Developing BIVV001, a new class of factor VIII replacement for hemophilia A that is von Willebrand factor-independent

Authors: Chhabra E S., Liu, T., Kulman, J., Patarroyo-White, S., Yang, B., Lu, Q., Drager, D., Moore, N., Liu, J., Holthaus, A. M., Sommer, J., Ismail, A., Rabinovich, D., Liu, Z., van der Flier, A., Goodman, A., Furcht, C., Tie, M., Carlage, T., Mauldin, R., Dobrowsky, T. M., Liu, Z., Mercury, O., Zhu, L., Mei, B., Schellenberger, V., Jiang, H., Pierce, G. F., Salas, J., and Peters, R.

Blood February 2020;

Affiliations: Amunix Pharmaceuticals, Inc, United States; Sanofi, Waltham, Massachusetts, United States ; Biogen Inc, United States

Abstract: Factor 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. While endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, it also subjects FVIII to a half-life ceiling of approximately 15-19 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 two XTEN(R) polypeptides. Plasma FVIII half-life after BIVV001 administration in mice and monkeys was 25-31 hours and 33-34 hours, respectively, representing a three- to four-fold increase in FVIII half-life. Our results show that multifaceted protein engineering, far beyond a few amino acid substitutions, can 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 and less frequent dosing. Protein engineering methods described in the paper can also be applied to other complex proteins.