Valoctocogene roxaparvovec delivers a B-domain deleted factor VIII (FVIII) coding sequence with an adeno-associated virus vector to reduce bleeding and FVIII concentrate use in people with severe hemophilia A. This study aimed to characterize the long-term trajectory of transgene-derived FVIII activity using a linear mixed effects (LME) model to estimate mean and median FVIII activity levels 5 years post-infusion.

In GENEr8-1, an open-label, single-arm, multicenter phase 3 trial, 134 participants with severe hemophilia A received a single 6 x 1013 vg/kg dose of valoctocogene roxaparvovec. FVIII activity was assessed using the chromogenic substrate assay and one-stage assay. A previously published quantitative pharmacokinetic (PK) modelwas updated to extrapolate FVIII activity levels to 5 years post-infusion. Ln-transformed FVIII activity values from week 76 to 104 were fit to the LME model with random effects for participants on slope and intercept using a restricted maximum likelihood method with the lmer package in the R statistical computing software (R Foundation for Statistical Computing, Vienna, Austria). The precision of parameter estimates and model diagnostics were evaluated to confirm goodness-of-fit. The model and extrapolation approach was further qualified by comparing to observed FVIII activity at week 156.

The final LME model dataset included 928 observations from 120 participants. The long-term trajectory of FVIII activity was consistent with first-order elimination kinetics starting at week 76. Model parameter estimates were consistent with the previously published model; diagnostic plots showed no major deficiencies. FVIII activity was extrapolated to 5 years post-gene transfer. Mean and median FVIII activity extrapolations at week 156 were consistent with observed values, confirming adequacy of the model.

Pharmacokinetic modeling indicates valoctocogene roxaparvovec-derived FVIII activity levels will remain in the mild hemophilia range for ≥5 years post-gene transfer for the majority of patients treated.

Suresh Agarwal is a paid employee of BioMarin Pharmaceutical Inc. and holds stock ownership with BioMarin Pharmaceutical Inc.