• Blood · Apr 2020

    BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice.

    • Ekta Seth Chhabra, Tongyao Liu, John Kulman, Susannah Patarroyo-White, Buyue Yang, Qi Lu, Douglas Drager, Nancy Moore, Jiayun Liu, Amy M Holthaus, Jurg M Sommer, Ayman Ismail, Deana Rabinovich, Zhan Liu, Arjan van der Flier, Allison Goodman, Chris Furcht, Mark Tie, Tyler Carlage, Randy Mauldin, Terrence M Dobrowsky, Zhiqian Liu, Oblaise Mercury, Lily Zhu, Baisong Mei, Volker Schellenberger, Haiyan Jiang, Glenn F Pierce, Joe Salas, and Robert Peters.
    • Sanofi, Waltham, MA.
    • Blood. 2020 Apr 23; 135 (17): 1484-1496.

    AbstractFactor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term outcomes associated with high sustained FVIII levels. Endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, but it also subjects FVIII to a half-life ceiling of ∼15 to 19 hours. Increasing recombinant FVIII (rFVIII) half-life further is ultimately dependent upon uncoupling rFVIII from endogenous VWF. We have developed a new class of FVIII replacement, rFVIIIFc-VWF-XTEN (BIVV001), that is physically decoupled from endogenous VWF and has enhanced pharmacokinetic properties compared with all previous FVIII products. BIVV001 was bioengineered as a unique fusion protein consisting of a VWF-D'D3 domain fused to rFVIII via immunoglobulin-G1 Fc domains and 2 XTEN polypeptides (Amunix Pharmaceuticals, Inc, Mountain View, CA). Plasma FVIII half-life after BIVV001 administration in mice and monkeys was 25 to 31 hours and 33 to 34 hours, respectively, representing a three- to fourfold increase in FVIII half-life. Our results showed that multifaceted protein engineering, far beyond a few amino acid substitutions, could significantly improve rFVIII pharmacokinetic properties while maintaining hemostatic function. BIVV001 is the first rFVIII with the potential to significantly change the treatment paradigm for severe hemophilia A by providing optimal protection against all bleed types, with less frequent doses. The protein engineering methods described herein can also be applied to other complex proteins.© 2020 by The American Society of Hematology.

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