From the Departments of Medicine and of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (A.C.), and Pfizer, Collegeville (J.F., J.R.) - both in Pennsylvania; the Division of Hematology, Department of Pediatrics, Ege University Faculty of Medicine, Izmir, Turkey (K.K.); the Department of Hematology, Hemophilia Care and Research, Necker Hospital, Institut Imagine, Paris (L.F.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); the Department of Translational Medicine, Lund University, Lund, and the Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Malmö - both in Sweden (J.A.); Instituto de Hematologia do Estado do Rio de Janeiro, Rio de Janeiro (M.H.C.), and Hemocentro UNICAMP, Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas (M.C.O.) - both in Brazil; the Departments of Health Research Methods, Evidence, and Impact and of Medicine, McMaster University, Hamilton, ON (A. Iorio), and the Division of Hematology, St. Michael's Hospital, University of Toronto, Toronto (J.T.) - both in Canada; the Blood Transfusion Center, National Reference Center for Congenital Bleeding Disorders, Laiko General Hospital, Athens (O.K.-F.); Vivantes Hospital in Friedrichshain, Berlin (R.K.), and the Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, and the Center for Rare Diseases Bonn, University Clinic Bonn, Bonn (J.B.O.) - all in Germany; Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Hemostasis and Thrombosis Unit, Division of Hematology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels (C.H.); the Division of Hematology, National Center for Child Health and Development, Tokyo (A. Ishiguro); the Departments of Medicine and of Laboratory Medicine, University of California, San Francisco, San Francisco (A.D.L.); the Faculty of Medicine and Health, Central Clinical School, and the Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, and the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital - all in Sydney (J.E.J.R.); Pfizer, New York (A.F.); Pfizer, Groton, CT (J.M.); Pfizer, Rome (F.B.); and Pfizer, Cambridge, MA (P.S.).
N Engl J Med. 2024 Sep 26;391(12):1108-1118. doi: 10.1056/NEJMoa2302982.
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.
We conducted a phase 3 open-label study of fidanacogene elaparvovec at a dose of 5×10 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.
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.
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.).
Fidanacogene elaparvovec 是一种用于治疗乙型血友病的腺相关病毒（AAV）基因治疗载体，含有高效人凝血因子 IX 变体（FIX-R338L/FIX-Padua）。在一项 1 期-2a 研究中，该药物与持续的凝血因子 IX 活性有关。
我们进行了一项开放标签的 3 期研究，使用 5×10 载体基因组拷贝/千克体重的剂量给予 Fidanacogene elaparvovec。年龄在 18 至 65 岁之间、乙型血友病、凝血因子 IX 水平为 2%或更低的男性，如果他们接受了至少 6 个月的预防性凝血因子 IX 浓缩物治疗，则有资格进行筛选。主要终点是与治疗前引入期相比，用 Fidanacogene elaparvovec 治疗后 12 周到 15 个月的年化出血率（治疗和未治疗的出血事件），用于检验非劣效性。此外，还评估了优效性、其他疗效终点和安全性。
在进行导入研究的 316 名男性中，有 204 名（64.6%）不符合条件；其中 188 名（59.5%）因存在抗 AAV 中和抗体而不合格。在接受 Fidanacogene elaparvovec 治疗的 45 名参与者中，有 44 名至少完成了 15 个月的随访。所有出血事件的年化出血率下降了 71%，从基线时的 4.42（95%置信区间[CI]，1.80 至 7.05）降至基因治疗后的 1.28（95%CI，0.57 至 1.98），治疗差异为-3.15 个事件（95%CI，-5.46 至-0.83；P=0.008）。这一结果表明 Fidanacogene elaparvovec 与预防相比具有非劣效性和优效性。在 15 个月时，通过一步法 SynthASil 测定，平均凝血因子 IX 活性为 26.9%（中位数，22.9%；范围，1.9 至 119.0）。共有 28 名参与者（62%）因天冬氨酸转氨酶水平升高或凝血因子 IX 水平下降（或两者兼而有之）而开始在 11 至 123 天之间接受糖皮质激素治疗。未观察到与输注相关的严重不良事件、血栓事件、凝血因子 IX 抑制剂的发展或恶性疾病。
Fidanacogene elaparvovec 优于预防乙型血友病患者的治疗，可减少出血并稳定凝血因子 IX 的表达。（由辉瑞公司资助；BENEGENE-2 ClinicalTrials.gov 编号，NCT03861273）。
