Factor IX-Padua AAV gene therapy in hemophilia B: phases 1/2 and 3 trials

作者：Feng Xue, Mankai Ju, Tienan Zhu, Zeping Zhou, Jing Sun, Linhua Yang, Zhenyu Yan, Hu Zhou, Xin Du, Changcheng Zheng, Jing Zheng, Xia Wu, Zengmin Du, Wei Jiang, Caifeng Yang, Xiao Xiao, Wei Liu, Renchi Yang, Lei Zhang · 发表于：Nature Medicine · 年份：2025 · DOI：10.1038/s41591-025-04012-y · 被引用次数：9 · 研究领域：Virus-based gene therapy research、Hemophilia Treatment and Research、RNA Interference and Gene Delivery

Gene therapy for hemophilia B with adeno-associated virus (AAV) vector has achieved great advances over the last decade. We previously conducted a pilot study demonstrating the safety and efficacy of AAV-factor IX (FIX) Padua gene therapy (BBM-H901) in ten male participants with hemophilia B. Here we report a single-arm dose-escalation phase 1/2 trial in 6 male participants and a multicentre phase 3 trial in 26 participants with hemophilia B in China. The phase 1/2 study tested a dose of 5 × 1012 vg kg−1 (n = 6), with primary endpoints assessing dose-limiting toxicities (DLT) and adverse events (AEs). The primary endpoint was met with no DLT observed in the 10 weeks postinfusion. The most common drug-related AEs were transaminitis (33.3%), and no grade 3 drug-related AE occurred within 52 weeks postintervention. The phase 3 study tested the 5 × 1012 vg kg−1 dose, as determined in the phase 1/2 study, in 26 patients. The primary endpoint evaluated the annualized bleeding rate (ABR) after gene therapy and secondary endpoints included vector-derived FIX:C, target joint and percentage of participants with zero bleeds postgene therapy. The study met its primary endpoint as the mean (95% confidence interval (CI)) ABR within 52 weeks after BBM-H901 infusion decreased to 0.60 (0.18–1.99), and the upper limit of the 95% CI (1.99) was lower than the predefined superiority margin of 5.0 (historical ABR assumed for patients receiving prophylactic FIX treatment in China). In the phase 3 t...