pathway. Based on input from management, we think that a pivotal study could cost from $4 to $5 million and be completed in a year.
Postpartum Depression
Postpartum depression (PPD) is a mood disorder that affects women after childbirth. Hormonal changes and neurotransmitter imbalances are believed to play a role. GABA (gamma-aminobutyric acid) is an inhibitory neurotransmitter in the brain that helps regulate mood and anxiety. GABA receptors are classified into different subtypes, including GABAA and GABAB receptors. These receptors have specific binding sites for GABA and are involved in different physiological processes.
The GABA receptors may be allosterically modulated, where a molecule binds to a specific receptor or enzyme at a site distinct from the active site, known as the allosteric site. There are both positive allosteric modulator (PAM) sites which augments the function of the primary receptor and negative allosteric modulator (NAM) sites which diminish the function of the primary receptor. When a PAM binds to the allosteric site, it induces a conformational change in the receptor or enzyme, leading to an increase in the affinity of the receptor for its natural ligand or enhancing the enzyme's catalytic activity. This positive modulation can result in an increase in the response or signaling produced by the receptor or enzyme, effectively amplifying its function.
Research suggests that GABAA receptors may be implicated in the development of postpartum depression. During pregnancy, the levels of certain hormones, such as progesterone and allopregnanolone (a neurosteroid), increase significantly. These hormones can enhance the activity of GABAA receptors, leading to increased GABAergic inhibition and a calming effect on the brain. However, after childbirth, there is a rapid decline in the levels of these hormones. This sudden hormonal shift can disrupt the balance of GABA receptor activation, leading to decreased GABAergic inhibition. This imbalance may contribute to the development of PPD symptoms, such as anxiety, irritability, and depressed mood.
Furthermore, alterations in GABA receptor function can affect the regulation of other neurotransmitters, such as serotonin and dopamine, which are also implicated in mood disorders. Imbalances in these neurotransmitter systems may further contribute to the development of PPD.
Brexanolone is a positive allosteric modulator of the GABAA receptor. In its approved form, it is administered over a 60-hour period in the hospital with the patient under observation. Many of the adverse events are related to IV infusion errors and patients must contend with the cost and difficulty of overnight stays, cost and accessibility.
LPCN PK Study Results
In a May 16th press release, Lipocine provided a summary of the pharmacokinetic bridging study results. The study was designed as an open label, randomized, partial crossover study in healthy postmenopausal women. The primary objective of the study was to compare the pharmacokinetics (AUC∞ and Cmax) of two LPCN 1154 oral multi-dose regimens and a continuous IV infusion dosing regimen of brexanolone, to inform the dose selection for the planned confirmatory pivotal PK registration study. Details and duration of the 1:1 administration of brexanolone in 12 subjects is included in the following graphic.
The primary goal of this smaller PK study was to identify an appropriate dose. Results from the study were provided in a summary comparing Lipocine’s oral version of brexanolone to the intravenous version of brexanolone branded Zulresso. While the FDA has final say regarding the specifics of this application, regulatory guidelines for pharmacokinetic parameters generally require the new formulation to fall within 80% to 125% for AUC and Cmax. In the data provided below, oral brexanolone (LPCN 1154) was generally within the set parameters. The pilot study is intended to identify the optimal dose, so we anticipate that results from the follow-on study will fall more closely within required parameters. The pilot study data will be used to interact with the FDA and determine the design for a larger pivotal PK study that would be required for filing for marketing authorization.
While explicit details of the safety parameters were not provided, the Lipocine team noted that, as in previous studies, LPCN 1154 appeared safe and well-tolerated in the study. Adverse events were mild or moderate in severity, and similar across trial arms. One of the primary concerns for Zulresso, hypoxia, was not observed in LPCN 1154 subjects, nor were any sedation related events.
While LPCN 1154 appears to improve several significant hurdles faced by PPD patients that may benefit from brexanolone, there are other considerations. It is unclear whether or not LPCN 1154 would maintain the black box warning that appears in the label for Zulresso. The risk of excessive sedation and loss of consciousness requires that patients be monitored by a provider and have blood oxygen levels measured over the duration of treatment.
Next Steps
Next steps for Lipocine management for LPCN 1154 are to share data from the pilot PK study with the FDA and design the pivotal study. After FDA assent, the study will launch in 2H:23. Assuming supportive results, LPCN 1154 will pursue a 505(b)(2) pathway. Expected cost for the pivotal study is estimated at $4 to $5 million.
LPCN 1154 may address many of the shortcomings of Zulresso; however, there are potential competitors waiting in the wings. Zuranolone is an investigational medication which is under development by SAGE Therapeutics for the treatment of depressive disorders and a variety of other indications. The oral, GABAA positive allosteric modulator has been submitted to the FDA in a new drug application for major depressive disorder (MDD) and PPD. A target action date of August 5, 2023 has been assigned.
LPCN 1148 Phase II Study in Decompensated Cirrhosis
Lipocine is conducting a Phase II study in decompensated cirrhosis with its LPCN 1148 asset. LPCN 1148 is a novel prodrug of androgen receptor agonist for oral administration with multi modal action to improve liver and muscle function. The compound proposes to improve quality of life for patients awaiting liver transplant, decrease hospital admissions and prevent or reduce the occurrence and recurrence of decompensation events. The 24-week trial completed enrollment of the targeted 30 patients and is expected to announce results in mid-2023. The ongoing Phase II proof of concept trial employs a prospective, multi-center, randomized, placebo-controlled two-stage design. The primary endpoint is change in skeletal muscle index at week 24. Secondary endpoints include change in liver frailty index and myosteatosis,5 rates of breakthrough hepatic encephalopathy and number of waitlist events including all-cause mortality. Total treatment duration which includes the placebo-controlled stage one and the single-active arm, open-label extension stage two is 52 weeks.
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1. Lipocine LPCN 1154 Presentation, May 16, 2023
2. Lipocine LPCN 1154 Presentation, May 16, 2023
3. Lipocine LPCN 1154 Presentation, May 16, 2023
4. Lipocine January 2023 Corporate Presentation
5. Myosteatosis, also known as "muscle fat infiltration," is a condition where fat accumulates in the skeletal muscle tissue, leading to decreased muscle quality and function. It is commonly observed in older adults and individuals with obesity, metabolic syndrome, or diabetes.
