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

Abstract

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.

Graphical abstract

Figure 1.

Study design. Loading dose of 3 mg/kg/week for 4 weeks in all cohorts; maintenance dose starting week 5. *With additional inclusion of persons with hemophilia A (PwHA) 12 to 17 years old weighing <40 kg. No PwHA <2 years old or 12 to 17 years old could enroll in groups B and C. A, group A; B, group B; C, group C; NIS, noninterventional study; PK, pharmacokinetics.

Figure 2.

Participant disposition. All participants received the same loading dose of emicizumab 3 mg/kg per week for 4 weeks. *Participant discontinued study treatment due to ADAs with neutralizing potential and subsequent lack of efficacy following a dose uptitration to 3 mg/kg per week (starting at week 9) and remained on study for safety follow-up.

Figure 3.

Intraindividual treated ABR comparison in participants <12 years receiving emicizumab prophylaxis who had participated in the NIS and then enrolled in HAVEN 2 (group A). *Model-based ABRs estimated using negative binomial regression, which accounts for different follow-up times on previous treatment vs emicizumab. Comparison of ABR for treated bleeds in individual participants receiving emicizumab 1.5 mg/kg once weekly during HAVEN 2 vs BPA prophylaxis in the NIS. The efficacy periods within NIS and HAVEN 2 for individual patients are described below the x-axis. Participants exposed to emicizumab started with loading dose 3 mg/kg per week for 4 weeks followed by 1.5 mg/kg per week. Treated bleed is defined as a bleed followed by treatment of bleed. Bleeds due to surgery/procedure are excluded.

Figure 4.

Trough plasma concentrations of emicizumab over time with administration once weekly, every 2 weeks, or every 4 weeks. Error bars indicate 95% CIs. Sampling time points are indicated on the x-axis. Values are slightly offset from each other at each time point for clarity. Participants in all groups received the same loading dose of 3 mg/kg emicizumab for 4 weeks (weeks 2-5), followed by the maintenance dose indicated.