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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

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.