Efficacy and safety of Factor IX Padua gene transfer via BBM-H901 among Chinese patients with haemophilia B: A multicentre, single-arm, phase 1/2 and 3 study and long-term follow-up of a phase 1 pilot study

Building on promising phase 1 pilot results demonstrating safety and efficacy of BBM-H901 (AAV-mediated FIX Padua gene therapy) in restoring factor IX activity (FIX:C) among 10 patients with haemophilia B, we conducted current studies to verify its efficacy and safety in larger Chinese haemophilia B patients. A multicentre, single-arm, open-label study (phase 1/2: dose-escalation, n = 6; phase 3: fixed-dose, n = 26) and a long- term phase 1 pilot study(n = 10) were conducted. Eligible participants received 5×10¹² vg/kg intravenously (selected post-phase 1/2 safety review). Primary endpoints included dose-limiting toxicity (DLT, phase 1/2) and annualized bleeding rate (ABR, phase 3). Second endpoints include vector derived FIX:C, proportion patients with zero bleeding, safety, etc, post gene therapy. FIX:C in long- term follow- up phase was evaluated as well. Results show 31 of 32 participants received prophylactic prednisone one day before vector infusion. No DLTs occurred in phase 1/2. Phase 3 outcomes at 52 weeks showed ABR reduction to 0.6 (95% CI 0.18–1.99) vs superiority margin 5.0, mean FIX:C (one-stage Actin FSL assay) of 41.9 IU/dL (SD 28.69), 80.8% (21/26) patients achieved zero bleeding events, FIX concentrate use decreased from 58.2 to 2.9 infusions/year. No serious adverse events and grade 3–4 vector related AE were observed. Nine of 32 participants had transaminitis and 8 self- resolved. Long-term FIX:C (one-stage Actin FSL assay) remained stable through 104 weeks (51.51 ± 41.84 IU/dL, n = 15). In conclusion, our studies come up with the point that BBM-H901 can decrease the ABR compare to the prophylactic treatment, elevate FIX:C sufficiently and rapidly to prevent bleeding events. The sustainable expression of FIX was also proved in long- term follow- up phase. Besides, the study demonstrates the safety profile of BBM-H901. Trial registration number : clinicaltirals.gov NCT05203679 and NCT04135300.