Phase 1–2 trial of AAVS3 gene therapy in patients with hemophilia B

Background: FLT180a (verbrinacogene setparvovec) is a liver-directed adeno-associated virus (AAV) gene therapy that uses a synthetic capsid and a gain-of-function protein and aims to normalize factor IX (FIX) levels in patients with hemophilia B.

Methods: B-AMAZE was a multicenter, open-label, Phase 1/2 trial to assess safety and efficacy of varying doses of FLT180a in patients with hemophilia B (FIX ≤2%). All patients received glucocorticoids ± tacrolimus for immunosuppression to decrease the risk of vector-related immune responses. After 26 weeks, patients enrolled in a long-term follow-up study.

Results: Ten patients received one of four FLT180a doses: 3.84x1011, 6.4x1011, 8.32x1011, or 1.28x1012 vg/kg with dose-dependent increases in FIX levels. At a median follow up of 27.2 months (range, 19.1 to 42.4), sustained FIX activity was observed in all patients except one, who resumed FIX prophylaxis. As of a September 2021 data cut, five patients had normal FIX levels (range, 51 to 78%), three patients had levels from 23 to 43%, and one high-dose patient was at 260%. Approximately 10% and 24% of adverse events were related to FLT180a and immunosuppression, respectively. Increases in liver transaminases were the most common FLT180a-related adverse events. Late increases in transaminases occurred in patients who received prolonged tacrolimus beyond the steroid taper. A serious adverse event of arteriovenous fistula thrombosis occurred in the patient with high FIX levels.

Conclusions: Sustained FIX levels in the normal range were achieved with low FLT180a doses but required immunosuppression with glucocorticoids ± tacrolimus.

Clinicaltrials.gov: NCT03369444 and NCT03641703