静脉注射用罗沙帕洛维治疗 A 型血友病的基因疗法。

Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A.

机构信息

From Hemocentro UNICAMP, Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil (M.C.O.); the Hemophilia Comprehensive Care Center, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand and NHLS, Johannesburg (J.M.); Barts and the London School of Medicine and Dentistry (K.J.P.), the Centre for Haematology, Imperial College London (M.L.), and Guy's and St. Thomas' NHS Foundation Trust (B.M.), London, and Cambridge University Hospitals NHS Foundation Trust, Cambridge (E.S.) - all in the United Kingdom; the Hemophilia Treatment Center, University of California, Davis, Sacramento (A.G.), the University of California, San Francisco, San Francisco (A.D.L.), the Orthopedic Hemophilia Treatment Center, Los Angeles (D.V.Q.), independent consultant, La Jolla (G.F.P.), and BioMarin Pharmaceutical, Novato (J.H., A.L., K.J., M.H., X.Y., W.Y.W., B.K.) - all in California; the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); the Department of Vascular Medicine and Hemostasis and Hemophilia Center, University Hospitals Leuven, Leuven, Belgium (K.P.); the Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor (S.W.P.); the UNC Blood Research Center, University of North Carolina, Chapel Hill (N.S.K.); the Irish Haemophilia Society and Trinity College, Dublin (B.O.); the Department of Pediatrics, Indiana University School of Medicine, IUPUI-Wells Center for Pediatric Research, Indianapolis (R.K.); and the Laboratory of Glycobiology, Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland (R.K.).

出版信息

N Engl J Med. 2022 Mar 17;386(11):1013-1025. doi: 10.1056/NEJMoa2113708.

DOI:10.1056/NEJMoa2113708

PMID:35294811

Abstract

BACKGROUND

Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus 5 (AAV5)-based gene-therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter. The efficacy and safety of the therapy were previously evaluated in men with severe hemophilia A in a phase 1-2 dose-escalation study.

METHODS

We conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors and who had been receiving prophylaxis with factor VIII concentrate received a single infusion of 6×10 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion. Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates. Safety was assessed as adverse events and laboratory test results.

RESULTS

Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus-negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval [CI], 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) reported serious adverse events. Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with immune suppressants. The other most common adverse events were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis occurred in any of the participants.

CONCLUSIONS

In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).

摘要

背景

Valoctocogene roxaparvovec（AAV5-hFVIII-SQ）是一种基于腺相关病毒 5（AAV5）的基因治疗载体，包含受肝选择性启动子驱动的凝血因子 VIII cDNA。该疗法的疗效和安全性曾在一项 1 期-2 期剂量递增研究中在患有严重甲型血友病的男性中进行过评估。

方法

我们开展了一项开放性、单组、多中心、3 期研究，旨在评估 valoctocogene roxaparvovec 在严重甲型血友病男性中的疗效和安全性，这些男性定义为因子 VIII 水平为每分升 1IU 或更低。参与者年龄至少 18 岁，没有预先存在的抗 AAV5 抗体或因子 VIII 抑制剂的发展史，并且一直在接受因子 VIII 浓缩物预防治疗，他们接受了每公斤体重 6×10 个载体基因组的 valoctocogene roxaparvovec 单次输注。主要终点是输注后第 49 周到第 52 周期间因子 VIII 活性（用显色底物测定法测量）的基线变化。次要终点包括年化因子 VIII 浓缩物使用量和出血率的变化。安全性通过不良事件和实验室检测结果来评估。

结果

总体而言，134 名参与者接受了输注并完成了超过 51 周的随访。在 132 名人类免疫缺陷病毒阴性参与者中，第 49 周到第 52 周期间的平均因子 VIII 活性水平增加了 41.9IU/分升（95%置信区间[CI]，34.1 至 49.7；P<0.001；中位数变化，22.9IU/分升；四分位距[IQR]，10.9 至 61.3）。在从前瞻性非干预性研究中招募的 112 名参与者中，输注后第 4 周，年化因子 VIII 浓缩物使用量和治疗性出血的平均发生率分别降低了 98.6%和 83.8%（均 P<0.001）。所有参与者均至少出现了一次不良事件；134 名参与者中有 22 名（16.4%）报告了严重不良事件。134 名参与者中有 115 名（85.8%）出现了丙氨酸氨基转移酶水平升高，并使用免疫抑制剂进行了治疗。其他最常见的不良事件是头痛（38.1%）、恶心（37.3%）和天门冬氨酸氨基转移酶水平升高（35.1%）。在任何参与者中均未发生因子 VIII 抑制剂或血栓形成。

结论

在患有严重甲型血友病的患者中，valoctocogene roxaparvovec 治疗可提供内源性因子 VIII 产生，并与因子 VIII 预防相比，显著减少出血和因子 VIII 浓缩物的使用。（由 BioMarin 制药公司资助；GENEr8-1 ClinicalTrials.gov 编号，NCT03370913。）