Brexanolone

Relmada purchases Sepranolone, a Phase 2b ready asset, for the treatment of Tourette syndrome (TS) and other compulsion-related conditions from Asarina Pharma AB Phase 2a results signaled improvement in Tourette symptoms, quality of life and robust overall safety, supporting Sepranolone as a new potential first line treatment option for TS Sepranolone (isoallopregnanolone) is a first-in-class compound from new subgroup of neurosteroids known as GAMSAs- GABAA Modulating Steroid Antagonists - acting selectively on the GABAA pathway, potentially alleviating the negative effect of Allopregnanolone in Tourette syndrome and other compulsive disorders CORAL GABLES, Fla., Feb. 06, 2025 (GLOBE NEWSWIRE) -- Relmada Therapeutics, Inc. (Nasdaq: RLMD, “Relmada”, “the Company”), a clinical-stage biotechnology company, today announced the acquisition of Sepranolone, a Phase 2b ready neurosteroid, from Asarina Pharma AB (Asarina), being developed for the potential treatment of Tourette syndrome (TS) and other compulsive disorders. “We are very pleased to announce this agreement with Asarina. Sepranolone aligns with our Company’s mission to find solutions for difficult-to-treat central nervous system (CNS) disorders. There is a serious unmet need for improved TS therapies not only reducing tics but also improving quality of life without serious side effects. We have been impressed by the encouraging Phase 2a efficacy signal with clinically meaningful tic reductions and quality-of-life improvements, combined with a robust safety data package showing no CNS off-target effects, that we believe reflect the compound’s selective binding properties,” said Sergio Traversa, Chief Executive Officer of Relmada. “We believe that this transaction is an excellent fit with our objective to build shareholder value by leveraging our core competencies of identifying and developing innovative compounds.” Luca Pani, MD, Professor of Clinical Psychiatry at the University of Miami Miller School of Medicine, commented, "While current treatments for Tourette syndrome provide only modest tic reduction and are often accompanied by significant side effects, the Phase 2a data suggest that Sepranolone has the potential to offer meaningful symptom relief with a more favorable safety profile. These findings are promising, and I look forward to seeing further clinical development of this novel therapy.” “Late last year we announced that Relmada would explore strategic assets and strategic options,” commented Maged Shenouda, Chief Financial Officer of Relmada. “Based on our extensive due diligence, including a carefully conducted review of the clinical and regulatory data, and consultation with well-respected outside experts, we believe the promising Phase 2a data suggest that Sepranolone has the potential to become first line treatment for TS.” Clinical Data on Sepranolone Sepranolone (isoallopregnanolone) is a first-in-class GABAA Modulating Steroid Antagonist (GAMSA), which selectively targets the GABAA (GABAA) pathway to counteract the effects of Allopregnanolone, a neurosteroid implicated in TS and other compulsive disorders. Data from an open-label Phase 2a randomized study demonstrated that Sepranolone has the potential to improve TS symptoms versus standard of care alone, as measured by changes in the YGTSS scoring system (the world-standard Yale Global Tic Severity Scale) compared to baseline. In the 12-week, dual-center, parallel-group study, 26 subjects were treated with Sepranolone (10 mg, administered by subcutaneous injection twice weekly in addition to standard of care (SOC) versus standard of care alone. The Phase 2a results showed competitive tic reduction and improved quality of life while displaying no CNS off-target effects. Sepranolone not only reduced tic severity in its primary clinical endpoint as measured by YGTSS by 28% (p=0.051) – but also achieved positive results in four key secondary endpoints compared with standard of care: 69% greater increase of Quality of Life (using the Gilles de la Tourette Syndrome Quality of Life total score (GTS-QOL) 50% greater reduction in impairment (YGTSS) 44% greater reduction of the premonitory urge to tic (PUTS – the Premonitory Urge to Tic scale) no off-target CNS effects or systemic side effects – a crucial metric for CNS drugs in an indication where legacy and new treatments in developments involve sometimes severe side effects Strategic Outlook Relmada continues to evaluate additional product and strategic opportunities. The Company anticipates hosting an investor update on Sepranolone’s next development steps later in 2025. About the Asarina Agreement Under the terms of the agreement, Relmada acquired full global ownership rights to Sepranolone from Asarina Pharma AB, a Swedish biopharmaceutical company through an asset purchase agreement for EUR 3 Million. About Neurotransmitter Modulators and Sepranolone Sepranolone is a pioneering GAMSA that selectively inhibits the effects of Allopregnanolone, a neurosteroid linked to compulsive disorders such as TS and obsessive-compulsive disorder (OCD). Evaluated in multiple clinical neuro/hormonal studies involving over 335 participants, Sepranolone has demonstrated a favorable safety profile. GABA (γ-aminobutyric acid) is the brain’s primary inhibitory neurotransmitter, helping to regulate anxiety and compulsive disorders. While Allopregnanolone typically enhances GABA’s calming effects, in some individuals it paradoxically exacerbates anxiety and compulsive. Sepranolone normalizes GABAA receptor activity by targeting two specific receptor subtypes (alpha-2 and alpha-4) without directly interfering with GABA signaling, making it a novel and selective treatment approach for TS and related disorders. Sepranolone is protected by multiple issued patents until 2038. About Tourette syndrome (TS) Tourette syndrome is a complex neurological condition characterized by involuntary tics. The Centers for Disease Control and Prevention (CDC) estimates that more than 350,000 children in the U.S. have TS, with onset typically occurring between ages five and ten. Though symptoms often improve in adulthood, many individuals experience chronic tics and associated psychosocial challenges. Existing treatments include dopamine D2 blockers, atypical antipsychotics, botulinum toxin injections, cognitive behavioral therapy (CBIT), and deep brain stimulation, but these options are often limited by significant side effects. TS is believed to be influenced by genetic, environmental, and neurochemical factors, including the role of Allopregnanolone in triggering compulsive behaviors. Current treatments target dopamine and other neurotransmitters, but the Company believes Sepranolone’s modulation of Allopregnanolone offers a novel and potentially safer alternative. About Relmada Therapeutics, Inc. Relmada Therapeutics is a clinical-stage biotechnology company focused on developing innovative therapies for central nervous system (CNS) and metabolic disorders. With a commitment to advancing breakthrough treatments, Relmada strives to improve patient outcomes and quality of life. For more information, visit www.relmada.com. Forward-Looking Statements The Private Securities Litigation Reform Act of 1995 provides a safe harbor for forward-looking statements made by us or on our behalf. This press release contains statements which constitute “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Any statement that is not historical in nature is a forward-looking statement and may be identified by the use of words and phrases such as “expects”, “anticipates”, “believes”, “will”, “will likely result”, “will continue”, “plans to”, “potential”, “promising”, and similar expressions. These statements are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described in the forward-looking statements, including potential failure of clinical trial results to demonstrate statistically and/or clinically significant evidence of efficacy and/or safety, failure of top-line results to accurately reflect the complete results of the trial, failure of planned or ongoing preclinical and clinical studies to recapitulate the results of prior studies, potential failure to secure FDA agreement on the regulatory path for Sepranolone or that future Sepranolone clinical results will be acceptable to the FDA, failure to secure adequate Sepranolone drug supply and the other risk factors described under the heading “Risk Factors” set forth in the Company’s reports filed with the SEC from time to time. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Relmada undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Readers are cautioned that it is not possible to predict or identify all the risks, uncertainties and other factors that may affect future results and that the risks described herein should not be a complete list. Investor Contact: Tim McCarthy LifeSci Advisors Tim@lifesciadvisors.com Media Inquiries: Corporate Communications media@relmada.com Released February 6, 2025

基观察-创新药组原创出品 作者 | 武月 在创新药领域，巨头与biotech的竞合博弈从未停止。最近的一场收购风波，更是将这种矛盾推到了风口浪尖。 1月10日，渤健向陷入困境的CNS开拓者 Therapeutics，抛出了4.42亿美元的收购要约。 过去一年，临床试验三连败，股价暴跌、大裁员、高管离职，股价跌至谷底。尽管渤健的报价相比当天收盘价溢价30%，但仍认为被低估了。 一周后，便以违反静默协议为由，将渤健告上了特拉华州大法官法院，寻求法院颁令强制执行一项停滞协议，阻止渤健继续推进收购行动。 从合作伙伴到对簿公堂，这背后，是渤健试图通过抄底来巩固其在CNS领域的布局，则不甘心就此被收购。他们认为，即使在困境中，独立性依然是公司未来发展的关键。 每一起收购案都是一场没有硝烟的战场，谈判桌上你来我往的交锋，各种商业手段很常见。毕竟，大家都希望各自利益最大化。而像这样直接起诉的，不多见。 无论是为了独立，还是提高收购价格，或许都意味着，渤健这起抄底行动，不会那么顺利了。这场法律博弈不单是商业利益的争夺，也是对biotech独立性的一次拷问。在动荡之中，biotech到底是选择被收购上岸，还是在困境中坚持独立发展呢？ / 01 / 憧憬 渤健的抄底意图，十分明显。 与渤健，原本是亲密的合作伙伴。 2020年，双方初次合作，共同开发和商业化两款CNS产品：用于治疗产后抑郁症（PPD）/重度抑郁症（MDD）的Zurzuvae，以及治疗原发性震颤的SAGE-324。 根据协议，渤健需要支付首付款8.75亿美元，后续最高16亿美元的里程碑付款，以及溢价40%（104.14 美元/股）的股权投资。 仅这笔交易的首付款，就是此次收购报价的两倍，更不用说渤健当初斥资6.5亿美元拿到 10%的股份。 目前，双方就Zurzuvae的合作仍在进行，渤健拥有该药物美国以外市场（除日本、中国台湾及韩国）的开发及商业化权益。 这也是的核心商业化产品。拥有两款商业化产品，一款是Brexanolone，另一款就是Zurzuvae。两者均是治疗PPD的产品，而后者是前者的迭代产品。 根据财报显示，Zurzuvae在2024年第三季度的销售额为1100万美元，呈增长趋势，而Brexanolone销售额仅有80万美元，同比下降70%。鉴于此，已与去年底决定将Brexanolone退出美国市场。 在研管线方面，由于核心管线Dalzanemdor先后在帕金森、阿尔茨海默病、亨廷顿病领域尝到三次败绩，公司也于去年10月宣布终止该药物开发。 随着Dalzanemdor的研发终止，剩余管线仅两款，且价值不高。针对社交互动障碍开发的 SAGE-319 目前处于I期，另一个项目就是渤健斥巨资引进的SAGE-324。 去年7月，SAGE-324在用于治疗原发性震颤的二期研究中未达主要终点，9月被渤健退货。 重重打击之下，为了生存，决定裁员和大规模重组，裁掉了约三分之一的员工，包括其首席财务官和首席技术与科学官在内的五名高管离职。尽管核心产品看点不少，商业化表现却差强人意，但还是希望通过精简运营，来靠Zurzuvae翻身。有分析师认为，Zurzuvae明年的销售额将达1亿美元。 只不过，市场并不买账。 股价一路暴跌，2024年其股价跌去74.94%，较最高点一度跌去了97%。如果渤健想要拿到Zurzuvae的全部效益，眼下正是好时候。 / 02 / 自救反击 1月10日，渤健宣布将以每股7.22美元的非约束性报价，收购。这一报价，相比前收盘价（5.5美元/股），溢价30%。 对于渤健来说，收购不仅能使其完全掌控Zurzuvae这一具有潜力的药物，还能进一步巩固其在CNS领域的布局。渤健近年来面临自身业务的挑战，包括多发性硬化症药物的市场压力和阿尔茨海默病药物Leqembi的缓慢增长。日前，渤健也正在对其研发部门进行调整，希望将资源转移到“外部机会”上。 在要约中，渤健CEO Chris Viehbacher更是直言，这笔交易是公司的优先事项，“我们坚信Biogen将是公司业务的合适管理者”，并称这是对股东具有吸引力的交易。 然而，并不这么认为，为了阻止渤健进一步收购行动，不惜与之对簿公堂。 核心在于，认为渤健的报价太低了。表面看，渤健的报价相比前收盘价溢价30%，总估值4.42亿美元。 但事实上，经历重大重组后，的财务状况比较稳健。截至2024年三季度末，公司账上总现金达5.69亿美元，提出7000万美元左右的负债后，净现金也达到4.99亿美元。 这意味着，如果完成收购，渤健不仅能获得Zurzuvae全部权益，还能得到约5亿美元的净现金。 考虑到渤健目前还持有约10%的股份，如果全资收购，也只需要在支付4亿美元左右。从小股东变大股东，里外仅现金就白赚1亿美元。 难怪海外分析师认为渤健的收购意图在财务方面很精明，但对解决公司更广泛的管道问题几乎没有帮助，因为的早期资产不太可能“成为渤健的关键差异化因素”。 Zurzuvae是新一代的γ-氨基丁酸（GABAA）受体的正向变构调节剂。大脑中的GABAA受体和NMDA（N-甲基-D-天冬氨酸）受体分别发挥抑制和刺激大脑神经元产生神经冲动的作用，这两种受体活性之间的失衡是包括抑郁症在内的多种精神疾病的原因。 Zurzuvae能够同时调节位于神经突触内和突触外的GABAA受体的功能，恢复大脑内前述两种受体活性间的平衡，因此具有治疗包括抑郁症在内的精神疾病的潜力。并且，Zurzuvae是首款产后抑郁口服药，相比Brexanolone需要注射60个小时，其在副作用和依从性管理上有显著优势。尽管售价不菲，但得益于纳入医保，去年三季度卖出了2200万美元。 不过，由于关键适应症MDD未能获得FDA批准，仅获批用于PPD，极大限制了其市场潜力。这也让外界对Zurzuvae多有诟病，认为这款产品入不敷出，投入过多。 困境之中，仍希望孤注一掷，停掉Zurzuvae其他临床，全力推进PDD商业化。为此，其选择了起诉渤健。 / 03 / 独立之问 实际上，翻看双方的合作经历和现在处境，无论是渤健，还是都有主张最大化自身权益的必要性。 渤健出价低也不难理解。当初其对的投入可谓大手笔，十几亿美元砸下去，本指望在Zurzuvae上大赚一笔。然而，现实却给了渤健当头一棒：押注的管线之一临床试验彻底失败，管线之二的商业化也不及预期。 如今，渤健希望通过低价收购，不仅能拿到账上的大笔现金，还能完全掌控Zurzuvae的商业化开发。渤健CEO认为，由渤健完全控制将“实现Zurzuvae的更精简操作和高效的商业执行”。 换句话说，这起收购纠纷本质是股东对公司代理权的争夺，渤健认为靠自己能让Zurzuvae卖得更好。 根据此前协议，渤健和共同负责Zurzuvae在美国地区的开发，渤健独立负责美国以外的市场开发和商业化。分成比例为五五开。 这样“优渥”的条件达成背后，无疑是对Zurzuvae前景的自信，以及渤健对Zurzuvae寄予厚望，希望能够在产后抑郁以外的适应症获得批准，尤其是期待重度抑郁症。 重度抑郁症市场要比产后抑郁症要大不少，强生日前披露的数据为，美国大约有2100万成年人患有MDD。外界曾普遍预期Zurzuvae会变成一颗“重磅炸弹”。 然而，这一预期随着FDA的拒绝而落空。 尽管如此，对于陷入“中年危机”的渤健来说，Zurzuvae仍值得抢救一番。此前，BMO估计，到2030年，将有近2.4万名美国女性接受Zurzuvae治疗，销售额将达到5.67亿美元。 而根据渤健最新财报，去年前三季度Zurzuvae销售额不足5000万美元。 显然，还有很大的增长空间。 这或许也是不惜与之对簿公堂的原因。 手握首款产后抑郁口服药，不甘心就这样被收购，尤其是被低价抄底。 众所周知，CNS领域研发难度极高，相应的回报也极为丰厚。无论是近期强生146亿美元收购Intra-Cellular，还是艾伯维83亿美元收购Cerevel、BMS140亿美元收购Karuna，都足以证明。 而即使在困境中，认为独立性依然是公司未来发展的关键。就在三季报中，还表示正在努力推动Zurzuvae成为PDD一线、标准疗法。 作为一家成立超10年，历经浮沉的biotech来说，或许不想错过Zurzuvae带给其跃迁的机会。事实上，从最初与渤健达成共同在美国开发、五五分成的协议也能看出，不想只是做一家“纯粹”的biotech。 尽管独立需要面对从研发到商业化的重重挑战，但最大的好处，是能够创造无限可能。这也是目前不少biotech的心声。 这场收购纠纷的走向，或许也将为我们提供一个重要的启示：面对巨头的强大优势，biotech的独立性究竟有多重要？ PS：欢迎扫描下方二维码，添加氨基君微信号交流。