CDKL5

Today, a brief rundown of news from GSK and Amgen, as well as updates from Roche, AbbVie, and Marinus Pharmaceuticals that you may have missed.Amgen set a list price of $1,665 per shot for its biosimilar version of Regenerons Eylea, a 10% discount from the eye drugs current wholesale cost, RBC analyst Brian Abrahams wrote in an Oct. 25 note to clients. On Tuesday, Amgen said it would launch its biosimilar, branded Pavblu, without a legal settlement with Regeneron following a court decision that lifted a temporary injunction on its launch. Such at risk launches are uncommon, and could result in steep penalties for Amgen if subsequent legal judgments side with Regeneron. The small discount means the market impact of Pavblu may be more muted than Amgen investors feared, Abrahams wrote. Further price erosion could occur when additional biosimilars launch. The FDA has approved four others. Jonathan GardnerGSK is making its largest investment in U.S. manufacturing, committing $800 million to expand a site in Marietta, Pennsylvania with new drugmaking facilities. One will handle production of sterile liquid vaccines and medicines, and should be ready by the end of 2028. Another will include a drug substance facility set to start operations by the end of 2027 as well as a pilot plant for making clinical trial medicines. Ned PagliaruloRoche has inked a second research collaboration with gene therapy specialist Dyno Therapeutics. The companies originally linked up in 2020 and, similar to that deal, the one announced Thursday revolves around neurological diseases. Roche and Dyno think the latter's technology can be used to create better “viral vectors“ the microscopic tools that shuttle genetic medicines to a desired target. The new deal tasks Dyno with designing these improved vectors, which will then be applied to potential gene therapies for nervous system disorders. Roche will be responsible for testing the therapies and, if they make it to the market, selling them. Dyno is getting $50 million upfront, plus research payments. It's also eligible for royalties on resulting products, and could nab north of $1 billion more by hitting certain milestones. Jacob BellLongtime partners AbbVie and Gideon Richter are working together on another brain-focused project. Through a sparsely detailed agreement announced Thursday, the companies hope to discover new targets that could be used to treat neuropsychiatric conditions. They plan to share the costs of the necessary research and development. Richter will receive $25 million upfront, and could take home more through milestone and royalty payments. AbbVie, meanwhile, will get worldwide rights to programs that advance to commercialization, except in traditional markets of Richter, such as Europe and Russia. Jacob BellMarinus Pharmaceuticals will lay off staff, cut costs and consider strategic alternatives, after results from a Phase 3 study showed the companys seizure drug ganaxolone did not meet the trials goal. On Thursday, Marinus said the data, while finding nominal reductions in seizure frequency that favored ganaxolone, were likely not enough to support an approval application. The study tested ganaxolone in people with epilepsy related to tuberous sclerosis complex; the drug is already cleared for use treating seizures in people with a condition called CDKL5 deficiency disorder. Ned Pagliarulo '

Marinus Pharmaceuticals is reducing its workforce again and taking other measures to reduce costs after its epilepsy treatment failed a late-stage trial. The TrustTSC trial investigating oral ganaxolone for the treatment of seizures associated with tuberous sclerosis complex (TSC) missed the primary endpoint of percent change in TSC-associated frequency of seizures at 28 days. While there was a reduction in seizures in the treatment arm, the results weren’t statistically significant. The median reduction in seizure frequency was 19.7% for patients on ganaxolone compared with 10.2% for placebo, earning a p-value of 0.09. The company’s stock $MRNS tumbled on Thursday morning, dropping about 80%. “We are disappointed that the results of the TrustTSC trial are not likely to be sufficient for an sNDA filing,” Marinus CEO Scott Braunstein said in a statement . Marinus now plans to discontinue all clinical development of ganaxolone, and it started a “strategic alternatives” process that includes layoffs. The company didn’t specify how many employees it would let go. As of Dec. 31, Marinus had 165 full-time employees, though it cut about 20% of its workforce in May when it also implemented other cost-reducing measures. Since 2022, ganaxolone has been approved as Ztalmy for the treatment of seizures associated with CDKL5 deficiency disorder.

近日，丹麦灵北制药宣布以每股60美元的现金收购Longboard Pharmaceuticals所有已发行股份进行要约收购，在完全稀释的基础上，该交易的股权价值约为26亿美元。 此次收购的核心资产，是Longboard的癫痫治疗药物Bexicaserin，这是一种新型5-HT2C受体激动剂，在早期试验中Bexicaserin显现出卓越疗效，显著减少了一组难治性的癫痫疾病的发作频率，这一成果推动了Longboard股价飙升。 01 一条抗罕见癫痫管线， 市值翻了近10倍 Longboard由Arena Pharmaceuticals于2020年1月成立，旨在推进一系列对特定G蛋白偶联受体（GPCR)具有高度选择性的中枢作用候选产品。Longboard的小分子候选药物是在与Arena公司20多年GPCR研究成果的同一平台上发现并筛选的。 Longboard主要专注于开发针对神经系统疾病的新型变革性药物，其中LP352和LP659两条管线均是通过与Arena签订许可协议获得的。 Longboard Pharmaceuticals管线 图片来源：Longboard官网 进展最快的Bexicaserin（LP352）是一种口服、中枢作用的5-HT2c受体超级激动剂，正在开发用于治疗与DEE（发育型和癫痫性脑病）相关的癫痫发作，例如Dravet综合征、Lennox-Gastaut综合征、结节性硬化症、CDKL5缺乏症和其他癫痫性疾病。 在临床前研究中，LP352对5-HT2b和5-HT2a受体亚型的影响可以忽略不计（5-HT2b和5-HT2a受体激动作用与显著的不良反应有关）。LP352具有新颖的化学性质和属性，对5-HT2c受体亚型更具特异性和选择性，通过调节GABA抑制，从而抑制癫痫发作特有的过度兴奋，并减少DEE患者的癫痫发作，同时可降低其他5-HT2靶向药物的已知安全风险。 2024年1月，Longboard公布了临床试验1b/2a期研究（又称PACIFIC研究）的积极顶线数据，疗效数据显示： （1）主要疗效终点：在DEE研究人群中，Bexicaserin使可数运动性癫痫发作的中位数减少53.3%，这是一个显著的疗效指标。 （2）安慰剂校正效果：与接受安慰剂治疗的受试者相比，Bexicaserin治疗组的癫痫发作频率降低更为显著，经安慰剂校正后降低32.5%。 （3）亚组分析：在Dravet综合征、Lennox-Gastaut综合征和其他DEE亚组中，Bexicaserin同样显示出积极的疗效，中位数降低分别为72.1%、48.1%和61.2%。 （4）安全性和耐受性：不良事件：Bexicaserin表现出良好的安全性和耐受性。观察到的最常见不良事件包括嗜睡、食欲减退、便秘和腹泻，这些通常可以通过医疗干预进行管理。 值得一提的是，从2024年年初开始，Longboard的股价就一路上涨，截止2024年9月，上涨了498.3%，与年初的1.4亿美元左右市值相比，公司市值最高涨了近10倍（市值达到14.03亿美元）。 Bexicaserin目前正在进行针对2岁及以上Dravet综合征患者的3期临床试验，同时，针对Dravet综合征和Lennox-Gastaut综合征等罕见癫痫疾病的1b/2a期临床试验的开放标签扩展也在进行中。 Longboard的另一个在研管线LP659是一种口服、中枢作用的下一代S1P受体亚型1和5（S1PR1和S1PR5）调节剂，该药物目前处于1期临床试验阶段，未来可能用于多种神经系统疾病的治疗。 自成立以来，Longboard一直处于亏损状态，此次被灵北制药收购，相信在强大资金流的支持下，其未来也能获得更稳健的发展，也将积极推动Bexicaserin的临床开发和商业化。 对灵北而言，Bexicaserin资产补充了其中后期管道，进一步巩固了其在神经罕见病治疗领域的领导地位，并且届时如果能顺利获批上市将为其注入新的盈利增长点，灵北估计Bexicaserin全球销售潜力峰值在15亿-20亿美元之间。 02 5-HT2C受体：高潜力靶点 发育性和癫痫性脑病综合征(DEEs)，是一组罕见的神经系统疾病，通常在儿童时期发病，影响大脑的发育和功能。这些疾病通常会导致多种类型的癫痫发作、认知障碍、运动障碍和行为问题。DEEs是一组异质性的疾病，包括多种不同的综合征，每种都有其特定的遗传原因、临床表现和治疗需求。 治疗DEE的抗癫痫药物包括氯巴占、氨己烯酸、唑尼沙胺、苯巴比妥、苯二氮卓类药物、氨己烯酸等；同时，对于药物控制不佳的DEE患儿，类固醇疗法、迷走神经电刺激、生酮饮食和癫痫切除手术也是可选择的治疗手段。 目前大多数DEE患者采用多种药物联合治疗，并随时间更换药物（平均2-4种抗癫痫药物+额外的非药物治疗），但几乎所有DEE患者都经历了多次癫痫发作和治疗相关的副作用。DEEs治疗领域存在挑战和未满足的医疗需求，对于这些疾病的患者来说，现有的治疗方案还远远不够，需要更多更好的治疗选择。 虽然优时比制药的Fintepla（芬氟拉明）和爵士制药的Epidiolex是较新的癫痫药物，可为Dravet综合征和Lennox-Gastaut综合征(DEE的两种形式)提供替代治疗方案。但两者都有其局限性。Fintepla是一种5-HT2激动剂，但它对密切相关的受体具有额外的活性，从而导致不良反应。该药物的标签上有一个黑框警告，该药物的活性成分与瓣膜性心脏病和肺动脉高压的风险有关。Epidiolex治疗癫痫的作用机制则尚不清楚。 5-HT2C受体是一种G蛋白偶联受体(GPCR)，它与5-羟色胺(5-HT)结合。5-HT2C受体已被确定为治疗肥胖和其他中枢神经系统(CNS)疾病(如精神分裂症和药物成瘾)的有效药物靶点。但5-HT2C受体与其他两个5-HT2亚型(5-HT2A和5-HT2B)具有约50%的序列相似性，因此导致大量药物存在脱靶效应或因选择性差从而与其他亚家族成员受体5-HT2A和5-HT2B结合产生幻觉和心脏瓣膜病等副作用。 5-HT2C受体与DEEs的关联：（1）神经递质调节：DEEs患者常表现出异常的神经递质活动，5-HT2C受体作为神经递质调节的关键点，可能影响癫痫发作的频率和强度。（2）抗癫痫作用：一些研究表明，5-HT2C受体的激活可能具有抗癫痫的潜力。通过调节这一受体，可能有助于减少癫痫发作。因此，开发高选择性5-HT2C受体激动剂，作为潜在治疗DEEs药物十分具有前景。 03 结语 此次重金收购Longboard标志着灵北制药在脑部疾病治疗领域迈出了重要一步，进一步巩固了其在神经罕见病治疗领域的领导地位。希望该款药物能进展顺利，为癫痫症患者带来更多希望。 参考资料： 1.Longboard Pharmaceuticals官网 2.《一条抗癫痫管线，带动市值10倍涨幅！》，求实药社 声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。 责任编辑 | 史蒂文 转载开白 | 马老师 18996384680（同微信） 商务合作 | 王存星 19922864877（同微信）  阅读原文，是受欢迎的文章哦