Background
Phase 3 single-arm study (GENEr8-1). N=134 adult males (≥18 yr) with severe hemophilia A (FVIII <1%) on FVIII prophylaxis ≥12 mo, without FVIII inhibitors or high anti-AAV5 neutralizing antibodies. Valoctocogene roxaparvovec (BMN 270; Roctavian): AAV5 vector delivering codon-optimized B-domain-deleted FVIII (SQ) under a liver-specific promoter, single IV infusion. FDA approved June 2023, first gene therapy for hemophilia A.
Interventions and follow up
Treatment: Single IV infusion of valoctocogene roxaparvovec 6×10^13 vg/kg (AAV5-FVIII-SQ); FVIII prophylaxis discontinued post-infusion
Primary endpoint: Difference in ABR (year 1–2 post-infusion vs prophylaxis run-in); FVIII activity at year 1
Median follow-up: 104 weeks (2 years)
Primary endpoint: Difference in ABR (year 1–2 post-infusion vs prophylaxis run-in); FVIII activity at year 1
Median follow-up: 104 weeks (2 years)
Results
ABR reduction from prophylaxis run-in: 84.5% reduction; model-estimated ABR 0.0 (0–0.8) at year 2 vs 4.1 during run-in
FVIII activity: Mean 41.9 IU/dL at year 2; declined from peak ~50 IU/dL at year 1 (mean decline ~18 IU/dL/yr)
FVIII prophylaxis discontinued: 84.8% of patients
Zero treated bleeds at year 2: 80% of patients
FVIII activity: Mean 41.9 IU/dL at year 2; declined from peak ~50 IU/dL at year 1 (mean decline ~18 IU/dL/yr)
FVIII prophylaxis discontinued: 84.8% of patients
Zero treated bleeds at year 2: 80% of patients
Adverse events
ALT elevation: 86% (most grade 1–2, responsive to corticosteroids)
Grade ≥3 ALT: 38%, requiring extended corticosteroid courses
Serious AEs: 16% (predominantly ALT management)
Other: Fatigue, nausea during infusion period common
Thrombotic events / FVIII inhibitors: None
Durability: Declining FVIII expression over years 1–5 in long-term follow-up
Grade ≥3 ALT: 38%, requiring extended corticosteroid courses
Serious AEs: 16% (predominantly ALT management)
Other: Fatigue, nausea during infusion period common
Thrombotic events / FVIII inhibitors: None
Durability: Declining FVIII expression over years 1–5 in long-term follow-up
Conclusions
A single infusion of valoctocogene roxaparvovec reduced ABR by 84.5% and allowed 85% of patients to discontinue FVIII prophylaxis at 2 years, establishing the first approved gene therapy for hemophilia A.
Key Limitations
Single-arm, intra-patient comparison vs prophylaxis run-in, not randomized. High rate of ALT elevation requiring immunosuppression. Waning FVIII expression over time threatens durability. Excludes anti-AAV5-positive patients and re-dosing not possible. Males only; surrogate endpoints (ABR, FVIII activity).
Clinical Context
Supported FDA approval of Roctavian (June 2023), first AAV gene therapy for severe hemophilia A. Positioned as a one-time alternative to lifelong prophylaxis for inhibitor-negative, AAV5-naive adults; durability and hepatotoxicity temper enthusiasm relative to factor and emicizumab prophylaxis.