Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

N Engl J Med. 2017 Aug 31;377(9):819-828. doi: 10.1056/NEJMoa1616569. Epub 2017 Jul 10.

Abstract

Background: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations.

Methods: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran.

Results: No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants.

Conclusions: Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

Publication types

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

MeSH terms

  • Adult
  • Antithrombin III / antagonists & inhibitors*
  • Antithrombins / blood
  • Dose-Response Relationship, Drug
  • Healthy Volunteers
  • Hemophilia A / blood
  • Hemophilia A / therapy*
  • Hemophilia B / blood
  • Hemophilia B / therapy*
  • Humans
  • Injections, Subcutaneous
  • Male
  • Middle Aged
  • RNAi Therapeutics*
  • Single-Blind Method
  • Thrombin / biosynthesis
  • Young Adult

Substances

  • Antithrombins
  • SERPINC1 protein, human
  • Antithrombin III
  • Thrombin

Associated data

  • ClinicalTrials.gov/NCT02035605
  • ClinicalTrials.gov/NCT02035605