在GENEr8-1期临床试验中，valoccogene roxaparvovec基因转移治疗严重血友病A后4年的疗效、安全性和生活质量

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis Pub Date : 2024-11-01 DOI:10.1016/j.rpth.2024.102615

Andrew D. Leavitt , Johnny Mahlangu , Priyanka Raheja , Emily Symington , Doris V. Quon , Adam Giermasz , Maria Fernanda López Fernández , Gili Kenet , Gillian Lowe , Nigel S. Key , Carolyn M. Millar , Steven W. Pipe , Bella Madan , Sheng-Chieh Chou , Robert Klamroth , Jane Mason , Hervé Chambost , Flora Peyvandi , Elaine Majerus , Dominic Pepperell , Margareth C. Ozelo

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引用次数: 0

摘要

valoccogene roxaparvovec是一种腺相关病毒介导的治疗严重血友病A的基因疗法，可使内源性因子(F)VIII表达并提供出血保护。目的评价伐罗替克治疗4年后的疗效、安全性和耐受性。方法在GENEr8-1 iii期临床试验中，134名患有严重血友病A且未使用抑制剂且先前使用过FVIII预防药物的成年男性患者接受了6 × 1013vg /kg的缬罗替克输注。疗效终点包括年化出血率、年化FVIII输注率、FVIII活性和成人血友病特异性生活质量问卷。评估不良事件和免疫抑制剂的使用情况。在受试者停止预防治疗（计划第4周）后，评估与基线的变化。2名参与者自上次数据截止后停止。与基线相比，平均治疗年化出血率下降(- 82.6%；P & lt;0.0001)和年化FVIII输注率(−95.5%；P & lt;.0001)的数据与前几年的非干预性研究纳入的112名参与者的主要分析人群保持一致。在第4年，110名轮转参与者中有81人经历了0次治疗出血。在第208周，130名修改意向治疗的参与者中，显色FVIII活性的平均值和中位数分别为16.1 IU/dL和6.7 IU/dL。自上次数据截止以来，7名参与者恢复了预防。成人血友病特异性生活质量问卷总分从基线到第208周的平均变化(P <；0.0001)对于修改意向治疗的参与者仍然具有临床意义。丙氨酸转氨酶升高是第4年最常见的不良事件（56/131参与者）；不需要免疫抑制剂。结论伐罗替克提供持续的FVIII表达、止血控制和健康相关生活质量改善，无新的安全信号。

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Efficacy, safety, and quality of life 4 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A in the phase 3 GENEr8-1 trial

Background

Valoctocogene roxaparvovec, an adeno-associated virus-mediated gene therapy for severe hemophilia A, enables endogenous factor (F)VIII expression and provides bleed protection.

Objectives

Determine valoctocogene roxaparvovec durability, efficacy, and safety 4 years after treatment.

Methods

In the phase 3 GENEr8-1 trial, 134 adult male persons with severe hemophilia A without inhibitors and previously using FVIII prophylaxis received a 6 × 10¹³ vg/kg infusion of valoctocogene roxaparvovec. Efficacy endpoints included annualized bleed rate, annualized FVIII infusion rate, FVIII activity, and the Haemophilia-Specific Quality of Life Questionnaire for Adults. Adverse events and immunosuppressant use were assessed. Change from baseline was assessed after participants discontinued prophylaxis (scheduled for week 4).

Results

Median follow-up was 214.3 weeks; 2 participants discontinued since the previous data cutoff. Declines from baseline in mean treated annualized bleed rate (−82.6%; P < .0001) and annualized FVIII infusion rate (−95.5%; P < .0001) were maintained from previous years in the primary analysis population of 112 participants who enrolled from a noninterventional study. During year 4, 81 of 110 rollover participants experienced 0 treated bleeds. Week 208 mean and median chromogenic FVIII activity were 16.1 IU/dL and 6.7 IU/dL, respectively, in 130 modified intention-to-treat participants. Seven participants resumed prophylaxis since the previous data cutoff. Mean change from baseline to week 208 in Haemophilia-Specific Quality of Life Questionnaire for Adults Total Score (P < .0001) remained clinically meaningful for modified intention-to-treat participants. Alanine aminotransferase elevation was the most common adverse event during year 4 (56/131 participants); none required immunosuppressants.

Conclusion

Valoctocogene roxaparvovec provides persistent FVIII expression, hemostatic control, and health-related quality of life improvements with no new safety signals.

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