Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is a gene therapy evaluated in the phase 3 GENEr8-1 trial that provides endogenous factor VIII (FVIII) production to prevent bleeding in people with severe hemophilia A and represents an alternative to emicizumab, a recombinant antibody mimicking the function of FVIII. Individuals receiving emicizumab were excluded from GENEr8-1 enrollment since emicizumab was then an investigational therapy. This study aimed to utilize pharmacokinetic simulations to provide guidance on maintaining hemostatic control while transitioning patients from emicizumab to valoctocogene roxaparvovec gene therapy.

A published emicizumab pharmacokinetic model, based on data from the HAVEN clinical trials, was used to simulate in vivo emicizumab concentrations and merged with FVIII activity time-course data for 134 GENEr8-1 participants to estimate bleeding risk at weekly intervals post-infusion with valoctocogene roxaparvovec. The analysis examined 3 approved emicizumab dosing regimens for 2 transition scenarios; first, the last emicizumab dose given the same day as infusion, and second, given 4 weeks after valoctocogene roxaparvovec.

Discontinuation of emicizumab the day of valoctocogene roxaparvovec infusion compared with continued dosing for 4 weeks offered similar levels of hemostatic control. The time course for bleeding risk was comparable across the emicizumab dosing regimens for both scenarios. An algorithm to provide guidance for discontinuing emicizumab was developed based on these results. To guide how treatment decisions for emicizumab discontinuation may vary among individuals, theoretical case examples were developed based on participants of GENEr8-1.

Regardless of the emicizumab dose or dosing regimen, pharmacokinetic simulations showed no meaningful difference in the risk of bleeding related to FVIII and FVIII equivalent activity determined by the dynamic balance of decaying emicizumab levels and increasing gene therapy–derived endogenous FVIII. These original data suggest individuals on emicizumab prophylaxis can safely transition to valoctocogene roxaparvovec. COIs for presenting author. Suresh Agarwal is an employee and stockholder of BioMarin Pharmaceutical Inc.