Onasemnogene abeparvovec

作者｜与安 2025年3月，罗氏制药（Roche）宣布对旗下基因疗法子公司Spark Therapeutics启动“根本性重组”，全额减记24亿美元商誉。财务数据显示，罗氏已累计为 Spark 投入超10亿美元的重组成本，其中包括2024 年1.84亿美元的前期重组费用和2025年预计达3.4亿美元的追加支出。然而，这场持续六年的资本实验最终却惨淡收场，成为基因疗法领域最惨痛的收购案例之一。 而这并非个例。过去三个月，基因治疗领域在希望与阵痛中交织前行，此前昭示熊熊野心的各家药企中，不乏惨淡收场的身影。跨国药企的管线重组、战略收缩与突破转型，再次将这一赛道的复杂性与不确定性推至台前，同时也代表着曾受资本狂热吹捧的基因疗法领域正逐步向理性发展回归转折。   01   43亿美元的深刻教训 技术瓶颈下散场的资本盛宴 2019年，罗氏以43亿美元天价收购Spark Therapeutics，看中的是其全球首个获批的遗传性视网膜病变疗法Luxturna，以及血友病A基因疗法SPK-8011（dirloctocogene samoparvovec）的3期临床潜力。 彼时Spark市值仅22亿美元，而罗氏以溢价125%的代价收购，创下当时基因疗法领域最大并购案，折射出行业对基因疗法商业化的狂热预期。然而截至 2024 年，Luxturna 年销售额仅 2050 万美元，同比暴跌 59%.此外，SPK-8011 项目则因安全性问题被紧急叫停，不达预期的商业表现和无法突破的技术难题，直接让这项大手笔并购案从"战略收购" 降级为 "产品交易"。 迅速击穿资本泡沫的主要是三重瓶颈。 首先是载体免疫性难题。Luxturna依赖的AAV2血清型载体，暴露了基因疗法最顽固的技术瓶颈之一，即预存免疫与后天免疫的双重绞杀。全球约30%-60%人群因自然感染携带AAV中和抗体，导致Luxturna治疗前必须进行抗体筛查。但Spark采用的"血清型切换"策略并未突破根本限制，数据显示超60%患者治疗后仍产生新中和抗体，直接导致疗效持久性不足。而后天免疫的影响在于，即使患者通过预存免疫筛查，治疗后仍可能因免疫系统激活产生新的抗AAV2免疫反应。 其次是产能不足。Spark费城工厂病毒载体年产能仅5000剂，在适应症人群本就狭窄（全球约6000名患者）的情况下，覆盖率仍旧不足85%。患者等待期过长，市场渗透未达预期。 最后则是临床表现的滑铁卢，完成收购时被列为重点的SPK-8011因安全性问题被叫停，于去年年底宣布终止研究。 当病毒载体的免疫原性、生产工艺、长期安全性三大技术关卡未获突破时，资本堆砌反而加速了泡沫破裂。   02   火热势头下的行业寒冬 难以走出的商业化困境 与此同时，罗氏的受挫并非个例。从去年开始，基因治疗领域接连出现“利空”消息，整体成绩远低于预期，市场表现陷入疲软，多家行业明星宣布因进展不佳关停管线或业务重组。 2月21日，辉瑞宣布将停止进一步开发和商业化血友病B基因疗法Beqvez（SPK-9001）。这款药物于2024年4月刚获FDA批准，定价高达350万美元（约合人民币2537万元），在2024年全美最贵药物前十排行榜中，仅次于定价 425 万美元的 Lenmeldy，并列第二。 2024年全美最贵十款药物 而Beqvez从获批上市到决定撤回，还不满一年时间。辉瑞表示，如此决定是因为“患者及医生对血友病基因疗法表现出的兴趣有限”，上市至今，尚未有患者接受过该药治疗。与此同时，辉瑞彻底清空了基因疗法管线。随着Beqvez退出，该司已没有任何基因疗法处于临床或商业化阶段。 实际上，彼时将基因治疗领域列为“优先发展领域”的辉瑞，近三年来正在逐步撤离基因治疗领域。2023年7月，该司将早期研发阶段的基因疗法打包以高达10亿美元的价格卖给了阿斯利康旗下的罕见病部门Alexion；2024年6月，其针对杜氏肌营养不良症（DMD）的基因疗法fordadistrogene movaparvovec因CIFFREO Ⅲ期试验结果未达主要终点，陷入停滞；而到9月，更是撤回了市场上所有批次的镰状细胞贫血疗法Oxbryta，同时终止所有相关试验。因其临床数据表明，该药在镰状细胞患者群体中的总体效益不再足以覆盖其风险。 至年底，辉瑞则终止了与Sangamo Therapeutics的全球合作及许可协议，放弃共同开发治疗A型血友病的基因疗法候选药物giroctocogene fitelparvovec（Giro-vec），尽管该药在去年完成的AFFINE III期临床试验中已取得积极结果，并已准备向FDA和EMA提交监管申请。临时放弃的主要原因大致有二，一是BioMarin同适应症的基因疗法Roctavian商业化进展不佳，市场表现惨淡，可谓现成的前车之鉴；二是辉瑞血友病新型抗体疗法Marstacimab于不久前才获批上市，作为给药便利性更加的抗体，对于基因疗法的市场空间也造成了一定冲击。总得来说，就是彼时看来，这款药物似乎难以实现大卖，而三个月后折戟的Beqvez也确实证实了这一点。 而就在辉瑞宣布从基因疗法退场的前一天，曾经估值百亿的蓝鸟生物宣布卖身私募资金，一同踩下急刹。 2018年初，凭借β地中海贫血疗法Zynteglo（定价280万美元）、脑肾上腺脑白质营养不良疗法Skysona（定价300万美元）和镰状细胞病疗法Lyfgenia（定价310万美元），蓝鸟生物一时声名鹊起，股价飙升至每股2300美元，市值突破300亿美元。其“一次性治愈”叙事吸引了黑石、富达等顶级资本加持，成为首个基因疗法领域“十角兽”企业。 然而，高昂定价和狭窄的患者群体让其商业化之路变得十分困难。受限于保险公司等支付方在高昂定价下的报销审批挑战，三款核心产品2023年总销售额为2910万美元，至今未实现盈利，其中，Zynteglo 2023年销售额为1670万美元，截至2024年11月累计治疗35例患者；Lyfgenia则仅完成4例患者治疗，虽与Vertex的CRISPR疗法同日获批，却因价格高出90万美元且因存在安全问题遭FDA发出黑框警告，市场份额遭到挤压。 去年10月，蓝鸟宣布裁员25%并启动重组，但现金流缺口仍无法填补。最终，该司以2900万美元（不足巅峰市值0.1%）被私募基金凯雷/SK资本收购，对赌条款上限仅1亿美元，蓝鸟最终“断翅”。   03   市场洗牌中的希望与曙光 大额盈利并非不可能 一度受挫的基因疗法领域也并非毫无商业进展。 与前文几款药物相比，Sarepta Therapeutics的Elevidys表现似乎截然不同。这是全球首款DMD基因疗法，可对携带任何类型DMD致病基因变异的患者生效，很好地填补了临床上的空白。值得注意的是，这还是和罗氏联合开发的疗法，同样高成本、高定价，售价320万美元，位列全美最贵药物第四（见图1）。2023年6月获FDA批准，8月正式上市销售，2024年便首度扭亏为盈。 2024年6月，Serepta扩大了该药的适应症，从原来的仅限于 4～5 岁具有行走能力的儿童，扩展为 4 岁及以上的儿童（无论是否有行走能力），进一步拓宽了市场覆盖面。至第三季度，Sarepta实现了净利润同比增长113%的好成绩，一举达到7619万美元。而诺华在AAV基因疗法上的投入则更是成效亮眼，针对脊髓性肌萎缩症（SMA）的Zolgensma可谓销冠，据其财报显示，2024年的年销售额仍然取得了12.14亿美元的好成绩。 Zolgensma2024年净销售额 或许还有一大关键原因在于适应症的选择。反观让多位巨头或挣扎前行、或认栽止损的血友病基因疗法，市场表现不佳主要还是因为有凝血因子替代疗法和双抗药物可供患者选择。自身售价不菲，疗效也并无绝对优势，在可替代方案充足的情况下，难以打开市场的情况或许也并非难以预料。 然而罗氏并未完全放弃。一方面，Spark的剩余业务将整合至集团，重组不影响Luxturna的持续供应，费城创新中心的一部分研发职能也仍然予以保留；另一方面，通过与Dyno Therapeutics达成的10亿美元合作，利用后者人工智能平台开发神经疾病新型AAV载体，罗氏将转向开发针对神经疾病的下一代基因疗法。 基因疗法的故事远未终章。尽管挑战重重，部分企业仍以战略调整与技术升级寻找生机。2025年的春天，基因治疗领域仍在冰火之间跋涉。但随着临床技术的进步、监管政策的完善和支付体系的创新，当基因治疗的商业化摆脱纯资本驱动，构建起“技术-临床-支付”的完整闭环，这一领域仍然有望在迎来更为明朗开阔的前景，重唱高歌，再次高速前行。 参考文献 https://www.fiercepharma.com/pharma/roche-overhauls-spark-gene-therapy-unit-recording-24b-full-impairment https://www.fiercepharma.com/pharma/pfizer-empties-gene-therapy-portfolio-discontinues-hemophilia-treatment-beqvez https://www.fda.gov/news-events/press-announcements/fda-expands-approval-gene-therapy-patients-duchenne-muscular-dystrophy https://www.pharmaceutical-technology.com/features/the-most-expensive-drugs-in-the-us/ 公众号文章 BioSeedin柏思荟 辉瑞“泪洒”基因疗法 https://news.bioon.com/article/98498658028f.html 各家药企官网新闻动态和财报数据 共建Biomedical创新生态圈！ 如何加入BiG会员？

iStock, doomu Since 2016, the FDA has approved three disease-modifying treatments for spinal muscular atrophy, with several companies—including Novartis, Scholar Rock and Biogen—progressing novel candidates through clinical trials. The last decade has fundamentally changed how clinicians treat spinal muscular atrophy. In 2016, Biogen’s Spinraza became the FDA-approved treatment for SMA, offering new hope for patients with the rare, neuromuscular disease. Since then, two more medicines—Novartis’ gene therapy Zolgensma and Roche’s SMN2 splicing modifier Evrysdi —have hit the market, and many more are in various stages of development. Before 2016, without treatment, many patients with the most severe form of SMA did not survive past two years of age without respiratory support, according to Biogen . “The landscape of SMA has changed drastically for the better,” Seth Perlman, a neurologist at Seattle Children’s Hospital, told BioSpace . “It is a completely different world. We’re not expecting to see children die before age two.” SMA is caused by a dysfunction in the survival motor neuron (SMN) protein, typically due to a mutation in the SMN1 gene. The SMN protein is critical for cell survival. It repairs DNA, manages cellular stress and preserves overall neuromuscular health. Without it, motor neurons waste away . Most investigational drugs seek to boost the amount of functional protein or deliver a functional copy of the SMN1 gene, but recent innovations in this space also target muscles directly. Here, BioSpace looks at six SMA therapies and novel formulations to watch in 2025 and beyond. Novartis’ IT Zolgensma (OAV101 IT) Last week, Novartis announced positive safety and efficacy readouts for OAV101 IT, an investigational intrathecal injection of its landmark gene therapy, Zolgensma (onasemnogene abeparvovec). The only gene therapy for SMA on the U.S. market, Zolgensma is currently FDA-approved for intravenous delivery in children under 2 years of age. Data from the Phase III STEER study, presented March 19 at the Muscular Dystrophy Association’s Clinical & Scientific Conference in Dallas, showed that treatment with OAV101 IT improves motor muscular ability in patients 2–17 years of age, potentially expanding the cohort of patients who can benefit from this therapy. OAV101 IT differs from the approved formulation of Zolgensma in that it is delivered directly into the spinal fluid, which Norman Putzki, global development head of neuroscience and gene therapy at Novartis, said allows for safer delivery of the drug in the higher doses required to effectively treat older patients. In STEER, OAV101 IT elicited a 2.39-point improvement on the Hammersmith Functional Motor Scale Expanded (HFMSE)—a gold standard SMA assessment tool, according to Novartis’ press release—compared to 0.51 points in the control arm. “We’ve seen motor gains that are clinically meaningful,” Putzki told BioSpace . “It’s really exciting.” Novartis plans to approval of OAV101 IT with regulators in the first half of 2025. Scholar Rock’s Apitegromab Scholar Rock’s apitegromab, a myostatin inhibitor, sailed through Phase III testing with flying colors. In the Phase III SAPPHIRE trial, reported by Scholar Rock in October 2024, patients aged 2 to 12 years receiving apitegromab experienced clinically meaningful benefits in motor function, with the treatment group seeing at least a 1.8-point improvement on the HFMSE compared to placebo. In addition, 30% of apitegromab-treated patients saw at least a 3-point improvement in HFMSE compared to 12.5% in the placebo group. Unlike other drugs, apitegromab directly targets muscles, selectively inhibiting the activation of myostatin. Perlman said apitegromab could be an effective “add-on” to other therapies, especially for people with SMA who may have already developed muscular weakness. NMD Pharma’s NMD670 NMD Pharma is testing NMD670 , a small molecule inhibitor of skeletal muscle-specific chloride ion channel 1 (CIC01), in a Phase II trial for SMA. The first patient in this trial, which is evaluating changes in a 6-minute walk test in ambulatory adults aged 18 to 75, dosed its first patient in late 2023, according to a company press release . The study is estimated to wrap up in January 2026, according to ClinicalTrials.gov . While earlier in development than other drugs on this list, NMD670 has shown promise in early-stage trials of other neuromuscular disorders. In a Phase I clinical trial , patients with myasthenia gravis experienced clinically meaningful improvements in the Quantitative Myasthenia Gravis (QMG) score—which assesses muscle control and function—and electrophysiological assessments. The drug is thought to enhance muscle excitability, amplifying responses to motor commands from the brain . Biogen’s Higher Dose Spinraza and BIIB115 In January , the FDA accepted Biogen’s supplemental new drug application for a higher dose of its Ionis-partnered Spinraza, an antisense oligonucleotide that alters the splicing of SMN2 , a “backup” gene for SMN1 that produces a truncated version of the SMN protein. The drug, which is injected into the spinal fluid, enables the SMN2 gene to make full-length SMN protein, increasing its production in patients with SMA. The higher-dose regimen, which comprises a loading regimen of two 50-mg doses 14 days apart, followed by a 28-mg maintenance regimen every four months, could “enable meaningful clinical benefits while maintaining a safety pro consistent with the approved 12-mg regimen,” Thomas Crawford, co-director of the Muscular Dystrophy Association Clinic at Johns Hopkins Medicine, said in Biogen’s acceptance announcement. But Biogen isn’t resting on the success of Spinraza. In January 2022, the big biotech exercised an option from Ionis for an exclusive global license for another antisense oligonucleotide, BIIB115, which according to Ionis offers the potential for extended dosing intervals. Biogen is currently testing BIIB115 in a Phase I trial intended to ascertain safety and pharmacokinetic effects in healthy adult male volunteers and pediatric SMA patients who were previously treated with Zolgensma. The study is expected to read out in November 2026, according to Clinicaltrials.gov . Biohaven’s Taldefgrobep Alfa Biohaven’s investigational myostatin and activin receptor blocker, taldefgrobep alfa, missed the mark in a recent Phase III trial, but the Connecticut-based biotech hasn’t given up on the drug yet. In Biohaven’s RESILIENT SMA study, taldefgrobep alfa failed to improve motor function in patients with SMA as compared with placebo, according to a November 2024 press release . Biohaven noted, however, that in Caucasian patients, the drug showed a statistically significant improvement. Patients in this subset treated with taldefgrobep alfa showed a statistically significant 2.2-point improvement in the Motor Function Measurement-32 (MFM-32) scale at 48 weeks. Non-Caucasian patients, however, showed a higher-than-average response to the placebo, Biohaven said. The company struck an optimistic tone regarding the drug’s efficacy and plans “to engage the FDA regarding potential steps forward” for the candidate. Biohaven also discovered that treatment with taldefgrobep alfa resulted in a reduction of body fat and improvements in lean muscle mass and bone density. Based on these findings, the company stated plans to launch a Phase II trial in obesity in Q4, 2024.