Safety analysis of rFVIIa with emicizumab dosing in congenital hemophilia A with inhibitors: Experience from the HAVEN clinical program

Background Recombinant activated factor VII (rFVIIa; eptacog alfa activated, NovoSeven (R), Novo Nordisk A/S) is a bypassing agent used in congenital hemophilia A patients with inhibitors. Emicizumab (Hemlibra (R); F Hoffmann-La Roche Ltd) is a recombinant, humanized, bispecific monoclonal antibody used for routine prophylaxis in patients with congenital hemophilia A with inhibitors. Concomitant use of the hemostatic agents rFVIIa and emicizumab carries a theoretical increased risk of thrombotic complications. Roche and Novo Nordisk collaboratively analyzed all available data on the use of rFVIIa in patients receiving emicizumab prophylaxis in the Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors (HAVEN) clinical development program. Objective Obtain further insights into the concomitant clinical use and safety of rFVIIa and emicizumab. Methods The initial individual rFVIIa dose, dosing intervals and cumulative dosing were evaluated in the HAVEN 1, HAVEN 2, and HAVEN 4 trials. All adverse events reported in each of the three trials in patients treated with rFVIIa, including available narratives, were assessed. Results The vast majority of bleeds occurred in HAVEN 1. When rFVIIa was used to treat a bleeding episode, a 100 +/- 20 mu g/kg dose was used to initiate treatment in the majority of cases. The dosing interval, as well as cumulative dosing were consistent with prescribing information and current practice. No serious adverse events, no thrombotic microangiopathy cases, or thromboembolic events were assessed to be associated with rFVIIa when used in conjunction with emicizumab prophylaxis in the HAVEN trials. Conclusion rFVIIa use in the context of emicizumab prophylaxis does not change the rFVIIa safety profile as described in the product information.