A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors.

Emicizumab, a bispecific humanized monoclonal antibody, bridges activated factor IX (FIX) and FX to restore the function of missing activated FVIII in hemophilia A. Emicizumab prophylaxis in children with hemophilia A and FVIII inhibitors was investigated in a phase 3 trial (HAVEN 2). Participants, previously receiving episodic/prophylactic bypassing agents (BPAs), were treated with subcutaneous emicizumab: 1.5 mg/kg weekly (group A), 3 mg/kg every 2 weeks (group B), or 6 mg/kg every 4 weeks (group C). Pharmacokinetics, safety, and efficacy (including an intraindividual comparison of participants from a noninterventional study) were evaluated. Eighty-five participants aged <12 years were enrolled. In group A (n = 65), the annualized rate of treated bleeding events (ABRs) was 0.3 (95% confidence interval [CI], 0.17-0.50), and 77% had no treated bleeding events. Intraindividual comparison of 15 participants who previously took BPA prophylaxis showed that emicizumab prophylaxis reduced the ABR by 99% (95% CI, 97.4-99.4). In groups B (n = 10) and C (n = 10), ABRs were 0.2 (95% CI, 0.03-1.72) and 2.2 (95% CI, 0.69-6.81), respectively. The most frequent adverse events were nasopharyngitis and injection-site reactions; no thrombotic events occurred. Two of 88 participants developed antidrug antibodies (ADAs) with neutralizing potential, that is, associated with decreased emicizumab plasma concentrations: 1 experienced loss of efficacy, and, in the other, ADAs disappeared over time without intervention or breakthrough bleeding. All other participants achieved effective emicizumab plasma concentrations, regardless of the treatment regimen. Emicizumab prophylaxis has been shown to be a highly effective novel medication for children with hemophilia A and inhibitors. This trial was registered at www.clinicaltrials.gov as #NCT02795767.