Risdiplam

作者：布布 2024年终制药领域再出收购大单，诺华斥资10亿美元预付款获取了美国制药公司PTC Therapeutics的亨廷顿舞蹈症（Huntington's disease, HD）药物PTC518的许可。如果达到特定开发、监管和商业里程碑，PTC还有可能从诺华获取19亿美元的潜在付款。 在完成正在进行的 PIVOT-HD 安慰剂对照部分（预计于 2025 年上半年完成）后，诺华将负责 PTC518 的开发、制造和商业化。两家公司将按 40/60 的比例（40% PTC 和 60% 诺华）分享美国市场的利润。预计该交易将于 2025 年第一季度完成。 01 亨廷顿舞蹈症是什么 亨廷顿舞蹈症（Huntington's disease, HD）是一种遗传性神经退行性疾病，主要影响大脑的神经元，导致运动、认知和精神功能的逐步恶化。HD是HTT基因中的突变导致的，该基因位于4号染色体上，编码亨廷顿蛋白。突变使得基因中产生异常的CAG重复序列，导致亨廷顿蛋白的异常积累，从而损害神经细胞，特别是大脑中控制运动的区域。HD是一种致命的遗传病，其症状类似于阿尔茨海默病、帕金森病和肌萎缩侧索硬化症（渐冻症）。 和其它众多神经退行性疾病一样，HD患者的大脑大多数在成年早期就开始出现了问题，HTT基因中重复的CAG序列导致大量亨廷顿蛋白的产生以及在神经元中的积累。罹患这种神经元疾病的患者在后期会大量死亡，尤其是控制运动的纹状体中的神经元。阿尔茨海默病患者的大脑整体萎缩，而亨廷顿病患者的纹状体位置则出现了一个洞。全球每十万人中就有3人会携带HTT基因。遗传这种疾病的人通常在 30 多岁或 40 多岁时开始出现症状，开始行走困难，四肢不由自主地抽搐，失去协调性，并过早死亡。但也有少年型亨廷顿病，早发于青少年时期。  HD的主要症状包括： · 运动症状：舞蹈症样不自主运动、肌肉僵硬、协调性差、步态异常。 · 认知症状：记忆力下降、注意力集中困难、决策能力减弱。 · 精神症状：抑郁、焦虑、易怒、行为和情感不稳定。 HD之所以被称为“舞蹈症”，是因为其主要的早期症状之一是舞蹈症样不自主运动（chorea）。这种症状表现为快速、无规律且不受控制的抽动或扭动，患者的动作看起来像是在跳舞一样，尤其是在四肢、面部和身体其他部位。 02 命运多舛的HD疗法开发 HD目前仍然处在无药可治的状态，此前众多的开发商在开发HD药物都遭遇了挫折，包括诺华。HD目前没有治愈方法，只有一些药物可以帮助缓解症状。但人们认为，降低突变基因导致的亨廷顿蛋白的水平就可以阻止纹状体神经元的大量丧失。然而在PTC518出现之前，几乎所有的HD药物开发都以失败而告终。 2021 年 3 月，罗氏公司终止了其亨廷顿蛋白降低疗法 tominersen 的 3 期研究，因为此疗法被证明无效。一周后，Wave Life Sciences 同样终止了他们两款HD候选药物，因为它们在早期试验中未能充分降低亨廷顿蛋白水平。HD开发一周之内遭遇两次暴击。 2022年8 月，诺华的HD候选药branaplam的2b期临床研究VIBRANT-HD也以失败告终，主要原因是外周神经损伤副作用。终止研究的决定是独立数据监测委员会 (DMC) 在数据审查后提出的，并得到了 VIBRANT-HD 指导委员会的认可。诺华在branaplam上的壮志未酬也解释了他们总价29亿美元收购PTC的HD中期资产的动机。 03 PTC518: HD疗法的新希望 PTC518 是一种口服小分子药物，可减少突变亨廷顿蛋白的产生。PTC518可穿透血脑屏障，具有选择性、可计量调节，且不会外排。 FDA在2024 年 9 月 26 日授予了PTC518 计划快速通道资格。快速通道资格通常授予有前途的、治疗高度未满足需求的疾病的疗法。 2024 年 6 月，PTC 宣布了 PTC518 在亨廷顿病患者中12 个月的中期研究PIVOT-HD的积极临床数据。结果显示，12个月后，HD患者血细胞中突变型亨廷顿蛋白含量出现持久的剂量依赖性下降。10 mg剂量组的下降水平达到43%。同时脑脊液中亨廷顿蛋白的剂量依赖性降低与血液中的水平相似。 此外， 12 个月的关键疾病测量值（包括总运动评分和 cUHDRS 量表）良好。中期结果还表明 PTC518 安全且耐受性良好，没有治疗相关的 NfL （神经丝蛋白，神经损伤相关的生物标志物）峰值。 PTC518 是使用 PTC 的创新剪接平台发现的。PTC依托此平台成功开发了脊髓性肌萎缩症的小分子药物Evrysdi (risdiplam)。Evrysdi是第一款获批的直接影响剪接的小分子药物，可产生稳定、有功能的 SMN 蛋白。Evrysdi的成功也被视为小分子药物靶向mRNA的里程碑事件。PTC518的发现同样是建立在PTC的剪切技术平台之上的。PTC518 导致不完全外显子（称为伪外显子）的剪接，从而阻止完整亨廷顿蛋白的产生并导致 HTT mRNA 快速降解。 PTC518不仅在发现平台上与Evrysdi一样，商业化的道路上也选择了与大公司合作的策略。罗氏获得了PTC对Evrysdi的特许权。2024年前三季度销售额为12亿瑞士法郎（13.5亿美元），为PTC创造了6140万美元的第三季度特许权使用费（2023年第三季度特许权费用为5020万美元）。 PTC518的发现和开发具有重要的前景和意义。作为一款针对HD的创新药物，PTC518利用PTC独特的剪接技术平台，通过调控mRNA剪接，抑制亨廷顿蛋白的生成，为HD患者提供了潜在有效的治疗方法。HD目前缺乏有效的治疗方法，而PTC518的潜力在于通过精准的剪接干预，能够减缓或阻止神经退行性病变的进展，带来显著的临床益处。 此外，PTC518的成功研发也代表了小分子药物在靶向mRNA剪接领域的进一步突破，预示着这一平台的广泛应用潜力。随着该药物在临床试验中的进一步推进，若能够证明其在HD中的疗效，PTC518可能成为该领域的首个有效治疗药物，极大地推动罕见神经退行性疾病的治疗创新。 从商业化角度来看，PTC518的成功可能会延续Evrysdi与罗氏的合作模式，推动与大公司合作的策略，进一步提升PTC在全球市场的影响力，并为公司带来可观的收入来源。 Ref. Molteni, M. On the long road to treating Huntington’s genetic stutter, scientists return to overlooked clues. STAT. 30. 11. 2022. Joseph, A. Huntington’s community grieves not just one therapeutic setback, but two. STAT. 13. 04. 2021. Branaplam : VIBRANT-HD Study Update. Novartis Press Release. 25. 08. 2022. FDA Grants Fast Track Designation to PTC518 Huntington's Disease Program. PTC Therapeutics Enters into a Global License and Collaboration Agreement with Novartis for PTC518 Huntington's Disease Program. PR Newswire. 02. 12. 2024. Sheridan, C. First small-molecule drug targeting RNA gains momentum. Nature Biotechnology. 39, pages 6–8 (2021). Joseph, A. Novartis to pay $1 billion upfront to license Huntington’s drug from PTC. STAT. 02. 12.2024. 关于贝壳社 贝壳社是国内领先的医健创新创业服务平台，为医健创业者提供全路径创业服务。通过产业空间运营、创业教育、投资孵化、数字化赋能、企业价值增长等服务体系，给医健创业企业提供产业空间、人才战略培养、投融资、产业生态资源、数字化转型等服务。同时，贝壳社布局澳洲，帮助国内生物医药企业加速走向海外；成立“泰格-泰珑-贝壳社企业经营服务中心”为企业成长提供全生命周期的增值服务，提高企业运营效率，加快企业成长发展。我们深度链接政府、科研院所、临床机构、投资机构、第三方服务商、CXO等行业资源，致力于赋能医疗健康创业公司成长，推动创新技术造福人类生命健康。 往 期 推 荐 1 “水土不服”的阿托品 2 时代的脚步已走到TCE双抗爆发的前夜 _ 3 药王放了个大 _ *声明：本文仅为作者观点，不构成任何投资建议，且非治疗方案推荐。 投稿请添加小助手：bioclub666

– PTC to receive $1.0B in cash at closing – – PTC is eligible to receive up to $1.9B in development, regulatory and sales milestones – – PTC to share profits in the U.S. and tiered double-digit royalties on ex-U.S. net sales – – Novartis will assume global development, manufacturing and commercial responsibilities following completion of placebo-controlled portion of ongoing PIVOT-HD study – – PTC will host a conference call on Dec. 2, 2024, at 8:30 am EST- WARREN, NJ, USA I December 2, 2024 I PTC Therapeutics, Inc. (NASDAQ: PTCT ) announced today the signing of an exclusive global license and collaboration agreement with Novartis Pharmaceuticals Corporation, a subsidiary of Novartis AG (NYSE: NVS ), for its PTC518 Huntington’s disease program, which includes related molecules. Under the agreement, PTC will receive an upfront payment of $1.0 billion, up to $1.9 billion in development, regulatory and sales milestones, a profit share in the U.S., and double-digit tiered royalties on ex-U.S. sales. “PTC518 is the leading oral disease-modifying therapy in development for Huntington’s disease and the economics of this agreement are consistent with the promise of this treatment,” said Matthew B. Klein, M.D., Chief Executive Officer, PTC Therapeutics. “This collaboration combines PTC’s expertise in developing small molecule splicing therapies with Novartis’s expertise in global development and commercialization of neuroscience therapies. We are excited to collaborate with Novartis to accelerate the potential of PTC518 for the hundreds of thousands of HD patients worldwide in need of a therapy designed to be well-tolerated and an effective disease-modifying therapy. PTC will use the proceeds of this transaction to expand our splicing platform as well as to support commercial and development portfolio activities.” “Huntington’s Disease is a devastating, fatal, familial disease. This agreement with PTC is intended to bolster our neuroscience pipeline and reflects our strategic focus and commitment to explore new and potentially transformative approaches for neurodegenerative diseases with high unmet needs,” said Vas Narasimhan, CEO of Novartis. “We look forward to building on our expertise in neurodegenerative diseases and experience in HD with the intention to advance this potential first in class oral therapy for the HD community.” PTC518 was discovered from PTC’s validated splicing platform and is currently being studied in the ongoing Phase 2 PIVOT-HD trial. Interim results reported in June 2024 demonstrated that PTC518 treatment resulted in durable, dose-dependent reduction in blood and cerebrospinal fluid (CSF) mutant Huntingtin protein (HTT) levels as well as early signals of dose-dependent benefit on key clinical measurements at 12 months. 1 Importantly, PTC518 continues to demonstrate a favorable safety and tolerability profile. 1 Novartis will assume responsibility for PTC518’s development, manufacturing and commercialization, following the completion of the on-going placebo-controlled portion of PIVOT-HD, which is expected to occur in H1 2025. The companies will share U.S. profits and losses, on a 40/60 basis (40% PTC and 60% Novartis). The closing of the transaction is subject to customary closing conditions, including regulatory clearance. The parties anticipate that the agreement will close in the first quarter of 2025. Conference Call and Webcast Details: PTC will hold a conference call at 8:30 am EST today to discuss this news. To access the call by phone, please click here to register and you will be provided with dial-in details. To avoid delays, we recommend participants dial in to the conference call 15 minutes prior to the start of the call. The webcast conference call can be accessed on the Investor section of the PTC website at https://ir.ptcbio.com/events-presentations . A replay of the call will be available approximately two hours after completion of the call and will be archived on the company’s website for 30 days following the call. About Huntington’s Disease Huntington’s disease (HD) is a fatal, hereditary, genetic disorder of the central nervous system. 2 It is caused by a defective gene. This gene produces a protein, called Huntingtin, which is involved in the functioning of the nerve cells in the brain (neurons). When the gene is defective, it produces an abnormal (or mutated) Huntingtin protein that is toxic and causes neuron damage and neuron death. 3 HD usually presents in people who are in their 30s or 40s. Symptoms can present earlier in life, and this is called the Juvenile HD. 3,4 There are also cases of infantile HD, when symptoms develop in children who are younger than 10 years old. 3 While symptoms vary from person to person, the disease primarily affects the brain and results in abnormal movements, difficulties with speech, swallowing and walking, as well as a number of other symptoms including behavioral, cognitive and motor symptoms. 5,6 While there are therapies approved for specific disease symptoms, currently, there is no cure for HD and there are no approved drugs that delay the onset or slow disease progression. About PTC’s Splicing Platform PTC has pioneered the use of advanced alternative splicing technology to identify small molecules that affect mRNA splicing for the treatment of disease of high unmet need. PTC’s validated splicing platform identified the first-ever approved small molecule splicing modifier – Evrysdi ® (risdiplam), and PTC has leveraged the extensive learnings from the SMA program to broaden the platform to support discovery programs across numerous therapeutic areas including neurodegenerative disease, oncology and metabolism. PTC has also developed a powerful high-throughput drug discovery platform (PTSeek™) that identifies small molecules that modulate pre-mRNA splicing to upregulate or down regulate targeted protein production, accelerating the discovery and early preclinical development process for candidate small molecule splicing agents. About PTC Therapeutics, Inc. PTC is a global biopharmaceutical company focused on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to children and adults living with rare disorders. PTC’s ability to innovate to identify new therapies and to globally commercialize products is the foundation that drives investment in a robust and diversified pipeline of transformative medicines. PTC’s mission is to provide access to best-in-class treatments for patients who have little to no treatment options. PTC’s strategy is to leverage its strong scientific and clinical expertise and global commercial infrastructure to bring therapies to patients. PTC believes this allows it to maximize value for all its stakeholders. To learn more about PTC, please visit us at www.ptcbio.com and follow us on Facebook, Instagram, LinkedIn and X. References: SOURCE: PTC Therapeutics