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Efficacy and safety of rVIII-SingleChain: results of a phase I/III multicenter clinical trial in severe hemophilia A

Johnny Mahlangu, Kazimierz Kuliczkowski, Faraizah Abdul Karim, Oleksandra Stasyshyn, Marina V. Kosinova, Lynda Mae Lepatan, Aleksander Skotnicki, Lisa N. Boggio, Robert Klamroth, Johannes Oldenburg, Andrzej Hellman, Elena Santagostino, Ross I. Baker, Kathelijn Fischer, Joan C. Gill, Stephanie P'Ng, Pratima Chowdary, Miguel A. Escobar, Claudia Djambas Khayat, Luminita Rusen, Debra Bensen-Kennedy, Nicole Blackman, Tharin Limsakun, Alex Veldman, Katie St. Ledger and Ingrid Pabinger

Key points

  • rVIII-SingleChain is a novel recombinant factor VIII, designed to have high stability and high binding affinity for von Willebrand Factor.

  • In severe hemophilia A patients, rVIII-SingleChain was well tolerated and resulted in low bleeding rates, when dosed twice per week.

Abstract

rVIII-SingleChain is a novel B-domain truncated recombinant Factor VIII (rFVIII), comprised of covalently bonded FVIII heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor. This Phase I/III study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). Participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N=146) or on-demand (N=27). The total cumulative exposure was 14,306 exposure days (ED), with 120 participants reaching ≥50 ED and 52 participants having ≥100 ED. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low annualized bleeding rate in patients on prophylaxis and a favorable safety profile in this large clinical study (www.ClinicalTrials.gov identifier: NCT01486927).

  • Submitted January 5, 2016.
  • Accepted June 2, 2016.