Efficacy and Safety of an Engineered, Liver-Tropic Adeno-Associated Virus Vector Expressing Factor IX Padua Administered with Prophylactic Glucocorticoids in Patients with Hemophilia B: A Multi-Center, Single-Arm, Phase 3 Trial
Authors: Xue Feng , Ju Mankai , Zhu Tienan , Zhou ZePing , Sun Jing , Yang Linhua , Yan Zhenyu , Zhou Hu , Du Xin , Zheng Changcheng , Wu Xia , Xiao Xiao , Yang Renchi , Zhang Lei 
Published: December 2024

Introduction
Gene therapy is the cutting- edge treatment for hemophilia B. We launched the Phase 3 clinical trial of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX (FIX) protein (BBM-H901) to evaluate its efficacy and safety in adult patients with hemophilia B.
Methods
A multi-center, single-arm, phase 3 trial was launched to evaluate the efficacy and safety of a single intravenous infusion of BBM-H901. The main inclusion criteria is adult patients with hemophilia B (aged≥18 years) with baseline FIX coagulation activity (FIX:C) of ≤2 IU/dL, no FIX inhibitor, and neutralizing antibodies against vector capsid ≤1:4. Eligible participants were intravenously infused with a single dose of 5 × 10¹² vector genomes (vg)/kg of BBM-H901 after 1 day of prophylactic oral prednisone at 1 mg/kg/d. The initial dose (1 mg/kg/d) lasted 2 weeks after vector infusion and tapered off in around 8-10 weeks. The primary endpoint is ABR (annualized bleeding rate), within 52 weeks after BBM-H901 injection infusion. We report the results of the prespecified 1-year analysis following complete enrolment. The trial is registered with ClinicalTrials.gov, NCT05203679.
Results
Between Aug 17, 2022, and Apr 21, 2023, 28 male participants were assessed, and 26 Chinese participants were enrolled and administered with BBM-H901 via intravenous infusion. After 52 weeks follow-up, average ABR is 0.6 (95%Cl: 0.18-1.99) which significantly lower than superiority margin 5.0 (identified ABR of patient with prophylactic treatment in China). Mean FIX:C reached 55.08 IU/dL (SD35.93) measured with one- stage method using SynthASil aptt reagents at week 52. Furthermore, as early as 3 days after infusion, mean FIX:C reached 49.70 IU/dL very quickly. The average number of FIX product infusion after BBM-H901 treatment is 2.9 (SD 10.71), lower than before 58.2 (SD 30.67). 21/26 participants had zero replacement therapy after gene therapy. The mean target joint number decreased from 1.1 (SD 1.2) to 0. No serious adverse events, no grade 3-4 BBM-H901 related adverse events were observed. Most common grade 1-2 adverse events related to BBM-H901 include elevation of alanine aminotransferase (7 [26.9%]), elevation of aspartate aminotransferase (2 [7.7%]), decrease of fibrinogen (3 [11.5%]). Factor IX inhibitors did not develop in any participants.
Conclusions
This phase 3 trial come up with the point that BBM-H901 can decrease the ABR compare to the prophylactic treatment, elevate FIX:C level sufficiently and rapidly to prevent bleeding events. Besides, the trial also supports the safety and tolerability.
In conclusion, BBM-H901 gene therapy is superior to prophylactic treatment with respect to the ABR, and it had a favorable safety profile.