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.

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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.).

232

项与 Fidanacogene elaparvovec 相关的新闻（医药）

2025-08-04

·同写意

被“清算”的FDA主任，与CGT的未来

Replimmune飙升近70%，Capricor大涨超20%，Sarepta涨幅约14%……7月30日盘前，一批CGT Biotech股价在市场乐观情绪中迅速爬升。 7月29日晚间，HHS发言人证实，FDA生物制品评估与研究中心（CBER）主任Vinay Prasad已离职。5月初，他走马上任的消息传来，业界瞬间被忧虑笼罩。进入FDA之前，Prasad就因对CGT依赖的“弹性监管”批评而闻名。不到三个月的任期，某种程度被视为一种“清算”。纵观Prasad这段经历，最引人注目的便是与他批评过的Sarepta的冲突，后者开发的基因疗法Elevidys在2023年获得加速批准后，已发生多例患者死亡。 Canaccord Genuity分析师认为，这个搅进多方势力的争端，可能促使Prasad不得不离开。正如外界所熟知的，Prasad更倾向于采用具有临床意义而非替代终点的随机对照试验（RCT）。然而，6月初参与CGT圆桌论坛时，他表示，FDA将保持足够的灵活性，并愿意探索伞状试验等其他多元化的方案设计。随着Prasad离开，FDA药品评估与研究中心（CDER）主任George Tidmarsh，被任命为CBER临时主任。但Prasad曾兼任的FDA首席医疗和科学官职位，尚未得到安排。业界希望，FDA将对CGT的监管转向更为宽松。现实恐怕仍有很大不确定性。今年特朗普政府掌权以来，包括FDA在内的美国科学机构，都先后进行大规模裁员——监管机构的连续性和专业性，在CGT领域至关重要。 TONACEA 01 “受害者” Prasad担任CBER主任期间，CGT行业确实算不上乐观。相反，由于他的主导，FDA发出数封CRL，相应公司股价出现暴跌。 7月11日，FDA就拒绝了Capricor针对Deramiocel的上市申请。与长期处在漩涡中的Elevidys类似，Deramiocel作为同种异体心脏球衍生细胞疗法候选药物，也预期被用于治疗DMD。不过，CRL让该公司股价暴跌33%。同期，另一家Biotech Ultragenyx也在两天内暴跌29%。此前，FDA驳回了UX111（ABO-102）的BLA。 UX111的路线更为成熟，采取AAV技术，拟用于治疗A型桑菲利波综合征。尽管如此，FDA以近期完成的生产设施检查为由，要求Ultragenyx提供更多关于CMC方面具体细节的信息，并进行改进。对于Replimune，失败的代价更加惨烈。 Replimune打算将RP1（vusolimogene oderparepvec）与nivolumab联合用于治疗晚期黑色素瘤，结果这一申请在7月22日没有得到FDA批准，随后公司股价暴跌76%。 CRL指出，Replimune所提交BLA依据的IGNYTE 试验，不被认为是一项充分且控制良好的临床研究，未能提供实质性的有效性证据。根据多份已发表的报告，韦德布什分析师称，Prasad更倾向于将总体生存期作为癌症终点，而不是无进展生存期或肿瘤缩小等替代终点，这解释了为什么他可能在RP1被拒绝的过程中发挥了关键作用。至于Capricor，STAT援引一位消息人士的话表示，Prasad因为“持怀疑态度”，取消了原定于7月30日举行的细胞、组织和基因治疗咨询委员会会议，该会议旨在审查该公司提交的Deramiocel申请。值得注意，此次咨询委员会会议是由CBER治疗产品办公室（OTP）主任Nicole Verdun安排，但她和副手Rachael Anatol从6月18日起就被安排“行政休假”。据报道，Prasad与“Verdun管理风格长期存在的紧张关系”，可能也是此次行动的原因。 HHS在一份声明中，暗示了Prasad与Verdun、Anatol之间的摩擦：“中心主任应该得到那些与积极目标保持一致的管理人员的支持，以便使用科学的黄金标准迅速推进罕见疾病的治疗。” TONACEA 02 离职余波 BMO资本市场分析师写道：“我们基本上将此视为一件好事，因为新任CBER主任可能会比我们迄今为止看到的更宽容地鼓励创新。” 虽然具体人选尚不确定，仅此一种可能性，就会使股价受益。 7月30日，Prasad离职后的首个交易日，Replimune股价最终上涨了一倍多，从每股3.75美元飙升至每股7.55美元，涨幅达101%。Capricor股价上涨21%，从每股6.74美元涨至每股8.18美元。Sarepta股价也出现6%的反弹。 Canaccord Genuity分析师也认为，Prasad离开FDA对于CGT等领域的影响总体上是积极的，毕竟“他在肿瘤学审批、临床研究设计和其他领域持有争议性的负面观点”。鉴于Prasad离职，肿瘤学的加速审批可能会有所回升——这对该行业来说是一个重大利好；Prasad此前对加速审批途径持强烈批评态度。他的离职，可能会让FDA在肿瘤学加速审批的试验设计方面拥有更大的灵活性。分析师还预测，针对ALS、亨廷顿舞蹈症和雷特综合征等罕见神经系统疾病的在研药物，有望迎来“一线希望”，审批流程将更加顺畅，而监管灵活性在这些疾病中至关重要。此外，针对更大患者群体的药物，也被认为是前景乐观。例如，AD和其他类型的痴呆症、帕金森病以及神经精神病领域，精准靶向、基于生物标志物的开发策略正日益重要。不过不乏异议者。Jefferies分析师就为Prasad在CGT监管决策做辩护。在一份报告中，分析师写道：“监管决策未必不合理，FDA也未必更失职。如果说有什么不同的话，我们认为Prasad在FDA审批方面考虑得更理性（也更保守），要求申办方提供更多临床证据（并且减少捷径）。” 换言之，在Prasad领导下，事态发展似乎相对更容易预测，因为CBER的决策背后有条理、框架和依据。此外，CRL似乎相当透明。 TONACEA 03 Sarepta之战最为引人注目的是，Prasad掌舵期间，FDA要求Sarepta暂停向可行走的DMD患者发货Elevidys。 7月，Elevidys被曝出第三名与DMD治疗相关的患者死亡，是一名巴西8岁男孩。除了FDA之外，华尔街也一片哗然。7月18日Sarepta拒绝FDA的要求，但三天后又改口同意。随后7月25日，FDA支持Sarepta，建议该公司恢复向无法行走的DMD患者提供Elevidys。FDA解释其改变决定的原因时，援引了巴西当局的说法，即排除Elevidys治疗是导致该男孩死亡的原因。然而，自Prasad离职以来，新闻报道却描绘了一幅截然不同的幕后景象。 Prasad对Sarepta的强硬态度在一定程度上有所转变，因为DMD患者权益倡导者积极通过Change.org网站发起请愿，近千人签名敦促FDA结束暂停行动。非营利组织Parent Project Muscular Dystrophy创始人Pat Furlong透露，患者权益倡导者还致信国会议员，并与他们会面。 7月28日，FDA宣布暂停期结束时表示：“患者群体是一个重要的声音，FDA将继续倾听并回应受DMD影响的群体的想法。” Jefferies分析师认为，这给FDA的未来提出了一个重要问题：Prasad的突然离职让人怀疑，FDA是否更容易受到外部因素——包括患者权益团体、政治、媒体——的影响。如果二者具有正相关性，那么，患者权益团体未来可能会成为左右药物监管的主导力量之一。患者群体的影响，可能反映了FDA内部的分歧。正如Leerink Partners分析师指出的，近期FDA和Sarepta的反复交锋，凸显了该机构自身存在紧张关系，表明FDA高层间出现分歧。随着Prasad作为CBER主任的任期结束，分析师怀疑，他的离职可能预示着，“MAHA运动”将转向更加宽松、以患者权益为中心的“尝试权”，以应对罕见病适应症。允许患者更容易获得尚未被FDA批准的实验性治疗，这一“尝试权”法案，长期是特朗普政府支持者的优先事项之一。 TONACEA 04 保守派 Prasad离职的另一个因素，被认为是保守派的运作，他们反对Prasad及其对Sarepta的处理方式。威斯康星州共和党参议员Ron Johnson向透露，HHS部长RFK Jr.安排他与FDA局长Marty Makary通话，随后他向RFK Jr.表达了对FDA处理Elevidys问题上的担忧，亲自向特朗普汇报了有关情况。此外，据Bloomberg援引消息人士称，前宾夕法尼亚州参议员Rick Santorum在其女儿被诊断出患有罕见遗传病18三体综合征后，转而成为家长倡导者，给特朗普政府官员打了电话。 “美国优先”旗手Laura Loomer在社交媒体抨击Prasad，文章引用了后者2020年至2022年期间发布的多篇帖子，它们都支持进步政治家，例如长期担任NIH国家过敏和传染病研究所（NIAID）所长的Anthony S. Fauci——Fauci关于美国政府应对COVID-19的监督批评，在保守派中非常不受欢迎。在Loomer看来，Prasad就是“FDA里的一匹特洛伊木马”，应该“把他从特朗普政府里开除”。 HHS的声明展现了众所周知的“高姿态”：“Prasad不想影响FDA在特朗普政府领导下所取得的卓越成就，他决定返回加州，花更多时间陪伴家人。” Makary已任Tidmarsh临时接替CBER主任的空缺。而数日前，Tidmarsh才刚刚当上CDER主任。还未加入FDA时，Tidmarsh曾在斯坦福大学医学院担任儿科和新生儿科兼职教授。他还是斯坦福大学转化研究与应用医学硕士项目的创始联席主任，领导了7种被FDA批准的药物的临床开发，参与多家药企的创办并担任CEO，其中包括Horizon，2023年安进以278亿美元的价格将之收购。 Jefferies分析师指出，与Prasad类似，Tidmarsh也长期直言不讳地反对前CBER主任Peter Marks，除了对FDA放行的Elevidys予以批评外，Tidmarsh还将渤健开发的AD新药Aduhelm为例，认为FDA监管过于宽松。 TONACEA 05 谁来拯救？对Sarepta等CGT Biotech的新一轮追捧，显露出二级市场投资者尚未完全放弃这个领域。但是，如果换到往产业更前端追索，情形似乎就并非如此。仅有的“天价爆款”Zolgensma，在诺华2023年财报中被冷落一旁。2021年成为卖出13.51亿美元、成为“重磅炸弹”后，Zolgensma开始出现瓶颈：2022年全球销售额仅增长1%，2023年则下降11%。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CGT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。当然，CGT仍存在不小的存量市场。公开数据显示，2025年，将有多款CGT的监管决策有待FDA做出，而全球正在进行的CGT临床试验数量将近2000项。问题在于，包括Prasad在内，FDA新的领导层似乎没有更高效的监管方案。随着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”。不到三个月就“败走”FDA的Prasad，草草交出下一棒。而CGT行业想要彻底转身，恐怕还需一定时日。参考资料： StockWatch: As Prasad Exits FDA, Analysts See Benefit for Sarepta, CGT Stocks

加速审批基因疗法细胞疗法高管变更

2025-07-29

·研发客

单次治疗、长期获益，基因治疗补足血友病群体缺失的人生“拼图”

// •波哌达可基注射液使用嗜肝性AAV843衣壳作为递送载体；•第一批接受波哌达可基注射液治疗的患者，经过4~5年临床数据观察，FIX 基因表达水平保持稳定；•在全球同类产品中，波哌达可基注射液的剂量更小、活性更高；•信念医药的生产基地可以“完全满足临床需求”，并实现 “关键耗材的国产替代”；•在支付上，武田与信念联合进行了多种积极探索和努力。在血友病治疗领域，基因治疗被认为是目前最前沿的疗法，目前全球已有3款血友病B基因治疗产品获批。2022年11月，由UniQure/CSL研发的全球首个针对血友病 B 的基因治疗产品Hemgenix获FDA批准上市；2024年，辉瑞推出了同类产品Beqvez。而在今年，中国患者迎来了首款本土创新基因疗法 —— 由信念医药研发的波哌达可基注射液（BBM-H901，商品名：信玖凝®），用于中重度血友病 B 成年患者的治疗。站在后发者的位置上，波哌达可基注射液的成绩单毫不逊色，甚至表现得更好。在接受波哌达可基注射液治疗一周后，罹患血友病 B 二十多年的牧歌（化名）的凝血因子 IX （Factor IX ，FIX）活性从近乎零升至正常水平。之后，他进行了一场全球首例，未接受任何外源性FIX药物治疗的全膝关节置换术。曾经举步维艰的他终于告别了卧床、疼痛、反复出血的生活。如今，驰骋草原不再是这位蒙古汉子遥不可及的梦。而他走出的人生第一个 5000 步，也是中国血友病 B 基因疗法迈出的第一个里程碑。AAV衣壳工程化改造，实现凝血因子IX水平持续高位稳定在全球首款基因疗法Glybera[1]横空出世后的十余年时间里，相继近10款基因治疗产品获批上市。该疗法已被认为是遗传性疾病及罕见病领域极具潜力的治疗手段。然而，以天然 AAV 为递送系统的第一代基因治疗药物，仍然面临着诸多挑战。相比于纳米颗粒和抗体，AAV 最大的优势在于能进入中枢神经、肌肉等各个组织，正因如此，也存在着脱靶的风险。目前，全球的基因治疗领域的研发者都在钻研下一代基因治疗药物，即通过工程化改造的方法，将 AAV 的衣壳稍做改变，实现 “不同的钥匙开不同的锁。” 比如，2022 年，Voyager 授权诺华其衣壳发现平台开发的创新 AAV 衣壳权益，针对 3 个 CNS 靶点，以及两个靶点衣壳的选择权；辉瑞也获得了 Voyager TRACER 衣壳发现平台生成的一款新型 AAV 衣壳的授权，针对罕见神经疾病靶点的基因治疗。可以说，在衣壳上下功夫，已经成为 AAV 基因治疗赛道重要的争夺点。在波哌达可基注射液的开发过程中，信念医药的团队经过反复、多轮筛选，寻找组织靶向性强、安全性高、预存抗体水平低、生产容易等方面均优秀的血清型。最终，采用了自主研发的嗜肝性 AAV843 衣壳，能将优化后的FIX基因精准递送至肝脏。“波哌达可基注射液的递送载体AAV843衣壳，是一个强肝靶向的衣壳，因为正常人都是通过肝脏来分泌FIX。AAV843 衣壳是经过一系列筛选和工程化改造后获得的，基于该衣壳制备的波哌达可基注射液在静脉注射之后，绝大部分都进入到肝脏，基因表达效率高，而且因为采用了双链 AAV设计，基因表达非常快。”信念医药联合创始人、董事长兼首席科学家肖啸博士说。据肖啸博士介绍，波哌达可基注射液在给药的第三天就可以检测到凝血因子活性显著提升，一个星期内即可达到峰值，患者的FIX活性水平可升至60%~70%（正常范围50%~150%），甚至更高。并且，绝大多数患者在接受基因治疗之前，已停用凝血因子重组蛋白，接受基因治疗之后也不用给予外源性FIX输注。而对比 UniQure/CSL的 Hemgenix，患者在注射之后的前一个月，仍需要接受外源性FIX辅助治疗，以应对初期表达量不足的情况。此外，信念的研发团队还对控制基因表达的启动子进行了工程化改造，并通过应用血友病B基因治疗主流的FIX-Padua基因，使FIX活性水平提高8倍，重建人 FIX 正常表达功能，实现 FIX 水平持续稳定，无波峰波谷变化。“第一批接受波哌达可基注射液治疗的患者，经过 4~5 年临床数据观察，FIX 基因表达水平从给药开始到第一年，再到第五年都非常稳定。”肖啸博士说。更小的剂量，更高的活性，是波哌达可基注射液有别于全球同类产品的一大特点。据肖啸博士介绍，从研究者发起的临床研究（investigator-initiated trial）和注册临床研究数据来看，以全球通用、一样的方法检测（基于SynthaSIL aPTT试剂的一期法），给药后52周时，波哌达可基注射液的 FIX 活性在正常水平的50%以上，Hemgenix在40%左右，辉瑞的Beqvez是20%左右。与此同时，波哌达可基注射液的剂量只有Hemgenix 的四分之一。除了技术创新突破之外，生产也是非常重要的环节，在肖啸博士看来，对新药而言，得生产者得天下。因此，信念在生产上花了大功夫，在上海临港建立 15000 平方米生产基地，具备 3 条质粒生产线、3 条重组腺相关病毒载体（rAAV）生产线、整套全自动无菌制剂灌装系统等，符合中国、美国和欧盟药品生产质量管理规范（GMP）标准。“我们的灌装系统能满足基因治疗药物不同阶段、不同规模的生产需求。比如血友病 B，因为患者群体比较小，一罐 200 升的药物可以治疗几十个病人，一年二十几罐的产能，完全满足临床需求。此外，通过工艺改进，在保证产品质量前提下实现了关键耗材的国产替代。”肖啸博士说。一步一个脚印，迈向血友病基因治疗时代血友病基因治疗的研发之路，每一步技术突破都需跨越多重科学难关，在临床试验过程中，还要接受长期安全性、疗效验证的挑战。2019 年，在中国医学科学院血液病医院张磊教授团队牵头之下，波哌达可基注射液的 IIT 正式启动，这也是亚洲首个肝靶向 AAV 载体血友病 B 基因治疗临床试验。张磊教授回忆道：“当时多数患者对基因治疗认知还不足，我们向患者进行了全面的解释，分享了国外基因治疗的数据。其实美国的基因治疗开始于 2011 年，相比之下，我们晚了七八年。在前人的基础上，我们对产品进行改造和提升，安全性和疗效有信心比肩国外的产品。”早期IIT 研究结果显示，单次静脉输注接受波哌达可基注射液治疗后，患者4~5年长期随访各访视点的平均FIX水平均> 35%（一期法 actin FSL ）。90%患者0出血，90%患者0补充注射。长期随访未发现肝毒性以及波哌达可基注射液相关SAE，未发现抑制物、血栓栓塞和恶性肿瘤事件。2021 年，波哌达可基注射液获批注册临床研究，并在 2024 年完成3 期临床试验给药后52周的随访。接受基因治疗后随访52周时的数据显示，26 例中、重型血友病 B 成年男性受试者，通过单次静脉输注接受波哌达可基注射液治疗后，平均FIX水平达55%（基于SynthaSIL aPTT试剂的一期法），平均ABR低至0.6。安全性方面，所有受试者均未观察到SAE、抑制物、血栓事件或3-4级药物相关不良事件。张磊教授感慨道：“遇到的难题并不少。首先，从众多改造的AAV衣壳中筛选合适的载体，是一个非常大的工程。改造完之后，申请专利，再开展一系列试验，每一步都伴随着失败的可能。从载体设计到细胞、动物实验、安全毒理实验，再到人体试验，每个技术环环相扣。只有选出最合适的产品，才可能应用到人体身上。”“在开展人体试验之前还要通过学术委员会，伦理委员会等专家们的审评。我们详细地呈现了安全性和疗效数据，并与国外产品进行对比。在人体上得到验证以后，再着手准备申报上市。现在回想起来，这是一个非常漫长的过程，但是团队坚持下来，最终获得了成功。”2022年，波哌达可基注射液被国家药品监督管理局药品审评中心纳入“突破性治疗品种”名单。2025年4月，波哌达可基注射液正式获批，成为中国首个无条件获批上市的、针对遗传性疾病的基因治疗产品，也象征着中国本土基因治疗的“破冰”。基于波哌达可基注射液丰富的循证医学证据，近期发布的《中国血友病管理指南(2024版)》、《中国血友病B腺相关病毒载体基因治疗临床应用指导意见(2025)》等指导性文件都对这一创新治疗手段给出推荐，并呼吁尽快在临床实践中落地推广。“单次治疗、长期获益”，基因治疗补足患者缺失的“拼图”血友病 B 是一种遗传性的FIX 缺乏的疾病。其中，重型（凝血因子活性小于 1%）和中间型（凝血因子活性 1%~5% 之间）的血友病患者，非常容易出血。比如牙龈出血，鼻子出血，更常见的是关节的出血，比如膝关节、踝关节、肘关节的反复出血，导致关节畸形。严重的出血（包括消化道出血、脑出血）甚至会危及生命。很多患者从小由于出血，不能上学，不能工作，长期居家。血友病B患者从出生起便深陷FIX缺失的困境，如同被命运抽走生命画卷中一块关键的“拼图”。目前，临床上应用最广泛的治疗手段是FIX替代治疗，而它的局限性也非常明显。由于FIX在体内的半衰期大约在20个小时左右，静脉输注两三天后逐渐代谢，意味着患者仍然会出血。因此，需要长期、终生，每周注射1~2次FIX治疗。并且，FIX产品的价格昂贵，无论生活成本、经济成本还是患者生活质量，都是巨大的负担。据张磊教授介绍，当下FIX的治疗费用并不低，且患者需要终生治疗，如果患者平均寿命是70~80岁的话，意味着总治疗费用可能高达上千万人民币。基因治疗作为一种创新疗法，与传统治疗最大的差异在于，单次治疗，长期有效。国外第一例接受治疗的患者到现在已有13~14年的时间。再以波哌达可基注射液为例，AAV 病毒载体携带高活性FIX，注射到体内后感染肝脏细胞，能持续自主表达高活性的FIX。通过这样的治疗，患者不再需要频繁、长期输注凝血因子，生活质量得到很大的提高。据张磊教授透露，一些患者在经过治疗之后达到了 “临床治愈” 的状态，能像正常人一样生活。张磊教授进一步分析认为，尽管基因治疗单次定价较高，但如果患者能实现一次性 “治愈”，不再需要长期输注FIX，那么，相对于终生的FIX治疗，费用其实低很多，这也是一些发达国家致力于推进基因治疗产品研发的重要原因。此外，如果通过基因治疗，能让患者达到临床的治愈，回归社会正常工作生活，患者能给社会带来的价值将远远超出医疗的付出。目前，全球各国针对基因治疗都在摸索创新的支付模式，包括政府医保、商保、慈善机构参与等多方支付的协同，以期让患者受益于医疗进步的同时，也能维护医保体系的可持续性。作为首个国产血友病基因治疗产品，信念选择了跨国制药企业武田制药作为其中国的商业合作伙伴，后者将负责波哌达可基注射液在中国内地、中国香港和中国澳门地区的商业化。为解决患者最为关心的支付问题，自产品上市以来，两家公司已经联合进行了多种积极探索和努力。据悉，波哌达可基注射液在中国大陆地区的单瓶价格为9万3千元。根据说明书，每位患者治疗的具体用药量（即瓶数）按照患者体重计算。为使更多血友病B患者尽快享受到基因治疗“单次治疗、长期获益”的创新成果，今年7月8日，北京病痛挑战公益基金会发起并运行“友”爱相助——血友病慈善援助项目，向国内符合项目条件的援助对象援助波哌达可基注射液，用于减轻血友病B患者经济负担，帮助患者实现正常生活的愿望。针对符合申请条件且审核通过后成功入组的血友病B患者，根据医嘱进行单次治疗过程中，只需自费购买30瓶药品。例如，70kg体重的处方用量是44瓶，其中高于30瓶以上的治疗药物，将由此公益项目免费援助支持；因此患者自付的治疗费用最高不会超过279万元。此外，武田中国与信念医药也在积极协同多方力量，系统性推进和探索多层次保障方案，希望能缓解患者因费用问题而面临的治疗困境，让医疗创新的成果能惠及更多罕见病患者。国产血友病 B 基因治疗药物的突破，不仅让患者迎来凝血功能的复原，随着最后一块“拼图”的归位，患者也将获得人生可能性的完整绽放，更标志着我国在血友病治疗领域从 “追赶” 迈向 “引领”。其成功经验给治疗遗传性疾病带来了范例，将激励更多中国的新药研发者们循着这条道路继续探索。资料来源：[1] Glybera治疗脂蛋白脂肪酶缺乏症的产品，是全球第一款AAV产品，于2012年在EMA获批上市，后又退市编辑 | 姚嘉yao.jia@PharmaDJ.com总第2520期访问研发客网站，深度报道和每日新闻抢鲜看www.PharmaDJ.com

基因疗法上市批准

2025-07-25

·FierceBiotech

\'We will crack gene therapy\': Elevidys fallout doesn\'t dent Roche\'s hopes for modality

Roche Pharma CEO Teresa Graham spoke to Fierce Biotech on the sidelines of the company\'s first-half earnings event.\n The uncertainty around the future of Elevidys hasn’t destroyed Roche’s belief in the potential of gene therapies, the Swiss company’s head of pharma has told Fierce Biotech, as the pharma continues to expand its research reach outside of its traditional oncology focus.Roche and its partner Sarepta Therapeutics both paused trials of Elevidys back in April following the death of a 16-year-old patient in the U.S. Since then, Roche—which markets the drug outside of the U.S.—has stopped all ex-U.S. distribution of the drug in the commercial setting for non-ambulatory patients, while the FDA requested that Sarepta halt Elevidys shipments in the U.S. Earlier this week, Roche paused shipments in all patients in countries where Elevidys’ approvals referenced the FDA.But Roche Pharma CEO Teresa Graham denied Fierce’s suggestion that the issues around Elevidys have altered how the company views gene therapy as a modality.“It doesn’t, actually,” Graham told Fierce in an interview at Roche’s headquarters in Basel, Switzerland on Thursday.“The reality is that gene therapy will be an important modality in the treatment of human health,” Graham continued. “There is a lot of promise in gene therapy. I think what the entire industry is learning is that, scientifically, it\'s just a little harder than we might have thought.” Even before the latest difficulties with Elevidys, Roche had announced a “fundamental reorganization” of Spark Therapeutics, the gene therapy unit the Swiss pharma bought for $4.3 billion in 2019. That overhaul closely followed Roche’s decision to end work on a hemophilia A gene therapy candidate, which was a focus of the Spark acquisition.Roche’s move came against a backdrop of wider industry retreat from gene therapy, with Pfizer pulling its FDA-approved hemophilia B treatment Beqvez. Bluebird bio, a gene therapy pioneer once valued at $10 billion at its peak, was sold for just $49 million upfront to private equity firms.But Roche still sees potential in the modality, according to Graham.“I am firmly convicted that over time we will crack gene therapy and we will be able to deliver really meaningful treatments to patients,” she said.Graham spoke to Fierce on the sidelines of the company’s first-half earnings event, where Roche CEO Thomas Schinecker reminded journalists that 760 boys have successfully received Elevidys in the ambulatory setting.“I\'m really hopeful that we can find a path forward for this medicine,” Graham said in the interview on Thursday. “We clearly need to talk to regulators; we clearly need to have some good conversations about the safety—but we do firmly believe in the risk-benefit of this product.”Not all regulators sound ready to be convinced, with the European Medicines Agency (EMA) announcing Friday morning that it won\'t recommend Elevidys for approval in the ambulatory setting. Roche said in a statement that it “plans to continue to work with the EMA to explore a potential path forward.” Mixed results from emerging pipeline Another drug that Roche is keeping faith in is the Parkinson’s disease prospect prasinezumab. The future of the Prothena Biosciences–partnered asset looked in doubt after the anti-alpha-synuclein antibody failed a phase 2 study in December 2024.But Roche is giving prasinezumab a second chance, with plans to launch a phase 3 trial by the end of the year off the back of an analysis of data from the failed study. Specifically, the pharma pointed to longer-term follow-up data from an open-label portion of the study suggesting a clinical benefit on top of symptomatic treatment in early-stage Parkinson’s.“Given the dramatic unmet need in Parkinson\'s, it does feel like it would be a miss not to explore this,” Graham explained.“There\'s only really been minor improvements in treatments for these patients over the last 50 years, and, in every conversation I\'ve had with [key opinion leaders], they have really encouraged us to take this forward,” she said.“There\'s a little bit of a finger feel that there\'s something there, and we\'re only really ever going to be able to pull the signal out in a phase 3,” Graham added. Roche had less faith in CT-173, an early-stage obesity drug picked up as part of its $2.7 billion acquisition of Carmot Therapeutics in 2023. The Swiss pharma had previously touted the long-acting PYY analog’s potential to drive weight loss past the GLP-1 plateau, but Graham announced at the earnings event that Roche would no longer take CT-173 into human trials after assessing its “developability and competitiveness.”Despite this early-stage setback, Graham still feels that combinations offer Roche a path to carving out its own corner of the increasingly crowded obesity space.“Obesity is inherent in something like 200 other diseases,” she said. “So the ability to actually look at where we believe our portfolio in combination with other drugs can really help address some of these comorbidities is one of the more exciting pieces.”“This is an incredibly big market,” Graham added. “It is very diverse. There are a lot of scientific pathways to explore here.”One of those pathways is amylin, a hormone involved in the regulation of food intake. In March, Roche paid Zealand Pharma $1.6 billion for the long-acting amylin analog petrelintide. Graham sees the drug’s potential growing as the obesity market segments among patients “looking for maybe different depths of weight loss or different tolerability profiles.”Meanwhile, Roche has yet to make a final call on whether to take the GLP-1/GIP receptor agonist CT-388—another Carmot asset—into a phase 3 obesity trial, but Graham said the company is “right on the cusp” of taking that program forward.“We plan to make those decisions later this year, and, once we get rolling here, I think you\'re really going to see us flesh out our [obesity] strategy,” she said. When it comes to bringing new drugs into Roche’s pipeline, Graham was tight-lipped on which of the company’s five core focus areas—neurology, oncology/hematology, immunology, ophthalmology and CVRM (cardiovascular renal metabolic)—the company is prioritizing for M&A.“Clearly, within our five therapeutic areas, there are definitely places where we would like to bring in additional assets,” she told Fierce. “As Thomas [Schinecker] said, we look at an unbelievably large number of deals every year, and are constantly on the hunt, not only for things that will fit that strategy but things that are truly transformational.”With such a multifaceted pipeline, what are the readouts Graham is most excited about?“It\'s like trying to choose your favorite child,” she said, before name-checking the recent “super exciting” phase 2 results for the BTK inhibitor fenebrutinib in relapsing multiple sclerosis (MS). “It could be a really huge step forward for MS patients,” she explained.There’s also the “high-risk, high-reward bet” on the Parkinson’s drug prasinezumab, said Graham, who ended by referencing the IgG1 monoclonal antibody afimkibart.Along with CT-388 and the Alzheimer’s disease prospect trontinemab, afimkibart was one of the assets Roche fast-tracked as part of its reallocation of R&D resources.“I\'m an immunology girl at heart—it’s where I started my career,” Graham explained. “There\'s so much opportunity in the immunological space and so many diseases that we could potentially tackle with afimki.”

$\'We will crack gene therapy\': Elevidys fallout doesn\'t dent Roche\'s hopes for modality$

并购临床2期临床3期

100 项与 Fidanacogene elaparvovec 相关的药物交易

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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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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	醖築艱淵鬱憲製獵衊窪(餘願觸願衊餘網窪蓋廠) = No factor IX inhibitors were detected 觸糧願夢願艱糧選艱鑰 (壓鏇醖鹹餘繭衊選齋遞 ) 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	廠簾膚醖夢顧製夢遞憲(衊壓艱鹽廠壓窪鏇鏇醖) = 製遞選鹹鬱繭範簾餘糧鹹鹽糧獵艱顧餘衊廠壓 (構憲廠膚繭衊構糧膚壓, 0.57 ~ 1.98)	优效	2024-09-25
	临床3期	血友病B	45	Prophylactic factor IX concentrate	廠簾膚醖夢顧製夢遞憲(衊壓艱鹽廠壓窪鏇鏇醖) = 網鹹觸憲鑰築蓋製襯糧鹹鹽糧獵艱顧餘衊廠壓 (構憲廠膚繭衊構糧膚壓, 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)	鏇範繭夢齋憲鏇淵壓糧(積窪網蓋鏇繭憲製壓艱) = 網醖遞窪鑰夢鏇製醖範艱獵選鹽網鹹醖鏇簾壓 (餘壓範鹽鏇願簾衊衊顧, 繭淵淵鬱願蓋獵鹹壓鑰 ~ 糧憲憲構蓋觸蓋鏇艱艱) 更多	-	2024-03-27
NCT03861273 (BENEGENE-2, CTgov)	临床3期	血友病B	51	PF-06838435 (PF-06838435)	鏇範繭夢齋憲鏇淵壓糧(積窪網蓋鏇繭憲製壓艱) = 觸蓋鏇鑰廠憲獵顧願艱艱獵選鹽網鹹醖鏇簾壓 (餘壓範鹽鏇願簾衊衊顧, 遞鑰鹽顧製觸積獵鹹襯 ~ 鑰齋觸顧製鏇蓋壓鑰衊) 更多	-	2024-03-27
NCT03861273 (BENEGENE-2, ASH2023)	临床3期	血友病B	45	Fidanacogene elaparvovec	窪衊廠遞壓廠選簾鏇鹽(鹹壓糧繭壓積獵網網鹽) = 蓋糧選選積鬱願範膚夢選鹹繭鏇鬱構築積齋範 (夢網鏇蓋簾糧夢願鹹獵 )	-	2023-12-09
NCT03861273 (BENEGENE-2, Corporate Publications) 人工标引	临床3期	血友病B	-	fidanacogene elaparvovec	觸鹹窪製壓廠膚遞網壓(遞淵憲簾糧簾選壓醖醖) = 蓋鏇鏇願觸鑰觸糧醖鏇簾觸憲繭鏇鹹艱窪窪鑰 (繭築鹽選壓蓋襯鏇廠餘 ) 达到更多	积极	2022-12-29
ISTH2020	临床1/2期	-	-	Fidanacogene elaparvovec	糧鏇廠鏇壓壓膚築糧積(鑰壓獵齋夢衊淵遞構廠) = 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. 顧齋鏇繭網艱憲選製遞 (衊衊夢簾艱範艱齋鬱觸 )	-	2020-07-12
NCT02484092 (CTgov)	临床2期	血友病B	15	SPK-9001 (SPK-9001 (5 x 10^11 vg/kg))	淵願構淵鬱構簾衊鑰願 = 淵鑰壓鑰鹽積醖築鹹範積鹽鑰簾簾鬱壓觸鏇築 (鏇鏇範醖觸夢顧築選淵, 網製鏇蓋構願膚壓衊顧 ~ 網蓋顧遞顧鏇夢憲膚襯) 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)	願鬱齋窪築夢選餘齋選(獵鏇夢範築鬱襯獵淵廠) = 繭構襯積膚獵醖製選簾選製蓋築壓齋願鹽夢膚 (觸繭繭糧糧衊觸衊衊鏇, 網窪鬱鑰鹹簾觸淵簾願 ~ 選鏇襯衊壓繭選製憲鹽) 更多	-	2020-05-19
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	淵鹹鬱醖遞獵鹽鏇顧糧(鏇顧構壓構膚艱遞窪遞) = 鹹夢觸鏇襯鹽範糧憲窪襯網醖獵糧繭鬱艱構廠 (簾壓鑰艱選繭鹹願膚積 )	积极	2017-12-07