Emicizumab Prophylaxis in Hemophilia A with Inhibitors

N Engl J Med. 2017 Aug 31;377(9):809-818. doi: 10.1056/NEJMoa1703068. Epub 2017 Jul 10.

Abstract

Background: Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors.

Methods: We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C.

Results: A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (P<0.001). A total of 22 participants in group A (63%) had zero bleeding events, as compared with 1 participant (6%) in group B. Among 24 participants in group C who had participated in a noninterventional study, emicizumab prophylaxis resulted in a bleeding rate that was significantly lower by 79% than the rate with previous bypassing-agent prophylaxis (P<0.001). Overall, 198 adverse events were reported in 103 participants receiving emicizumab prophylaxis; the most frequent events were injection-site reactions (in 15% of participants). Thrombotic microangiopathy and thrombosis were reported in 2 participants each (in the primary analysis) who had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. No antidrug antibodies were detected.

Conclusions: Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no prophylaxis among participants with hemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .).

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antibodies, Bispecific / adverse effects
  • Antibodies, Bispecific / pharmacokinetics
  • Antibodies, Bispecific / therapeutic use*
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Blood Coagulation Factors / adverse effects
  • Blood Coagulation Factors / therapeutic use
  • Child
  • Drug Therapy, Combination
  • Factor VIII / immunology
  • Factor VIII / therapeutic use
  • Factor VIIa / therapeutic use
  • Hemophilia A / drug therapy*
  • Hemophilia A / immunology
  • Hemorrhage / prevention & control*
  • Humans
  • Injections, Subcutaneous
  • Isoantibodies / blood
  • Male
  • Middle Aged
  • Recombinant Proteins / therapeutic use
  • Thrombosis / chemically induced
  • Young Adult

Substances

  • Antibodies, Bispecific
  • Antibodies, Monoclonal, Humanized
  • Blood Coagulation Factors
  • Isoantibodies
  • Recombinant Proteins
  • prothrombin complex concentrates
  • emicizumab
  • Factor VIII
  • Factor VIIa

Associated data

  • ClinicalTrials.gov/NCT02622321
  • ClinicalTrials.gov/NCT02622321