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

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. 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-DʹD3 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.

2021 clinical trials update: Innovations in hemophilia therapy

“…Molecular engineering attempts to overcome this barrier by introducing the D'D3 proportion of the VWF molecule to help protect the exogenous FVIII from interaction with endogenous VWF and thus eliminate premature clearance. Two molecules rD'D3‐FP (CSL626, CSL‐Behring) and rFVIIIFc‐VWF‐XTEN (BIVV001, Sanofi) have been reported in development 41,42 …”

Enhanced Half-Life Recombinant Factor VIII Concentrates for Hemophilia A: Insights from Pivotal and Extension Studies

“…Thus, BIVV001is able to achieve a fourfold extension of half-life in hemophilia animal models (mice and monkeys) compared with conventional FVIII, well beyond the approximately twofold half-life extension limit demonstrated by other long-acting FVIII variants that bind endogenous VWF. 48 This innovative molecule breaks VWF-imposed half-life limitations. This novel approach is currently being tested in an open-label, doseescalation phase 1/2a study to determine the safety, tolerability, and PKs of a single dose of BIVV001 in 16 patients with severe hemophilia (NCT03205163).…”

Recent trends in protein and peptide-based biomaterials for advanced drug delivery

“…More recently, a von-Willebrand factor independent FVIII-XTEN fusion, termed BIVV001, has demonstrated good safety and efficacy in early stage clinical trials ( NCT03205163 ) and is currently recruiting for Phase 3 ( NCT04161495 ) [ 421 , 422 ]. XTENylation of FVIII increases its plasma half-life three to four-fold relative to recombinant FVIII, achieving a half-life of up to 34 h in cynomolgous monkeys [ 423 ]. This resulted in four-fold longer hemostatic control, suggesting that this formulation could provide clotting protection for patients for up to one week [ 423 ].…”

“…XTENylation of FVIII increases its plasma half-life three to four-fold relative to recombinant FVIII, achieving a half-life of up to 34 h in cynomolgous monkeys [ 423 ]. This resulted in four-fold longer hemostatic control, suggesting that this formulation could provide clotting protection for patients for up to one week [ 423 ].…”