Brexanolone

In 2010, neuroscientist and former Eli Lilly research leader Steve Paul started a company that he hoped would spark a revolution in drug discovery, built around a class of compounds dubbed neurosteroids that could help calm overactive brain circuits and fire up sleepy ones for a long list of psychiatric and neurological conditions. That company, Sage Therapeutics, briefly became one of the hottest tickets in neuroscience. Last year, it won a long-awaited approval for Zurzuvae, the first pill for postpartum depression, a condition that affects one in eight new mothers. But that landmark approval was marred by a sharp downturn in Sage’s fortunes. The FDA rejected the antidepressant’s much broader use in major depressive disorder, for which the data were murky. A slower-than-expected uptake of that pill — and three clinical failures of its other experimental drugs — have sent Sage’s stock down 76% this year, putting its market cap well below the amount of cash it has on hand. Those setbacks spurred two large rounds of layoffs and the departure of several longtime executives. Now, the company’s best shot at a turnaround hinges on a notoriously difficult-to-treat condition: Huntington’s disease, a rare neurodegenerative disorder that causes brain cells to die typically by the time a patient is in their 30s or 40s. Within the next six weeks, it expects to have the results from a Phase 2 study of its neurosteroid-inspired drug dalzanemdor, which Sage once hoped would help treat several neurodegenerative conditions. If the drug succeeds, it could provide Sage a lifeline. Huntington’s patients currently have extremely limited treatment options and, like in postpartum depression, an approval would mark a significant scientific milestone. But if the readout fails, it will prompt a lot of questions for Sage, according to Stifel analyst Paul Matteis. Given how the Zurzuvae story played out — winning a historic approval in postpartum depression but failing to expand that into the larger MDD market — the onus will be on Sage to convince investors it can move the drug forward. “Huntington’s is not necessarily existential for Sage,” Matteis said. “But it could, if it’s negative, start to initiate those types of conversations on, ‘What will actually become of Sage? Why should we have any confidence in the rest of your pipeline?’” Warning signs are already flashing. In July, Sage adjusted the primary endpoint in its Huntington’s trial after a separate study showed only a “small numerical difference” between the dalzanemdor and placebo arms on the primary endpoint, which measures cognitive decline. And dalzanemdor failed to improve cognition in mid-stage studies of two other diseases earlier this year. “Usually when companies have something profound and a remarkable effect size, they lead with it, right? That’s the headline on the press release,” TD Cowen analyst Ritu Baral said in an interview. “And it’s very clear that they did not see on this interim Huntington’s update some sort of blow-the-doors-off signal.” Sage executives have said they believe that Huntington’s disease is where dalzanemdor is most likely to succeed. That said, it’s the only drug in Sage’s pipeline after the company cut its other early-stage research last month. For now, the company is focused on increasing postpartum access to Zurzuvae, which pulled in $11 million in sales in the third quarter. A spokesperson for Sage declined an interview request about the Huntington’s program and what’s next for the company. Paul departed Sage’s board in June. In an interview with Endpoints News , he declined to comment on dalzanemdor or Sage’s future, but he said that even if Zurzuvae is the last drug Sage ever launches, he still views the company as a success. “Quite bluntly, I think people don’t give Sage enough credit for the work they did on zuranalone for postpartum depression,” Paul said. Neurosteroids help fine-tune the effects of GABA and glutamate, the brain’s main inhibitory and excitatory molecules, respectively. These counterparts, sometimes called the yin and yang of the brain, play a role in just about everything that goes on inside our heads. An imbalance between the two systems is implicated in most major psychiatric diseases, including anxiety, depression and schizophrenia. Sage’s work on drugs that enhance GABA receptors led to its sole success in postpartum depression amid failures in major depression, essential tremor and a severe form of epilepsy. Its work on glutamate receptors, specifically enhancing the activity of ones called NMDA receptors, has only led to disappointment so far. Dalzanemdor, previously called SAGE-718, is inspired by a natural neurosteroid called 24(S)-hydroxycholesterol that binds NMDA receptors. It boosts glutamate signaling without directly competing with the neurotransmitter to help stabilize neural networks in the brain. “More than 50 years of research has really suggested that this receptor is a critical node in higher-order cognitive processes, including things like learning and memory,” Sage chief scientific officer Mike Quirk told Endpoints earlier this year. Sage has been testing dalzanemdor in three neurodegenerative diseases, with those readouts marking what Quirk referred to as “a critical inflection point, not just for Sage, but I think also for the field.” The drug failed in Parkinson’s in April and Alzheimer’s in October. Sage executives have repeatedly insisted that there wouldn’t be any read-through from the Parkinson’s trial to the Alzheimer’s study, but analysts viewed success in either disease as a long shot. An added justification for Sage’s final test of dalzanemdor is the imbalance in NMDA signaling in Huntington’s disease that damages neurons. “Mechanistically, if one thing was going to work because of the NMDA mechanism and the NMDA toxicity that’s part of Huntington’s, it was going to be the Huntington's program,” Baral said. A reduction of the natural neurosteroid that dalzanemdor is based on is correlated with cognitive decline in Huntington’s. CMO Laura Gault previously told Endpoints that the drug is designed to improve patients’ cognitive outcomes rather than slow disease progression — a strategy that has worked for some older drugs for treating symptoms of Alzheimer’s. Paul said he still thinks that the drug’s mechanism of enhancing NMDA receptors makes sense. “But there's all kinds of reasons why a drug might not work,” he added. Sage is long past its Wall Street heyday, evidenced by the sharp decline of R&D announcements. In the years immediately following its IPO in 2014, Sage would unveil a new program at seemingly every earnings call, touting its ability to develop a sustainable pipeline and the company itself into a neurology powerhouse. That hasn’t happened, and it remains an open question as to what will happen to the remnants of the R&D engine, Baral said. The investor community feels there is an “opacity” to the R&D platform and whether it can continue to churn out more pipeline programs. Sage employed about 360 people on its R&D team in February 2023. After multiple rounds of layoffs, the remaining group is roughly one-third of its prior size, based on financial filings. The fate of Sage’s early-stage pipeline is even murkier. It doesn’t have anything beyond Zurzuvae and dalzanemdor after a restructuring last month. On its third-quarter earnings call in October, executives alluded to ensuring “longer-term value” but did not provide specifics about any new experimental drugs. A turnaround would have to be driven by CEO Barry Greene. He has consistently wanted to build Sage into the big company that investors want, according to Baral. “Even if Huntington's works, Zurzuvae and a Phase 2 Huntington’s asset is not where he wants Sage,” Baral said. “It's not what he wants for the Sage story in the near- to mid-term.” Sage’s path to success may have been finding a way to get Zurzuvae approved for major depression, an annual market that it estimated is 40 times larger than postpartum depression. Analysts had guided toward $1 billion in peak sales for Zurzuvae in MDD and up to $500 million in postpartum depression. But Sage recently said it would no longer pursue approval for the common condition. In April, two weeks after Paul announced he would step down from Sage’s board, he launched a new company called Seaport Therapeutics. The startup’s lead drug is a novel formulation of allopregnanolone, the same GABA-enhancing neurosteroid used in Sage’s original intravenous infusion for postpartum depression and the inspiration for its more recent pill. Despite Sage’s failed trials, Paul is convinced it will work in major depression. “There’s a lot of evidence that either reduced GABA levels or receptor function is involved in not just postpartum depression, but depression,” he said. “I still believe in the mechanism.”

SALT LAKE CITY, Nov. 7, 2024 /PRNewswire/ -- Lipocine Inc. (NASDAQ: LPCN), a biopharmaceutical company leveraging its proprietary technology platform to augment therapeutics through effective oral delivery, today announced financial results for the third quarter and nine months ended September 30, 2024 and provided a corporate update. Neuroactive Steroids LPCN 1154, oral brexanolone, is being developed as a treatment for postpartum depression (PPD). It is targeted to be a highly effective, oral, fast-acting and short duration treatment option. The Company has completed labeling studies such as a food effect study and PK profiling in women with PPD, and is targeting NDA submission for LPCN 1154 by the end of 2024. In October, Lipocine announced positive results from a quantitative electroencephalogram (qEEG) study conducted in healthy subjects administered single doses of LPCN 1154. The results indicated robust central nervous system (CNS) activity of LPCN 1154, with concentration- and time-dependent post-dose changes in qEEG. The study confirmed GABAA positive allosteric modulation and supports future development of LPCN 1154 in neuropsychiatric indications. LPCN 2401 for obesity management LPCN 2401 is an oral formulation comprised of a proprietary anabolic androgen receptor agonist targeted for once daily regimen. In October, Lipocine hosted a virtual key opinion leader (KOL) event on LPCN 2401. The event highlighted positive data from the Phase 2 study of LPCN 2401 and the data support the potential for the product to be used as an adjunct with incretin mimetics (GLP-1/GIP agonists) or as a monotherapy, including post incretin mimetic discontinuation. Frank Greenway, MD (Professor and Chief Medical Officer at Pennington Biomedical Research Center) discussed the unmet needs and current treatment landscape in obesity management with a focus on fat loss and lean muscle mass preservation for patients on incretin therapies. A poster "Oral LPCN 2401 Reduces Fat Mass and Increases Lean Mass in Men With Obesity" featuring the Phase 2 data was presented by Dr. Greenway at the Obesity Society's Annual ObesityWeek® conference on November 5, 2024 in San Antonio, TX. Lipocine plans to meet with the FDA to discuss the study design for a proof-of-concept Phase 2 study for LPCN 2401 and expansion to the female population. LPCN 1148 Management of Cirrhosis Lipocine is evaluating LPCN 1148 for the management of decompensated cirrhosis and has conducted a successful Phase 2 study that met its primary endpoint. The Company plans to request a Type C meeting with the FDA to discuss the clinical development plan for LPCN 1148. TLANDO® In October, Lipocine signed an exclusive supply and distribution agreement with Pharmalink to commercialize TLANDO, its oral testosterone replacement therapy, in the Gulf Cooperation Council (GCC) countries consisting of Saudi Arabia, Kuwait, the United Arab Emirates (UAE), Qatar, Bahrain, and Oman. In September, Lipocine signed an exclusive distribution and license agreement with SPC Korea to commercialize TLANDO in South Korea. The company continues to pursue opportunities for partnering and/or development arrangements for the continued development and/or marketing of our remaining pipeline candidates. Third Quarter Ended September 30, 2024 Financial Results Lipocine reported a net loss of $2.2 million, or ($0.44) per diluted share, for the third quarter ended September 30, 2024, compared with a net loss of $6.7 million, or ($1.27) per diluted share, for the quarter ended September 30, 2023. There were no revenues recorded during the third quarter ended September 30, 2024. In the third quarter of 2023, the company recorded a non-cash revenue reversal of variable consideration for minimum guaranteed royalties of $3.1 million related to the termination of the Antares License Agreement. Research and development expenses were $1.6 million and $2.9 million, respectively, for the quarters ended September 30, 2024 and 2023. The decrease was a result of a decrease in TLANDO related costs, a decrease in contract research organization expense and outside consulting costs related to the wind down of the LPCN 1148 study in 2024, and a decrease in costs related to LPCN 1154 clinical studies, offset by increases in personnel related costs and other research and development related costs and supplies. General and administrative expenses were $1.0 million in each of the quarters ended September 30, 2024 and 2023. As of September 30, 2024, Lipocine had $19.8 million of unrestricted cash, cash equivalents and marketable investment securities compared to $22.0 million at December 31, 2023. Nine Months Ended, September 30 2024, Financial Results Lipocine reported a net loss of $1.8 million, or ($0.33) per diluted share, for the nine months ended September 30, 2024, compared with a net loss of $14.1 million, or ($2.72) per diluted share, for the nine months ended September 30, 2023. Revenues for the nine-month period ended September 30, 2024 were $7.7 million, primarily consisting of licensing revenue received from our Verity License Agreement, in addition to TLANDO royalty revenue of $206,000. During the nine months ended September 30, 2023, the company recognized a non-cash revenue reversal of variable consideration for minimum guaranteed royalties of $3.1 million relating to the termination of the Antares License Agreement offset by licensing revenue of approximately $55,000 for payments received related to the Spriaso license agreement. Research and development expenses were $6.3 million and $8.5 million, respectively, for the nine months ended September 30, 2024 and 2023. The decrease was a result of a decrease in contract research organization expense and outside consulting costs related to the wind down of the LPCN 1148 study in 2024, a decrease in TLANDO related costs, a decrease in personnel related costs, and a decrease in other research and development related costs. These decreases were offset an increase in costs related to the LPCN 1154 clinical studies. General administrative expenses were $4.1 million and $3.8 million respectively, for the nine months ended September 30, 2024 and 2023. The increase in general and administrative expenses was a result of increases in business development expenses, corporate legal fees and director fees, offset by decreases in corporate insurance expense, professional fees, other administrative consulting fees, personnel related costs, and travel related costs. For more information on Lipocine's financial results, refer to Form 10-Q filed by the Company with the SEC. About Lipocine Lipocine is a biopharmaceutical company leveraging its proprietary technology platform to augment therapeutics through effective oral delivery to develop differentiated products. Lipocine has drug candidates in development as well as drug candidates for which we are exploring partnerships. Our drug candidates represent enablement of differentiated, patient friendly oral delivery options for favorable benefit to risk profile which target large addressable markets with significant unmet medical needs. Lipocine's clinical development candidates include: LPCN 1154, oral brexanolone, for the potential treatment of postpartum depression, LPCN 2101 for the potential treatment of epilepsy, LPCN 2203 an oral candidate targeted for the management of essential tremor, LPCN 2401 an oral proprietary anabolic androgen receptor agonist, as an adjunct therapy to incretin mimetics, as an aid for improved body composition in obesity management and LPCN 1148, a novel androgen receptor agonist prodrug for oral administration targeted for the management of symptoms associated with liver cirrhosis. Lipocine is exploring partnering opportunities for LPCN 1107, our candidate for prevention of preterm birth, LPCN 1154, for rapid relief of postpartum depression, LPCN 2401 for obesity management, LPCN 1148, for the management of decompensated cirrhosis, and LPCN 1144, our candidate for treatment of non-cirrhotic NASH. TLANDO, a novel oral prodrug of testosterone containing testosterone undecanoate developed by Lipocine, is approved by the FDA for conditions associated with a deficiency of endogenous testosterone, also known as hypogonadism, in adult males. For more information, please visit . Forward-Looking Statements This release contains "forward-looking statements" that are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and include statements that are not historical facts regarding development and commercialization of TLANDO and TLANDO XR by our licensees, the amount of the license fee, milestone payments, and royalty payments we will ultimately receive, the ability of our licensees to grow the TLANDO franchise, our product development efforts, the application of our proprietary platform in developing new treatments for CNS disorders, our product candidates and related clinical trials, our development of our product candidates and related efforts with the FDA, including with respect to LPCN 1148 and LPCN 2401, the timing of our submission of a NDA with the FDA for LPCN 1154, and the potential uses and benefits of our product candidates. Investors are cautioned that all such forward-looking statements involve risks and uncertainties, including, without limitation, the risks that we may not be successful in developing product candidates to treat CNS disorders, we may not have sufficient capital to complete the development processes for our product candidates, we may not be able to enter into partnerships or other strategic relationships to monetize our non-core assets, the FDA will not approve any of our products, risks related to our products, expected product benefits not being realized, clinical and regulatory expectations and plans not being realized, new regulatory developments and requirements, risks related to the FDA approval process including the receipt of regulatory approvals and our ability to utilize a streamlined approval pathway for LPCN 1154, the results and timing of clinical trials, patient acceptance of Lipocine's products, the manufacturing and commercialization of Lipocine's products, and other risks detailed in Lipocine's filings with the SEC, including, without limitation, its Form 10-K and other reports on Forms 8-K and 10-Q, all of which can be obtained on the SEC website at . Lipocine assumes no obligation to update or revise publicly any forward-looking statements contained in this release, except as required by law. SOURCE Lipocine Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED