Phase 3, open label, single arm study to evaluate efficacy and safety of FIX gene transfer with PF-06838435 (rAAV Spark100-hFIX-Padua) in adult male participants with moderately severe to severe hemophilia B (FIX:C =2%) (BeneGene 2)

开始日期2023-09-15

申办/合作机构

Kyung Hee University Hospital at Gangdong

NCT03861273

/ Active, not recruiting临床3期

Phase 3, Open-label, Single-arm Study to Evaluate Efficacy and Safety of FIX Gene Transfer With PF-06838435 (rAAV-Spark100-hFIX-R338L) in Adult Male Participants With Moderately Severe to Severe Hemophilia B (FIX:C =2%) (BeneGene-2)

This study will evaluate the efficacy and safety of PF-06838435 (a gene therapy drug) in adult male participants with moderately severe to severe hemophilia B (participants that have a Factor IX circulating activity of 2% or less). The gene therapy is designed to introduce genetic material into cells to compensate for missing or non-functioning Factor IX. Eligible study participants will have completed a minimum 6 months of routine Factor IX prophylaxis therapy during the lead in study (C0371004). Participants will be dosed once (intravenously) and will be evaluated over the course of 6 years. The main objective of the study will evaluate the annualized bleeding rate [ABR] for participants treated with gene therapy versus standard of care (SOC) therapy (FIX prophylaxis replacement regimen).

开始日期2019-07-29

申办/合作机构

Pfizer Inc.

NCT03307980

/ Active, not recruiting临床2期

A FACTOR IX (FIX) GENE TRANSFER, MULTI CENTER EVALUATION OF THE LONG TERM SAFETY AND EFFICACY STUDY OF PF 06838435 AND A DOSE ESCALATION SUBSTUDY IN INDIVIDUALS WITH HEMOPHILIA B

Long-term safety and efficacy follow-up for participants with Hemophilia B who were previously treated in the C0371005 (formerly SPK-9001-101) study, and a dose-escalation sub-study evaluating safety, tolerability, and kinetics of a higher dose with long-term safety and efficacy follow-up. Participants in the substudy do not need to have participated in C0371005.

开始日期2017-06-22

申办/合作机构

Pfizer Inc.

100 项与 Fidanacogene elaparvovec 相关的临床结果

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100 项与 Fidanacogene elaparvovec 相关的转化医学

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100 项与 Fidanacogene elaparvovec 相关的专利（医药）

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项与 Fidanacogene elaparvovec 相关的文献（医药）

2025-05-01·MOLECULAR THERAPY

The deLIVERed promises of gene therapy: Past, present, and future of liver-directed gene therapy

Review

作者: Kay, Mark A ; Puzzo, Francesco

Gene therapy has revolutionized modern medicine by offering innovative treatments for genetic and acquired diseases. The liver has been and continues as a prime target for in vivo gene therapy due to its essential biological functions, vascular access to the major target cell (hepatocytes), and relatively immunotolerant environment. Adeno-associated virus (AAV) vectors have become the cornerstone of liver-directed therapies, demonstrating remarkable success in conditions such as hemophilia A and B, with US Food and Drug Administration (FDA)-approved therapies like etranacogene dezaparvovec, Beqvez, and Roctavian marking milestones in the field. Despite these advances, challenges persist, including vector immunogenicity, species-specific barriers, and high manufacturing costs. Innovative strategies, such as capsid engineering, immune modulation, and novel delivery systems, are continuing to address these issues in expanding the scope of therapeutic applications. Some of the challenges with many new therapies result in the discordance between preclinical success and translation into humans. The advent of various genome-editing tools to repair genomic mutations or insert therapeutic DNAs into precise locations in the genome further enhances the potential for a single-dose medicine that will offer durable life-long therapeutic treatments. As advancements accelerate, liver-targeted gene therapy is poised to continue to transform the treatment landscape for both genetic and acquired disorders, for which unmet challenges remain.

2025-04-17·NEW ENGLAND JOURNAL OF MEDICINE

Fidanacogene Elaparvovec for Hemophilia B — A Multiyear Follow-up Study

Article

作者: Teitel, Jerome M. ; High, Katherine A. ; Rasko, John E.J. ; George, Lindsey A. ; Chhabra, Amit ; Winburn, Ian ; de Jong, Ype P. ; Rupon, Jeremy ; O’Brien, Amanda ; Giermasz, Adam ; Ducore, Jonathan M. ; Smith, Lynne M. ; McGuinn, Catherine E. ; Samelson-Jones, Benjamin J.

BACKGROUND:

Treatment with fidanacogene elaparvovec, a recombinant adeno-associated virus (AAV) vector developed for the treatment of hemophilia B, led to sustained expression of the high-activity factor IX variant (FIX-R338L, or FIX-Padua) in a phase 1-2a study. The long-term safety and efficacy of this treatment are not known.

METHODS:

In a 12-month study, 15 participants with severe or moderately severe hemophilia B (factor IX coagulant activity, ≤2% of the normal value) received fidanacogene elaparvovec at a dose of 5×10¹¹ vector genomes (vg) per kilogram of body weight; thereafter, participants could enroll in a 5-year follow-up study. Safety end points included adverse events and changes in laboratory measures. Efficacy end points included the annualized rate of treated bleeding events (annualized bleeding rate) and factor IX activity.

RESULTS:

A total of 14 participants provided consent and completed at least 3 years of follow-up (median, 5.5; range 3 to 6); participation was ongoing among 8 at the data cutoff. None of the participants reported treatment-related adverse events after year 1. Throughout follow-up, nine serious adverse events were noted in 4 participants; none were thrombotic or treatment-related. No factor IX inhibitors were detected. Throughout follow-up, mean factor IX activity was in the mild hemophilia range; the mean annualized bleeding rate was less than 1, and 10 participants had no treated bleeding episodes. Surveillance liver ultrasounds obtained from year 1 onward showed no evidence of cancer but showed steatosis in 4 participants who had weight gain and elevated aminotransferase levels (maximum alanine aminotransferase level, 77 U per liter). One participant with a history of hepatitis C, hepatitis B, human immunodeficiency virus infection, and an elevated body-mass index had progression of underlying advanced liver fibrosis. A total of 13 surgical procedures were performed in 8 participants; exogenous factor IX was administered for 10 procedures, and no associated unexpected bleeding complications occurred.

CONCLUSIONS:

Fidanacogene elaparvovec was associated with no or only low-grade adverse effects over a period of 3 to 6 years. Efficacy was maintained in the long term at 5×10¹¹ vg per kilogram, one of the lowest intravenous doses of AAV used for any indication. (Funded by Pfizer; ClinicalTrials.gov number, NCT03307980.).

2024-09-26·NEW ENGLAND JOURNAL OF MEDICINE

Gene Therapy with Fidanacogene Elaparvovec in Adults with Hemophilia B

Article

作者: Hermans, Cédric ; Cuker, Adam ; Kavakli, Kaan ; Teitel, Jerome ; Sun, Pengling ; Oldenburg, Johannes B ; Rasko, John E J ; Rupon, Jeremy ; Iorio, Alfonso ; Biondo, Francesca ; Leavitt, Andrew D ; Katsarou-Fasouli, Olga ; Cerqueira, Monica H ; Shapiro, Amy D ; Klamroth, Robert ; Fuiman, Joanne ; Fang, Annie ; Wang, Jiaan-Der ; McKay, John ; Astermark, Jan ; Frenzel, Laurent ; Ozelo, Margareth C ; Ishiguro, Akira

BACKGROUND:

Fidanacogene elaparvovec, an adeno-associated virus (AAV) gene-therapy vector for hemophilia B containing a high-activity human factor IX variant (FIX-R338L/FIX-Padua), was associated with sustained factor IX activity in a phase 1-2a study.

METHODS:

We conducted a phase 3 open-label study of fidanacogene elaparvovec at a dose of 5×10¹¹ vector genome copies per kilogram of body weight. Men 18 to 65 years of age with hemophilia B and a factor IX level of 2% or less were eligible for screening if they had received at least 6 months of therapy with prophylactic factor IX concentrate. The primary end point, tested for noninferiority, was the annualized bleeding rate (treated and untreated bleeding episodes) from week 12 to month 15 after treatment with fidanacogene elaparvovec as compared with the prophylaxis lead-in period. Superiority, additional efficacy end points, and safety were also assessed.

RESULTS:

Of 316 men who underwent screening for the lead-in study, 204 (64.6%) were not eligible; 188 (59.5%) of those were ineligible owing to the presence of anti-AAV neutralizing antibodies. Of the 45 participants who received fidanacogene elaparvovec, 44 completed at least 15 months of follow-up. The annualized rate of bleeding for all bleeding episodes decreased by 71%, from 4.42 (95% confidence interval [CI], 1.80 to 7.05) at baseline to 1.28 (95% CI, 0.57 to 1.98) after gene therapy, a treatment difference of -3.15 episodes (95% CI, -5.46 to -0.83; P = 0.008). This result shows the noninferiority and superiority of fidanacogene elaparvovec to prophylaxis. At 15 months, the mean factor IX activity was 26.9% (median, 22.9%; range, 1.9 to 119.0) by one-stage SynthASil assay. A total of 28 participants (62%) received glucocorticoids for increased aminotransferase levels or decreased factor IX levels (or both) starting between 11 and 123 days. No infusion-related serious adverse events, thrombotic events, development of factor IX inhibitors, or malignant conditions were observed.

CONCLUSIONS:

Fidanacogene elaparvovec was superior to prophylaxis for the treatment of participants with hemophilia B, leading to reduced bleeding and stable factor IX expression. (Funded by Pfizer; BENEGENE-2 ClinicalTrials.gov number, NCT03861273.).

221

项与 Fidanacogene elaparvovec 相关的新闻（医药）

2025-06-28

·精准药物

基因疗法还远未成功：患者死亡，股价暴跌

一针即可治愈，长期以来构成了基因疗法的一条叙事主线。药企通过把遗传密码装入改造后的病毒中，再将之注射到患者体内，诱使细胞产生所需的蛋白，从而解决原本需要反复给药的麻烦——这一度成为业界的期望。COVID-19之前，基因疗法眼看走到新时代的大门下了，千帆竞发。根据DealForma的资料，MNC在该技术上投入了数百亿美元：2018年，涉及收购基因疗法公司的交易额总计高达220亿美元，2019年这一数字也有近百亿美元。然而，五年过去了，这种热情大多已消散。包括辉瑞在内的制药巨头陆续退出，这片过去看似拥有无限可能的领域，眼下充斥着安全风险、商业失败。近期的临床试验死亡事件，再次加剧了业界的担忧。而FDA堪称动荡的人员调整，让未来变得不甚明朗。需要指出，基因疗法并非没有成功突围者。可这并不能阻止产业之问：2025年以后，基因疗法还会好吗？TONACEA01“阿喀琉斯之踵”最新的失败案例，发生在6月中旬，一名患者参加Sarepta Therapeutics的基因疗法试验时不幸出现死亡。消息一出，Sarepta股价暴跌42%。涉事的是一款已上市的治疗杜氏肌营养不良症（DMD）的产品Elevidys。简单来说，其原理旨在诱导患者自身细胞制造一种改良的肌肉构建蛋白，从而治疗这种疾病。不过，这种基因疗法的疗效一直备受争议。Sarepta采取积极的监管策略，在III期临床试验完成之前就获得针对某些患者的批准。2023年底结果公布时，Elevidys错过了主要终点，FDA却仍在继续扩大适用患者的范围。2024年6月，无法行走的DMD患者被允许使用Elevidys，而这类人群参与的试验仍在进行中。Elevidys没有等来完全批准，而是意外死亡。今年3月，一名16岁男性患者在接受Elevidys治疗后因急性肝衰竭死亡。三个月后，第二例死亡患者也急性肝衰竭有关。近期电话会议上，Sarepta高管承认，这两例患者情况有相似之处。尽管Elevidys的标签警告存在“急性严重肝损伤”风险，在接受Elevidys治疗的900多名患者中，却从未发生像这两起安全性事件的情况。Sarepta并未唯一的受挫者。5月，另一家Biotech Rocket Pharmaceuticals也宣布，其正在进行的一项II期临床中，一名受试者在给药RP-A1501后离世。消息披露当天，Rocket股价下跌近60%，几天后FDA叫停相关试验。Rocket称，正在调查具体的死亡原因，重点是最近加入到治疗方案中的一种新的免疫抑制剂——这原本是为了提高治疗的安全性。分析师曾对RP-A1501的试验成功抱有相当的信心：2月，Jefferies发布的文章预计，该疗法有65%至75%的可能获得阳性结果。如今受到安全性事件的影响，RP-A1501能否重启临床开发都成问题。Rocket一方面仍相信，RP-A501还有“前进的道路”，但另一方面也宣布保留现金余额的计划。截至2025年第一季度，其现金余额为3.182亿美元。该公司透露，随着此番管线的优先级调整，公司运转所需现金可以维持到2027年。对于一只脚已经跨进商业化市场的Sarepta，两起负面案例也影响颇大。HC Wainwright分析师认为，除非获得可靠的长期安全数据，特别是证明治疗相关死亡风险接近于零，否则越来越多的患者和医生将不会接受Elevidys。援引FactSet的数据，3月Sarepta报告患者死亡之前，分析师设想，今年Elevidys的销售额将超过20亿美元，占该公司当时估计31亿美元年度总收入的绝大部分。可想而知，目前，这笔收入以及公司的未来都成了一个大问号。TONACEA02爆款，难以复制2025年由Elevidys开启的安全性质疑，是影响深远的。Jefferies分析师称，自那以来，投资者的幻想越来越破灭，如此观点得到越来越多共鸣：基因疗法整体上来说不值得投资，为什么还要费心关注？这与五年前的热情形成鲜明对比。2019年，诺华推出脊髓性肌萎缩症（SMA）基因疗法Zolgensma，并很大程度这一疾病领域的治疗范式。表达SMN蛋白的正常基因借助AAV9病毒载体进行静脉给药，只需注射一次即可长期获益。上市首年的七个月内，定价212.5万美元的Zolgensma的销售额就有3.61亿美元；2020年，销售额同比增长增加150%，达到9.2亿美元；2021年继续卖出13.51亿美元，成为基因疗法领域的首款“重磅炸弹”。业界一度以为，这样的传奇还会继续发生。但很可惜，Zolgensma的成功难以复制。按照Leerink Partners分析师的讲法，在很多方面，SMA都是AAV技术的“杀手级应用”，正如每个在iPhone之后开发手机的人可能都不会有iPhone那样的销量，后续的基因疗法商业表现也基本不会更加出色。现阶段，美国市场上的AAV基因疗法不足10种，其中三种用于治疗血友病，但它们也未能从罗氏旗下的Hemlibra等高效的非基因疗法方案中，抢夺大量患者市场。值得注意的是，就连Zolgensma也开始出现瓶颈。2023年财报公布之际，诺华首席执行官Vas Narasimhan甚至对Zolgensma只字未提。2022年这款天价基因疗法的全球销售额仅增长1%，2023年则下降了11%，降至12.1亿美元。在其最大的单一市场美国，2023年Zolgensma销售额则下降14%——这已经是连续第二年下降了。不可否认，Zolgensma仍然是一款“重磅炸弹，分析师预计2025年的销售额将达到13亿美元，但其中的曲折与乏力，凸显了基因疗法的普遍困境。更多大公司正在放弃这个领域，辉瑞就是典型之一。2月，辉瑞以患者接受度低为由，将一款上市不到一年的血友病基因疗法Beqvez撤出市场。这意味着，作为“宇宙大药厂”的辉瑞几乎完全退出基因疗法赛道。随后的3月，罗氏宣布，对其基因疗法子公司Spark Therapeutics进行“根本性重组”。约六年前，罗氏将之收购以增强自身基因治疗业务。而据报道，今年有超过300个岗位面临裁员，这引发人们对Spark能否继续存在的质疑。Biotech股票同样在走低：过去十二个月，Solid Biosciences和Regenxbio都下跌了近30%。Leerink Partners分析师表示，很多投资者对基因疗法的情绪，“介于不感兴趣和厌恶之间”。意料之中，项目交易几乎枯竭。DealForma数据显示，2024年基因疗法方面的并购总额仅为12亿美元，2025年迄今为止更是没有。至于基因疗法研究合作，预付款已从2017年17亿美元峰值降至2024年的1.55亿美元。TONACEA03未来在“余震”中显然，基因疗法在华尔街仍拥有支持者。高盛分析师就认为，业界只是需要解决一些问题，而不必将整个方案抛弃。Cantor Fitzgerald分析师也呼吁对基因疗法的安全性风险加以更多关注，因为“我们还没有很好的可行替代方案”。问题在于，当前的美国环境是否提供足够的试错空间。近期FDA最新的人员调整中，弥散出一股越加浓厚的担忧。STAT报道称，6月18日，FDA负责审查细胞和基因疗法的产品办公室（OTP）主任Nicole Verdun及其副手Rachael Anatol，“暂时被解除职务”并“被护送离开”。自2012年以来，Verdun一直在FDA工作。2023年，她被提拔至OTP主任一职。HHS发言人回应说，生物制品审评与研究中心（CBER）主任“应该得到那些有着积极目标的管理人员的支持，他们要利用科学的黄金标准，迅速推进罕见病的治疗”。换言之，Verdun和5月新上任的CBER主任Vinay Prasad存在分歧。被后者替代的CBER前主任Peter Marks曾表示，新任HHS部长RFK Jr.只希望“得到对他错误信息和谎言的卑躬屈膝的证实”。Marks致力于以科学方法推动基因疗法的开发。如今深陷安全性危机的Elevidys，就是在Marks的主导下获得加速批准的。这也成为其被攻击之处：进入FDA前，Prasad就公开批评Marks的一些做法。然而，FDA新的领导层似乎没有更好的监管方案。FDA资深人士大批离开后，新药评审所需的专业能力是在减弱而非得到加强。因此，行业的观察是，FDA对新的IND、BLA以及NDA的审批速度将大大减慢，许多产品和公司可能要“面临漫长而昂贵的停滞期，迟迟得不到任何进展”。一些担心指出，部分FDA视为优先事项的产品，在看似数据较少的情况下突然获得批准，这与其说是对科学的包容，不如看作是这个机构新领导层“意识形态和政治高于数据”的注脚。在FDA前局长Scott Gottlieb看来，Verdun的离职对细胞和基因疗法而言是一次“重大挫折”，因为Verdun和其他最近离职的FDA员工“知道如何让这些细胞和基因疗法的研发途径更加可行”。公开数据显示，2025年，将有五项细胞和基因疗法的监管决策有待FDA做出，而全球正在进行的细胞和基因疗法临床试验数量将近2000项，因此，CBER和OTP的效率、科学性至关重要。因此，也就不难理解Sarepta为代表的基因疗法公司目前遭受华尔街冷遇。面对行业的震荡、安全性问题，Elevidys销售额预期下滑，Piper Sandler将Sarepta股票评级从“增持”下调至“中性”，HC Wainwright则将其评级从“中性”下调至“卖出”。参考资料：1.Gene Therapy Stocks Fall Amid More Turmoil at FDA2.Gene Therapy Was the Biggest Idea in Biotech. Now It Has Lost Support on Wall Street.3.Sarepta Stock Plunges After Death of Second Patient Receiving Its Gene Therapy4.As Gene Therapy Endures ‘Cold Winter,’ FDA Leaders Promise Support5.史上最贵的天价药怎样了？声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

基因疗法临床3期临床2期

2025-06-27

·同写意

基因疗法，败走华尔街

同写意年度巨献！！大会特设“基因治疗”分会，7月25-26日，邀您相聚金鸡湖畔，与5000人一起为中国医药创新“同写意”！一针即可治愈，长期以来构成了基因疗法的一条叙事主线。药企通过把遗传密码装入改造后的病毒中，再将之注射到患者体内，诱使细胞产生所需的蛋白，从而解决原本需要反复给药的麻烦——这一度成为业界的期望。COVID-19之前，基因疗法眼看走到新时代的大门下了，千帆竞发。根据DealForma的资料，MNC在该技术上投入了数百亿美元：2018年，涉及收购基因疗法公司的交易额总计高达220亿美元，2019年这一数字也有近百亿美元。然而，五年过去了，这种热情大多已消散。包括辉瑞在内的制药巨头陆续退出，这片过去看似拥有无限可能的领域，眼下充斥着安全风险、商业失败。近期的临床试验死亡事件，再次加剧了业界的担忧。而FDA堪称动荡的人员调整，让未来变得不甚明朗。需要指出，基因疗法并非没有成功突围者。可这并不能阻止产业之问：2025年以后，基因疗法还会好吗？TONACEA01“阿喀琉斯之踵”最新的失败案例，发生在6月中旬，一名患者参加Sarepta Therapeutics的基因疗法试验时不幸出现死亡。消息一出，Sarepta股价暴跌42%。涉事的是一款已上市的治疗杜氏肌营养不良症（DMD）的产品Elevidys。简单来说，其原理旨在诱导患者自身细胞制造一种改良的肌肉构建蛋白，从而治疗这种疾病。不过，这种基因疗法的疗效一直备受争议。Sarepta采取积极的监管策略，在III期临床试验完成之前就获得针对某些患者的批准。2023年底结果公布时，Elevidys错过了主要终点，FDA却仍在继续扩大适用患者的范围。2024年6月，无法行走的DMD患者被允许使用Elevidys，而这类人群参与的试验仍在进行中。Elevidys没有等来完全批准，而是意外死亡。今年3月，一名16岁男性患者在接受Elevidys治疗后因急性肝衰竭死亡。三个月后，第二例死亡患者也急性肝衰竭有关。近期电话会议上，Sarepta高管承认，这两例患者情况有相似之处。尽管Elevidys的标签警告存在“急性严重肝损伤”风险，在接受Elevidys治疗的900多名患者中，却从未发生像这两起安全性事件的情况。Sarepta并未唯一的受挫者。5月，另一家Biotech Rocket Pharmaceuticals也宣布，其正在进行的一项II期临床中，一名受试者在给药RP-A1501后离世。消息披露当天，Rocket股价下跌近60%，几天后FDA叫停相关试验。Rocket称，正在调查具体的死亡原因，重点是最近加入到治疗方案中的一种新的免疫抑制剂——这原本是为了提高治疗的安全性。分析师曾对RP-A1501的试验成功抱有相当的信心：2月，Jefferies发布的文章预计，该疗法有65%至75%的可能获得阳性结果。如今受到安全性事件的影响，RP-A1501能否重启临床开发都成问题。Rocket一方面仍相信，RP-A501还有“前进的道路”，但另一方面也宣布保留现金余额的计划。截至2025年第一季度，其现金余额为3.182亿美元。该公司透露，随着此番管线的优先级调整，公司运转所需现金可以维持到2027年。对于一只脚已经跨进商业化市场的Sarepta，两起负面案例也影响颇大。HC Wainwright分析师认为，除非获得可靠的长期安全数据，特别是证明治疗相关死亡风险接近于零，否则越来越多的患者和医生将不会接受Elevidys。援引FactSet的数据，3月Sarepta报告患者死亡之前，分析师设想，今年Elevidys的销售额将超过20亿美元，占该公司当时估计31亿美元年度总收入的绝大部分。可想而知，目前，这笔收入以及公司的未来都成了一个大问号。TONACEA02爆款，难以复制2025年由Elevidys开启的安全性质疑，是影响深远的。Jefferies分析师称，自那以来，投资者的幻想越来越破灭，如此观点得到越来越多共鸣：基因疗法整体上来说不值得投资，为什么还要费心关注？这与五年前的热情形成鲜明对比。2019年，诺华推出脊髓性肌萎缩症（SMA）基因疗法Zolgensma，并很大程度这一疾病领域的治疗范式。表达SMN蛋白的正常基因借助AAV9病毒载体进行静脉给药，只需注射一次即可长期获益。上市首年的七个月内，定价212.5万美元的Zolgensma的销售额就有3.61亿美元；2020年，销售额同比增长增加150%，达到9.2亿美元；2021年继续卖出13.51亿美元，成为基因疗法领域的首款“重磅炸弹”。业界一度以为，这样的传奇还会继续发生。但很可惜，Zolgensma的成功难以复制。按照Leerink Partners分析师的讲法，在很多方面，SMA都是AAV技术的“杀手级应用”，正如每个在iPhone之后开发手机的人可能都不会有iPhone那样的销量，后续的基因疗法商业表现也基本不会更加出色。现阶段，美国市场上的AAV基因疗法不足10种，其中三种用于治疗血友病，但它们也未能从罗氏旗下的Hemlibra等高效的非基因疗法方案中，抢夺大量患者市场。值得注意的是，就连Zolgensma也开始出现瓶颈。2023年财报公布之际，诺华首席执行官Vas Narasimhan甚至对Zolgensma只字未提。2022年这款天价基因疗法的全球销售额仅增长1%，2023年则下降了11%，降至12.1亿美元。在其最大的单一市场美国，2023年Zolgensma销售额则下降14%——这已经是连续第二年下降了。不可否认，Zolgensma仍然是一款“重磅炸弹，分析师预计2025年的销售额将达到13亿美元，但其中的曲折与乏力，凸显了基因疗法的普遍困境。更多大公司正在放弃这个领域，辉瑞就是典型之一。2月，辉瑞以患者接受度低为由，将一款上市不到一年的血友病基因疗法Beqvez撤出市场。这意味着，作为“宇宙大药厂”的辉瑞几乎完全退出基因疗法赛道。随后的3月，罗氏宣布，对其基因疗法子公司Spark Therapeutics进行“根本性重组”。约六年前，罗氏将之收购以增强自身基因治疗业务。而据报道，今年有超过300个岗位面临裁员，这引发人们对Spark能否继续存在的质疑。Biotech股票同样在走低：过去十二个月，Solid Biosciences和Regenxbio都下跌了近30%。Leerink Partners分析师表示，很多投资者对基因疗法的情绪，“介于不感兴趣和厌恶之间”。意料之中，项目交易几乎枯竭。DealForma数据显示，2024年基因疗法方面的并购总额仅为12亿美元，2025年迄今为止更是没有。至于基因疗法研究合作，预付款已从2017年17亿美元峰值降至2024年的1.55亿美元。TONACEA03未来在“余震”中显然，基因疗法在华尔街仍拥有支持者。高盛分析师就认为，业界只是需要解决一些问题，而不必将整个方案抛弃。Cantor Fitzgerald分析师也呼吁对基因疗法的安全性风险加以更多关注，因为“我们还没有很好的可行替代方案”。问题在于，当前的美国环境是否提供足够的试错空间。近期FDA最新的人员调整中，弥散出一股越加浓厚的担忧。STAT报道称，6月18日，FDA负责审查细胞和基因疗法的产品办公室（OTP）主任Nicole Verdun及其副手Rachael Anatol，“暂时被解除职务”并“被护送离开”。自2012年以来，Verdun一直在FDA工作。2023年，她被提拔至OTP主任一职。HHS发言人回应说，生物制品审评与研究中心（CBER）主任“应该得到那些有着积极目标的管理人员的支持，他们要利用科学的黄金标准，迅速推进罕见病的治疗”。换言之，Verdun和5月新上任的CBER主任Vinay Prasad存在分歧。被后者替代的CBER前主任Peter Marks曾表示，新任HHS部长RFK Jr.只希望“得到对他错误信息和谎言的卑躬屈膝的证实”。Marks致力于以科学方法推动基因疗法的开发。如今深陷安全性危机的Elevidys，就是在Marks的主导下获得加速批准的。这也成为其被攻击之处：进入FDA前，Prasad就公开批评Marks的一些做法。然而，FDA新的领导层似乎没有更好的监管方案。FDA资深人士大批离开后，新药评审所需的专业能力是在减弱而非得到加强。因此，行业的观察是，FDA对新的IND、BLA以及NDA的审批速度将大大减慢，许多产品和公司可能要“面临漫长而昂贵的停滞期，迟迟得不到任何进展”。一些担心指出，部分FDA视为优先事项的产品，在看似数据较少的情况下突然获得批准，这与其说是对科学的包容，不如看作是这个机构新领导层“意识形态和政治高于数据”的注脚。在FDA前局长Scott Gottlieb看来，Verdun的离职对细胞和基因疗法而言是一次“重大挫折”，因为Verdun和其他最近离职的FDA员工“知道如何让这些细胞和基因疗法的研发途径更加可行”。公开数据显示，2025年，将有五项细胞和基因疗法的监管决策有待FDA做出，而全球正在进行的细胞和基因疗法临床试验数量将近2000项，因此，CBER和OTP的效率、科学性至关重要。因此，也就不难理解Sarepta为代表的基因疗法公司目前遭受华尔街冷遇。面对行业的震荡、安全性问题，Elevidys销售额预期下滑，Piper Sandler将Sarepta股票评级从“增持”下调至“中性”，HC Wainwright则将其评级从“中性”下调至“卖出”。参考资料：1.Gene Therapy Stocks Fall Amid More Turmoil at FDA2.Gene Therapy Was the Biggest Idea in Biotech. Now It Has Lost Support on Wall Street.3.Sarepta Stock Plunges After Death of Second Patient Receiving Its Gene Therapy4.As Gene Therapy Endures ‘Cold Winter,’ FDA Leaders Promise Support5.史上最贵的天价药怎样了？

基因疗法临床3期

2025-06-26

·FiercePharma

Pfizer's hemophilia drug Hympavzi notches phase 3 win as pharma eyes label expansion

Trial results indicate that Pfizer’s Hympavzi is effective in patients with hemophilia A and B who are inhibitors, setting it up for a label expansion. The treatment was approved last year for hemophilia A and B patients who are non-inhibitors. Approved eight months ago for a certain class of patients with both hemophilia A or B, Pfizer’s Hympavzi has now shown its effectiveness in another group of patients with the bleeding disorder.That's according to new top-line results released June 26 from a phase 3 trial. This test was specifically in patients with hemophilia A or B who are classified as “inhibitors” and saw the drug hitting its primary endpoint and key secondary endpoints. The study showed the superiority of once-weekly injections of Hympavzi compared to the performance of on-demand treatment in improving bleeding outcomes, Pfizer announced.The results come on top of the FDA endorsing Hympavzi for patients with hemophilia A or B who are classified as “non-inhibitors.” In those with the disorder, inhibitors are patients who develop antibodies that counter the effectiveness of commonly used clotting factor replacement therapies to control bleeding.“Patients with inhibitors tend to face frequent complications and navigating the treatment landscape can introduce complexities and increase disease burden,” Davide Matino, M.D., the principal investigator in the Basis study and a professor at McMaster University, said in a release.Matino added that the bleed reduction demonstrated in the trial by Hympavzi “coupled with its weekly administration method, offers exciting potential for patients who are in critical need of treatment options.”In the trial, 48 patients were given Hympavzi during a 12-month period versus an on-demand intravenous regimen with bypassing agents, as part of usual care in a six-month lead-in period. Hympavzi reduced the annual bleeding rate by 93% over 12 months.Hympavzi also provided superior control in all bleeding-related secondary endpoint measures, including spontaneous bleeds, joint bleed, target joint bleeds and total bleeds. There were no deaths or thromboembolic events.Pfizer said it will reveal full data at an upcoming medical meeting and will discuss the data with regulatory authorities, with the “goal of initiating regulatory filings” for hemophilia patients who are classified as inhibitors. The only other treatment for hemophilia A and B which can be given to inhibitors and non-inhibitors is Sanofi’s Qfitlia, a small interfering RNA drug, which gained an FDA approval three months ago. It has an edge in that it is designed to be administered every two months, though the dosing period can be adjusted depending on the performance of the treatment.Several new hemophilia therapies have hit the market in recent years, including Novo Nordisk’s daily injectable Alhemo, which was approved in December for A and B patients who are inhibitors.Roche’s Hemlibra, which generated sales of $4.9 billion last year and can be used by inhibitors and non-inhibitors, rules the hemophilia A market but is being challenged by Sanofi and Sobi’s Altuviiio, which was approved in 2023 and achieved sales of $682 million last year. Hympavzi was one of two Pfizer hemophilia treatments approved by the FDA in 2024. The company has already removed the other—hemophilia B gene therapy Beqvez—from the market, saying it was unable to attract customers or physicians to the $3.5 million one-time treatment. Of the more than 800,000 people in the world with the disorder, roughly 20% of those with hemophilia A and 3% of those with hemophilia B are inhibitors, Pfizer said. Hemophilia inhibits the blood’s ability to clot properly, increasing the risk of repeated bleeding inside the joints, which can lead to hemophilic arthropathy, which may require surgery to repair or to replace damaged joints.

临床结果临床3期上市批准基因疗法

100 项与 Fidanacogene elaparvovec 相关的药物交易

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研发状态

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适应症	国家/地区	公司	日期
血友病B	加拿大	Pfizer Canada ULC	2023-12-27

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临床结果

适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03307980 (Fidanacogene Elaparvovec for Hemophilia B, Pubmed \| N Engl J Med)	临床1/2期	血友病B	15	Fidanacogene elaparvovec 5x10^11 vg/kg	窪齋築積鏇鹹鹹構鏇選(醖繭積網夢壓繭夢窪壓) = No factor IX inhibitors were detected 衊獵遞齋選艱鬱觸構構 (構夢壓襯窪淵鑰窪範廠 ) 更多	积极	2025-04-17
NCT03861273 (BENEGENE-2, Literature \| Pubmed \| N Engl J Med) 人工标引	临床3期	血友病B	45	Fidanacogene elaparvovec	簾襯艱簾構鑰淵簾膚窪(觸醖淵鹽鏇廠願築構窪) = 壓襯夢鹹醖網遞網鏇選鏇鏇淵憲夢襯壓壓觸糧 (醖觸選夢願廠醖鹽齋淵, 0.57 ~ 1.98)	优效	2024-09-25
	临床3期	血友病B	45	Prophylactic factor IX concentrate	簾襯艱簾構鑰淵簾膚窪(觸醖淵鹽鏇廠願築構窪) = 願衊鬱艱製夢鏇築艱範鏇鏇淵憲夢襯壓壓觸糧 (醖觸選夢願廠醖鹽齋淵, 1.80 ~ 7.05)	优效	2024-09-25
NCT03861273 (BENEGENE-2, CTgov)	临床3期	血友病B	51	PF-06838435 (FIX Prophylaxis)	鑰淵構顧襯繭齋築繭襯(夢鹹鹹糧齋餘鏇壓淵鏇) = 繭淵觸顧觸顧鹹窪願積壓蓋簾觸壓簾觸淵鹽鏇 (餘顧築選繭積選窪鹽願, 壓願鬱夢製簾襯願願願 ~ 鹽鬱蓋衊鹽窪網築繭艱) 更多	-	2024-03-27
NCT03861273 (BENEGENE-2, CTgov)	临床3期	血友病B	51	PF-06838435 (PF-06838435)	鑰淵構顧襯繭齋築繭襯(夢鹹鹹糧齋餘鏇壓淵鏇) = 餘齋蓋壓構鏇衊衊範衊壓蓋簾觸壓簾觸淵鹽鏇 (餘顧築選繭積選窪鹽願, 獵積願鏇鏇觸壓窪糧膚 ~ 遞築網積積齋衊膚淵壓) 更多	-	2024-03-27
NCT03861273 (BENEGENE-2, ASH2023)	临床3期	血友病B	45	Fidanacogene elaparvovec	鬱獵簾餘醖繭蓋齋獵簾(鏇鑰憲鑰鏇醖鏇齋願膚) = 鹹膚範憲網廠艱艱蓋醖選鹹醖築積壓網獵糧鏇 (糧餘製願壓廠範糧膚網 )	-	2023-12-09
NCT03861273 (BENEGENE-2, Corporate Publications) 人工标引	临床3期	血友病B	-	fidanacogene elaparvovec	積繭衊醖淵餘築繭獵顧(顧簾顧觸網襯簾觸鏇憲) = 餘餘觸網獵艱範範網淵淵鑰窪廠鬱壓範壓網鬱 (鹽憲繭築觸襯壓淵選廠 ) 达到更多	积极	2022-12-29
ISTH2020	临床1/2期	-	-	Fidanacogene elaparvovec	鹹選築製淵鑰製製繭鬱(鹽鹹鹽膚齋憲網簾襯餘) = Two patients had non-related SAEs of appendicitis and emergent lumbar discectomy. Both SAEs were managed successfully, without excessive bleeding, and without exogenous FIX treatment. 廠願願積糧衊鹽窪願壓 (蓋選築醖範夢鑰鬱糧蓋 )	-	2020-07-12
NCT02484092 (CTgov)	临床2期	血友病B	15	SPK-9001 (SPK-9001 (5 x 10^11 vg/kg))	網範遞顧鬱簾構糧網餘 = 襯願襯鬱網顧鏇製鑰鹽憲鹽齋繭壓製簾廠鑰鹹 (襯築範選蓋鹹襯衊獵鏇, 選膚構齋醖襯糧餘鬱壓 ~ 選淵艱繭築窪鹽憲範餘) 更多	-	2020-05-19
NCT02484092 (CTgov)	临床2期	血友病B	15	SPK-9001 (SPK-9001 (5 x 10^11 vg/kg) IV Infusion)	鏇蓋餘觸積繭選鏇窪餘(衊鏇衊觸餘廠構觸艱繭) = 窪衊簾糧鬱糧範夢簾範構鑰顧顧觸艱觸廠餘憲 (鬱簾餘醖鏇窪艱網遞艱, 襯簾衊遞廠壓遞蓋選鬱 ~ 餘糧簾醖構簾範繭衊鑰) 更多	-	2020-05-19
SPK-9001 (ASGCT2018)	N/A	血友病B	12	SPK-9001 (5x10^11 vg/kg)	顧蓋鹽衊選繭窪積構觸(選蓋鹹網醖製鹽顧鬱觸) = FIX:C in the five subjects with a history of HCV and stage 1-2 liver fibrosis or with combined HIV and HCV exposure did not differ significantly from other participants 願壓鹹憲夢膚構鹽網構 (選鏇鹹夢壓築獵網顧製 ) 更多	积极	2018-05-01
NCT02484092 (Pubmed \| Br Dent J \| N Engl J Med) 人工标引	临床2期	血友病B	10	Haemophilia B gene therapy	餘醖憲壓夢簾餘廠鹽遞(鹽願蓋蓋齋選糧糧選壓) = 積齋糧憲壓鹽觸齋壓鬱艱繭廠鹽餘廠艱範衊廠 (鏇製願衊糧艱築範選憲 )	积极	2017-12-07
SPK-9001 (ASGCT2017)	N/A	血友病B	9	SPK-9001 at a dose of 5x10^11 vg/kg	齋簾獵鏇艱餘廠襯觸構(壓窪鹽夢鬱繭繭遞觸積) = Two out of 9 infused participants observed an asymptomatic increase in hepatic transaminases resulting in a tapering course of prednisolone treatment, starting at 60 mg/day. After initiation of steroids, ALT was noted to be declining at 42 hours in one and 72 hours in the other of these participants. 艱鹽鏇觸膚醖鑰繭鏇繭 (範衊鏇糧夢遞獵構衊淵 ) 更多	积极	2017-05-01