Mahlangu Johnny, Kaczmarek Radoslaw, von Drygalski Annette, Shapiro Susan, Chou Sheng-Chieh, Ozelo Margareth C, Kenet Gili, Peyvandi Flora, Wang Michael, Madan Bella, Key Nigel S, Laffan Michael, Dunn Amy L, Mason Jane, Quon Doris V, Symington Emily, Leavitt Andrew D, Oldenburg Johannes, Chambost Hervé, Reding Mark T, Jayaram Kala, Yu Hua, Mahajan Reena, Chavele Konstantia-Maria, Reddy Divya B, Henshaw Joshua, Robinson Tara M, Wong Wing Yen, Pipe Steven W
From the Hemophilia Comprehensive Care Center, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand, and National Health Laboratory Service, Johannesburg (J. Mahlangu); the Department of Pediatrics, Indiana University School of Medicine, IUPUI-Wells Center for Pediatric Research, Indianapolis (R.K.); the Laboratory of Glycobiology, Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland (R.K.); the Department of Medicine, University of California, San Diego, La Jolla (A.D.), the Orthopedic Hemophilia Treatment Center, Los Angeles (D.V.Q.), the University of California, San Francisco, San Francisco (A.D.L.), and BioMarin Pharmaceutical, Novato (K.J., H.Y., R.M., K.-M.C., D.B.R., J.H., T.M.R., W.Y.W.) - all in California; Oxford University Hospitals NHS Foundation Trust, the Radcliffe Department of Medicine, University of Oxford, and the Oxford National Institute for Health Research Biomedical Research Centre, Oxford (S.S.), Guy's and St. Thomas' NHS Foundation Trust (B.M.) and the Centre for Haematology, Imperial College London (M.L.), London, and Cambridge University Hospitals NHS Foundation Trust, Cambridge (E.S.) - all in the United Kingdom; the Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei (S.-C.C.); Hemocentro UNICAMP, Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil (M.C.O.); the National Hemophilia Center, Sheba Medical Center, Tel Hashomer, and the Amalia Biron Research Institute of Thrombosis and Hemostasis, Tel Aviv University, Tel Aviv (G.K.) - both in Israel; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, and Università degli Studi di Milano, Department of Pathophysiology and Transplantation - both in Milan (F.P.); the Hemophilia and Thrombosis Center, University of Colorado Anschutz Medical Campus, Aurora (M.W.); the UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill (N.S.K.); Nationwide Children's Hospital and the Ohio State University College of Medicine, Columbus (A.L.D.); the Queensland Haemophilia Centre, Cancer Care Services, Royal Brisbane and Women's Hospital, and the University of Queensland - both in Brisbane, Australia (J. Mason); the Institute of Experimental Haematology and Transfusion Medicine and Center for Rare Diseases, University Hospital Bonn, Bonn, Germany (J.O.); Assistance Publique-Hôpitaux de Marseille, Department of Pediatric Hematology Oncology, Children's Hospital La Timone and Aix Marseille University, INSERM, Institut National de la Recherche Agronomique, Center for Cardiovascular and Nutrition Research, Marseille, France (H.C.); the Center for Bleeding and Clotting Disorders, University of Minnesota, Minneapolis (M.T.R.); and the Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor (S.W.P.).
N Engl J Med. 2023 Feb 23;388(8):694-705. doi: 10.1056/NEJMoa2211075.
Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously.
We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis 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 the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII.
At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P<0.001) among the participants. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics; the model-estimated typical half-life of the transgene-derived factor VIII production system was 123 weeks (95% confidence interval, 84 to 232). The risk of joint bleeding was estimated among the trial participants; at a transgene-derived factor VIII level of 5 IU per deciliter measured with chromogenic assay, we expected that participants would have 1.0 episode of joint bleeding per year. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred.
The study data show the durability of factor VIII activity and bleeding reduction and the safety profile of valoctocogene roxaparvovec at least 2 years after the gene transfer. Models of the risk of joint bleeding suggest that the relationship between transgene-derived factor VIII activity and bleeding episodes is similar to that reported with the use of epidemiologic data for persons with mild-to-moderate hemophilia A. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).
罗沙泊韦基因疗法通过腺相关病毒载体递送删除了B结构域的凝血因子VIII编码序列，以预防重度A型血友病患者出血。先前已发表了一项关于罗沙泊韦基因疗法在重度A型血友病男性患者中应用52周后的疗效和安全性的3期研究结果。
我们开展了一项开放标签、单组、多中心3期试验，134名接受凝血因子VIII预防性治疗的重度A型血友病男性患者每千克体重接受一次6×10载体基因组的罗沙泊韦基因疗法单次输注。主要终点是输注后第104周时治疗出血事件年化率相对于基线的变化。对罗沙泊韦基因疗法的药代动力学进行建模，以评估相对于转基因衍生的凝血因子VIII活性的出血风险。
在第104周时，共有132名参与者仍在研究中，其中112名有基线时前瞻性收集的数据。参与者中，年化治疗出血率较基线下降了84.5%（P<0.001）。从第76周起，转基因衍生的凝血因子VIII活性轨迹呈一级消除动力学；模型估计转基因衍生的凝血因子VIII产生系统的典型半衰期为123周（95%置信区间，84至232）。对试验参与者的关节出血风险进行了评估；用显色法测得转基因衍生的凝血因子VIII水平为每分升5国际单位时，预计参与者每年会发生1.0次关节出血。输注后2年，未出现新的安全信号，也未发生与治疗相关的新的严重不良事件。
研究数据显示了基因转移后至少2年凝血因子VIII活性的持久性、出血减少情况以及罗沙泊韦基因疗法的安全性。关节出血风险模型表明，转基因衍生的凝血因子VIII活性与出血事件之间的关系与使用轻度至中度A型血友病患者的流行病学数据所报告的相似。（由BioMarin制药公司资助；GENEr8-1临床试验注册号，NCT03370913。）
