Valoctocogene roxaparvovec gene therapy provides durable haemostatic control for up to 7 years for haemophilia A

Abstract

Introduction: Valoctocogene roxaparvovec is an adeno-associated virus vector serotype 5 (AAV5)-mediated gene therapy approved for severe haemophilia A (HA).

Aim: To report the safety and efficacy of valoctocogene roxaparvovec 7 years after dosing in a phase 1/2 clinical study (NCT02576795).

Methods: Males ≥18 years with severe HA (factor VIII [FVIII] ≤1 international unit [IU]/dL) who were previously receiving exogenous FVIII and had no history of FVIII inhibitors or anti-AAV5 antibodies received valoctocogene roxaparvovec treatment and were followed for 7 (6 × 10¹³ vg/kg; n = 7) and 6 (4 × 10¹³ vg/kg; n = 6) years.

Results: In the last year, one participant in each cohort reported treatment-related adverse events (AEs): grade 1 (G1) hepatomegaly (6 × 10¹³), and G1 splenomegaly and G1 hepatic steatosis (4 × 10¹³). During all follow-up, mean annualized treated bleeds and exogenous FVIII infusion rates were ≥88% lower than baseline values. At years 7 and 6, mean (median) FVIII activity (chromogenic assay) was 16.2 (10.3) and 6.7 (7.2) IU/dL in the 6 × 10¹³ (n = 5) and 4 × 10¹³ (n = 4) cohorts, respectively, corresponding to mild haemophilia. Regression analyses of the last year estimated rate of change in FVIII activity was -0.001 and -0.07 IU/dL/week for the 6 × 10¹³ and 4 × 10¹³ cohorts, respectively. Two participants (6 × 10¹³) resumed prophylaxis in year 7: one after a non-treatment-related G4 serious AE of spontaneous internal carotid artery bleed, and the other to manage bleeds and FVIII activity.

Conclusions: The safety and efficacy of valoctocogene roxaparvovec remain generally consistent with previous reports, with good haemostatic control for most participants. Two participants returned to prophylaxis.

Keywords: adeno‐associated virus; clinical trial; factor VIII; gene therapy; haemophilia; internal carotid artery bleed.