Safety and efficacy of valoctocogene roxaparvovec with prophylactic glucocorticoids: 1-year results from the phase 3b, single-arm, open-label GENEr8-3 study.

Background: Valoctocogene roxaparvovec, an adeno-associated virus vector that transfers a human factor VIII (FVIII) coding sequence to hepatocytes, provides bleeding protection for people with severe hemophilia A (HA).

Objective: Determine the efficacy and safety of valoctocogene roxaparvovec with concomitant prophylactic glucocorticoids in the open-label, single-arm, phase 3b GENEr8-3 trial.

Methods: Participants with severe HA who were using HA prophylaxis received one 6x10¹³ vg/kg infusion of valoctocogene roxaparvovec concomitantly with daily prophylactic glucocorticoids (40 mg prednisolone equivalent/d weeks 0‒8; taper to 5 mg/d weeks 9‒19). The primary efficacy endpoint was change from baseline in FVIII activity (chromogenic substrate assay) at week 52. Secondary efficacy endpoints included annualized rate of FVIII use and annualized bleeding rate (ABR) for treated bleeds. Safety was assessed by adverse events (AEs). Analysis populations were intent-to-treat (ITT; received valoctocogene roxaparvovec) for safety analyses and modified ITT (mITT; ≥52 FVIII infusions in the year before dosing) for efficacy analyses.

Results: Overall, 22 participants with severe HA received valoctocogene roxaparvovec. In the mITT population (n = 21), mean week 52 FVIII activity increased from baseline (imputed as 1 IU/dL) to 16.1 IU/dL (standard deviation [SD], 22.4; P = 0.0057); post-HA prophylaxis, mean treated ABR and mean annualized FVIII use decreased 67.1% and 91.6% from baseline, respectively (P <0.05). The most common AE was alanine aminotransferase elevation (20/22 participants). Glucocorticoid-related AEs occurred in 19/22 participants. No participants discontinued the study.

Conclusions: Based on cross-trial comparisons, prophylactic glucocorticoids do not confer safety or efficacy benefits compared with reactive glucocorticoid regimens.