BACKGROUND: Emicizumab is a bispecific monoclonal antibody that bridges activated factor IX and factor X to replace the function of missing activated factor VIII, thereby restoring hemostasis. In a phase 3, multicenter trial, we investigated its use as prophylaxis in persons who have hemophilia A without factor VIII inhibitors.
METHODS: We randomly assigned, in a 2:2:1 ratio, participants 12 years of age or older who had been receiving episodic treatment with factor VIII to receive a subcutaneous maintenance dose of emicizumab of 1.5 mg per kilogram of body weight per week (group A) or 3.0 mg per kilogram every 2 weeks (group B) or no prophylaxis (group C). The primary end point was the difference in rates of treated bleeding (group A vs. group C and group B vs. group C). Participants who had been receiving factor VIII prophylaxis received emicizumab at a maintenance dose of 1.5 mg per kilogram per week (group D); intraindividual comparisons were performed in those who had participated in a noninterventional study.
RESULTS: A total of 152 participants were enrolled. The annualized bleeding rate was 1.5 events (95% confidence interval [CI], 0.9 to 2.5) in group A and 1.3 events (95% CI, 0.8 to 2.3) in group B, as compared with 38.2 events (95% CI, 22.9 to 63.8) in group C; thus, the rate was 96% lower in group A and 97% lower in group B (P<0.001 for both comparisons). A total of 56% of the participants in group A and 60% of those in group B had no treated bleeding events, as compared with those in group C, who all had treated bleeding events. In the intraindividual comparison involving 48 participants, emicizumab prophylaxis resulted in an annualized bleeding rate that was 68% lower than the rate with previous factor VIII prophylaxis (P<0.001). The most frequent adverse event was low-grade injection-site reaction. There were no thrombotic or thrombotic microangiopathy events, development of antidrug antibodies, or new development of factor VIII inhibitors.
CONCLUSIONS: Emicizumab prophylaxis administered subcutaneously once weekly or every 2 weeks led to a significantly lower bleeding rate than no prophylaxis among persons with hemophilia A without inhibitors; more than half the participants who received prophylaxis had no treated bleeding events. In an intraindividual comparison, emicizumab therapy led to a significantly lower bleeding rate than previous factor VIII prophylaxis. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 3 ClinicalTrials.gov number, NCT02847637 .).
Even though this study was not designed for the pediatric population, the findings are interesting for me as a pediatric hematologist. The results show the impact of a novel therapy for persons with hemophilia A. However, the long term follow-up for the complications of this medication is required. Moreover, a study to confirm the preventive efficacy in terms of musculoskeletal deterioration is also needed.