Background
Phase 3 single-arm study (HOPE-B). N=54 adult males (≥18 yr) with moderately severe to severe hemophilia B (FIX activity ≤2%) on stable FIX prophylaxis ≥6 mo, without FIX inhibitors, anti-AAV5 titers below threshold. Etranacogene dezaparvovec (AMT-061; Hemgenix): AAV5 vector delivering the Padua FIX variant (FIX-R338L, ~8× higher activity). FDA approved Nov 2022, first hemophilia B gene therapy and (at approval) the world's most expensive single-dose drug ($3.5 million).
Interventions and follow up
Treatment: Single IV infusion of etranacogene dezaparvovec 2×10^13 gc/kg (AAV5-FIX-Padua); FIX prophylaxis discontinued post-infusion
Primary endpoint: ABR of treated bleeds in months 7–18 vs lead-in prophylaxis period; FIX activity
Median follow-up: 18 months (primary analysis); 2+ years extension
Primary endpoint: ABR of treated bleeds in months 7–18 vs lead-in prophylaxis period; FIX activity
Median follow-up: 18 months (primary analysis); 2+ years extension
Results
ABR reduction (months 7–18): 64% reduction; annualized 1.51 treated bleeds vs 4.19 during lead-in; rate ratio 0.36 (95% CI 0.21–0.63), P<.001
FIX activity (month 18): Mean 36.9 IU/dL (vs <2 at baseline)
FIX prophylaxis discontinued: 96% of patients
Zero treated bleeds (months 7–18): 54%
FIX activity (month 18): Mean 36.9 IU/dL (vs <2 at baseline)
FIX prophylaxis discontinued: 96% of patients
Zero treated bleeds (months 7–18): 54%
Adverse events
ALT elevation: 50% (most responsive to corticosteroids)
Grade ≥3 ALT: 10% (substantially lower than valoctocogene roxaparvovec)
Serious AEs: 9%
Other: Fatigue, headache, nausea during infusion common
Thrombotic events / FIX inhibitors: None
Durability: FIX-Padua activity appears more durable than FVIII gene therapy at 2–3 yr
Grade ≥3 ALT: 10% (substantially lower than valoctocogene roxaparvovec)
Serious AEs: 9%
Other: Fatigue, headache, nausea during infusion common
Thrombotic events / FIX inhibitors: None
Durability: FIX-Padua activity appears more durable than FVIII gene therapy at 2–3 yr
Conclusions
A single infusion of etranacogene dezaparvovec reduced ABR by 64% and enabled 96% of patients to discontinue FIX prophylaxis at 18 months, the first approved gene therapy for hemophilia B, with more durable FIX expression than hemophilia A gene therapy via the high-activity FIX-Padua variant.
Key Limitations
Single-arm, intra-patient lead-in comparison, not randomized. Small cohort (n=54), males only. Hepatotoxicity (ALT) and one HCC case in long-term follow-up raise surveillance concerns. Durability beyond a few years unknown; re-dosing precluded by anti-AAV immunity. Extremely high cost limits access.
Clinical Context
Supported FDA approval of Hemgenix (Nov 2022), first gene therapy for hemophilia B. Offers a one-time alternative to lifelong FIX prophylaxis for inhibitor-negative, AAV5-naive adults; the FIX-Padua variant yields more durable expression than hemophilia A AAV therapy.