Arvenacogene sanparvovec: A novel gene therapy for hemophilia B – results from A phase I–II first-in-human trial

Abstract Introduction: ANB-002 (INN: arvenacogene sanparvovec) is a gene construct for the therapy of hemophilia B. It utilizes an adeno-associated virus type 5 (AAV5) vector containing the human Factor IX (FIX) gene with the Padua mutation. Following a single intravenous infusion, the therapy is designed to deliver the FIX gene to hepatocytes, leading to sustained FIX protein production by the liver. Its production can potentially reduce or eliminate the need for factor replacement therapy in patients with hemophilia. Methods: ANB-002-1/SAFRAN is an ongoing, open-label, single-arm, phase 1/2 first-in-human clinical trial evaluating the safety and efficacy of arvenacogene sanparvovec in patients with moderately severe or severe hemophilia B (NCT06120582). According to eligibility criteria, male patients aged 18 years or older with moderately severe or severe hemophilia B (FIX activity ≤2%) and a documented history of at least 150 days of previous FIX prophylaxis were included. The absence of both FIX inhibitor and anti-AAV5 antibodies was confirmed for all patients before enrollment. Thirteen patients with hemophilia B received a single dose of arvenacogene sanparvovec in one of three dose cohorts (2.5×10¹² vector genomes (vg) per kilogram (kg) of body weight in four participants, 5×10¹² vg/kg in three participants and 2×10¹³ vg/kg in six participants) between May 2023 and July 2024. Results: The mean FIX activity ± standard deviation (±SD) (one-stage assay) was 26.3±19.7% at the cohort 1, 35.7±17.0% at the cohort 2 at 52 week and 14.7±9.6% at the cohort 3 at 24 week. The mean of annualized bleeding rate (ABR) was 7.2 (±7.8) at cohort 1 and there were no bleedings at cohort 2. The mean annualized bleeding rate for 24 weeks was 1.9 (±3.6) at cohort 3. Ten patients from thirteen discontinued FIX prophylaxis. Grades 1–2 adverse reactions (AR) were reported in 50% (2/4), 66.7% (2/3) and 66.7% (4/6) of participants in cohorts 1, 2 and 3 respectively. Six of thirteen participants experienced adverse reactions of elevated transaminase levels and 3 of 13 experienced infusion-related reactions. All adverse reactions cases resolved without sequelae. No AR of grade 3 or higher were reported in any of the cohorts. No FIX inhibitor was detected in all cohorts. Conclusion: A single administration of ANB-002 (arvenacogene sanparvovec) gene therapy to 13 patients with moderately severe or severe hemophilia B resulted in durable factor IX expression, sustained clinical benefit that made it possible completely discontinue the FIX prophylaxis for 10 from 13 participants. Therapy was well tolerated.