Dalzanemdor

Nearly six months ago, PTC Therapeutics reported positive interim data for a drug in mid-stage development for Huntington’s disease, an inherited neurological disorder with limited treatment options and a history of stymied drug research efforts. The PTC drug’s data readout prompted another company to make an unsolicited bid for the program. Rather than jump at the offer, PTC decided to see if others might also be interested in the asset. Novartis has won this competitive process. On Monday, the companies announced the Swiss pharma giant is paying $1 billion up front to license global rights to the PTC Huntington’s drug, PTC518. PTC is still responsible for completing the ongoing placebo-controlled portion of the Phase 2 test of PTC518, and the Warren, New Jersey-based biotech will lead planned discussions with the FDA later this month to discuss the Phase 3 clinical trial. Novartis will take over the program for its pivotal study and is also responsible for the drug’s manufacturing and commercialization, though the deal calls for the companies to share profits from U.S. sales of an approved product — 60% to Novartis and 40% to PTC. The biotech is in line for up to $1.9 billion in milestone payments from Novartis plus royalties from sales of the drug in other markets. This deal is expected to close in the first quarter of 2025. Exclusive Heard at HLTH 2024: Insights from Innovative Healthcare Executives Executives from Imagine360, Verily, BrightInsight, Lantern, and Rhapsody shared their approaches to reducing healthcare costs and facilitating digital transformation. By MedCity News Huntington’s stems from a genetic mutation that leads to defective versions of huntingtin, a protein key to neuronal function. Mutated huntingtin causes neuronal damage and cell death that affects movement, speech, and swallowing. The disease also leads to behavioral, cognitive, and motor symptoms. Drugs used to treat Huntington’s address certain disease symptoms. There are no approved therapies that delay Huntington’s onset or slow its progression. PTC518 is a small molecule that affects the splicing of messenger RNA in order to reduce levels of a target protein. The drug comes from the same PTC technology that yielded Evrysdi, an mRNA-splicing drug that won FDA approval in 2020 as a treatment for the rare muscle disease spinal muscular atrophy (Evyrsdi is marketed by Roche under a partnership). The PTC518 data that prompted deal interest from other companies are interim results from a Phase 2 test showing the once-daily tablet led to dose-dependent lowering of mutant huntingtin protein in the blood and cerebrospinal fluid. The company also reported favorable trends on several clinical assessments of Huntington’s. PTC said the drug was safe and well tolerated by study participants. Additional Phase 2 data are expected in the second quarter of 2025. Huntington’s drug research has yielded many disappointments. In 2021, Roche halted a Phase 3 test of tominersen at the recommendation of the trial’s independent data monitoring committee. The drug candidate, an antisense oligonucleotide from Roche’s partnership with Ionis Pharmaceuticals, is designed to bind to mRNA in order to prevent production of mutant huntingtin. Roche has not given up on this drug entirely. In 2022, the pharma giant revealed plans for a new Phase 2 trial in younger Huntington’s patients with less severe disease. More recently, Sage Therapeutics reported it would stop dosing of dalzanemdor, a small molecule that had reached Phase 2 testing in Huntington’s. The November decision was based on the recommendation of independent observers of the clinical trial. Novartis has also experienced disappointment in Huntington’s. Its internally discovered drug candidate, branaplam, was initially developed as a treatment for spinal muscular atrophy before the company changed the small molecule’s focus to Huntington’s. In 2022, Novartis suspended dosing of branaplam after findings suggested the experimental drug may have caused peripheral neuropathy in some study participants. The mid-stage study was subsequently discontinued. presented by Market Trends to Watch for Health Systems and Their Specialty Pharmacies The future looks bright for the integrated specialty pharmacy model – for health systems, providers, and most importantly, for patients. By Jake Gaffey, MBA, Chief Strategy Officer at Shields Health Solutions In a note sent to investors, Leerink Partners analyst Joseph Schwartz said Novartis seems like a logical partner for PTC518, as branaplam’s approach to Huntington’s was similar to the PTC drug. In a Monday conference call, PTC executives said besides Novartis’s competitive financial offer, the pharma giant was selected because of its experience developing neuroscience drugs. William Blair analyst Sami Corwin wrote in an investor note that the deal makes financial sense for PTC, which last week struck a $150 million deal to sell the priority review voucher (PRV) it received for the recent FDA approval of gene therapy Kebilidi for an inherited enzyme deficiency. She said PTC now has additional funds to support its drug portfolio without needing to also pay for a pivotal clinical trial. “We see the $1 billion upfront payment, in addition to the $150 million PRV sale, as providing the company with sufficient financial funds to reach cash flow break even in the future without the need to raise additional funds,” Corwin said. “In addition, the deal provides PTC with a strategic partner that has experience developing drugs for CNS-based diseases, which could accelerate the clinical development and bolster the commercialization of PTC518, in our view. We also see the deal as validating PTC518 and PTC’s splicing platform.” In the hands of a big pharma company with neuroscience experience, William Blair gives PTC518 a 50% probability of success, modeling peak revenue of $5 billion, about $1.43 billion of which would go to PTC. In the nearer term, PTC is preparing to meet with the FDA later this month to discuss the design of the Phase 3 study. Schwartz noted that PTC is seeking alignment with the regulator on using lowering of huntingtin levels as a potential surrogate endpoint to support accelerated approval. This endpoint could also serve as the primary endpoint of a Phase 3 study supporting a traditional approval.

欢迎参加2024肝病新药联盟年会暨减重新药论坛！ 是抄底良机，还是巨石天坑？ 传奇对冲基金Baker Brothers表示，十分理解Biogen。 今年第三季度，Baker Brothers清仓了Sage Therapeutics。据悉，Baker Brothers刚在今年第一季度建仓。 Baker Brothers是百济神州的“二股东”，其持股比例仅次于大股东安进。今年6月，还入股了康方的合作伙伴Summit。 仅隔一个季度，Baker Brothers就“风紧扯呼”，意味着其投资判断出现了失误，“你以为是谷底，实际却在半山腰。” 无独有偶，四年前的Biogen以31.25亿美元的价格（包括股权投资：104.14 美元/股，溢价40%），引进Sage两款CNS候选产品时，也曾想着“抄底”一波。 如今，Sage股价“很美”，报5.17美元/股。 0-3完败 2024年11月20日，Sage第三次宣布了Dalzanemdor（SAGE-718，以下简称718）的临床失败，在用于治疗亨廷顿病（HD）的II期试验中，未达主要终点， 今年4月，Sage公布718的首次失败，在用于治疗帕金森病相关认知障碍的II期试验中，未达主要终点，该适应症被放弃开发； 今年10月，Sage公布718的第二次失败，在用于治疗阿尔茨海默病（AD）的II期试验中，同样未达主要终点，AD适应症也被放弃。 与所有在研适应症交手后，718 0-3完败，Sage最终宣布终止该药物开发。 718是一款NMDA受体（N-甲基-D-天冬氨酸）正向变构调节剂。NMDA受体是中枢神经系统发育的重要组成部分，其作用是控制突触可塑性，介导学习和记忆功能。 如果NMDA受体被过度激活，会导致Ca2+过量流入神经元，引起细胞死亡，这种现象被称为兴奋毒性，而兴奋毒性又与神经退行性病变（中风、帕金森、老年痴呆等）有关。 反之，当NMDA受体被阻断时，会改变突触间的信号传递，导致幻听、认知障碍、精神分裂等。 那么理论上，只要合理控制NMDA受体的活性，便可治疗由此（NMDA受体过度激活/阻断）引发的一系列疾病。 据不完全统计，全球针对该靶点在研药物超过200种，其中关于NMDA受体负向异构调节剂的相关研究较为成功，氯胺酮、Auvelity（右美沙芬+安非他酮）被广泛用于抑郁症治疗。 至于NMDA受体正向异构调节剂，718就是全球首创（FIC），他的失败将影响着市场对所有NMDA受体正向异构调节剂在研药物的看法。 穷途末路？ 随着主要资产718的研发终止，Sage剩余管线相对较少，且价值不高。针对社交互动障碍开发的 SAGE-319 目前处于 I 期，而另外两个项目（689/421）正处于临床前开发阶段。 至于SAGE-324，就是文章开头Biogen斥资30多亿引进的产品之一。该药物于今年7月，在用于治疗原发性震颤（ET）的二期研究中未达主要终点；今年9月，324被Biogen退货，该药物的后续开发仍在评估（如有）。 目前，唯一能支撑起Sage运转下去的，就只剩下两款商业化产品Brexanolone与zuranolone，两者均是治疗产后抑郁症（PPD）的产品，zuranolone算是Brexanolone的迭代产品。 如今，Brexanolone销售额不断下滑，2024年Q3单季度，仅卖出80万美元，同比下降70%。且Sage官网介绍，该药将于2024年12月31日起终止在美销售。 至于zuranolone虽然2024年Q3单季度，卖出1100万美元，比Brexanolone强，但需要与Biogen一起分钱，Biogen拥有该药物美国以外市场（除日本、中国台湾以及韩国）的开发及商业化权益。（这就是30多亿美元引进的第二款产品）。 截止2024年9月30日，Sage 拥有 5.69 亿美元的现金、现金等价物和有价证券，加上近期两轮重大裁员，以及终止718节省下的成本，现金流仍算健康。 穷途末路倒不至于，只是，未来Sage的路将怎么走，将不得而知。 封面图来源：pixabay 把握时代机遇，攻克肝病顽疾！— 2024肝病新药联盟年会暨减重新药论坛（第一轮通知） 往期推荐 定了！特朗普公布FDA局长人选 11亿美元！诺华重磅加码「细胞与基因疗法」 进军非洲市场！没有专利也可以~ | 药时代BD项目 版权声明/免责声明 本文为原创文章。 本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。 文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。 如有任何问题，请与我们联系。 衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 点击查看更多精彩!