Sanofi and Sobi Announce Positive Phase 1/2a Clinical Results for BIVV001, a Long-Acting Factor VIII Replacement Therapy with 3–4-Fold Extended Half-Life in Hemophilia A

Today, Sanofi announced that BIVV001 (rFVIIIFc-VWF-XTEN), an innovative factor VIII replacement therapy co-developed with Sobi, achieved positive results in a Phase 1/2a clinical trial. The trial results demonstrated that BIVV001 extends the half-life by three to four times compared with traditional factor VIII (FVIII) replacement therapies. This study has been published in the New England Journal of Medicine.

Hemophilia A is a genetic disorder caused by mutations in the gene encoding factor VIII (FVIII), leading to FVIII deficiency. The current standard treatment for hemophilia A involves regular infusions of FVIII; however, patients typically require 3–4 infusions per week, which imposes significant inconvenience on their daily lives.

Natural FVIII has a half-life of only about 12 hours in the bloodstream because it forms a complex with von Willebrand factor (VWF). Although binding to VWF enhances the stability of FVIII in circulation, the degradation rate of VWF itself imposes an upper limit on the residence time of FVIII in the blood, as FVIII bound to VWF is degraded concurrently when VWF is broken down.

BIVV001 is designed by linking FVIII to a VWF fragment, forming a complex that does not bind to endogenous VWF in the bloodstream, thereby overcoming the half-life ceiling imposed by VWF. It aims to enable patients with hemophilia A to maintain near-normal FVIII activity levels for most of the week following a single injection.

▲Schematic structure of BIVV001 (Image source: Reference [2])

The open-label, multicenter study named EXTEN-A evaluated the safety, tolerability, and pharmacokinetic profile of BIVV001 at doses of 25 IU/kg (n=6) and 65 IU/kg (n=8) in subjects aged 19–63 years with severe hemophilia A. The trial results showed:

BIVV001 demonstrated good tolerability, with no detection of FVIII inhibitor development within 28 days post-dosing. No allergic reactions or clinically significant treatment-related adverse events were observed during the study period.

In the 65 IU/kg dose cohort, a single administration of BIVV001 achieved an FVIII half-life of 43 hours, which is more than three times longer than the 13-hour half-life of conventional recombinant FVIII. Over the 4 days following a single infusion of BIVV001, the mean factor VIII activity level was ≥51%, within the normal range, and the factor VIII activity level was 17% at 7 days post-infusion.

▲ Mean plasma FVIII activity data in hemophilia patients after a single infusion of BIVV001 (Image source: Reference [2])

In the 25 IU/kg dose cohort, the half-life of FVIII after a single dose of BIVV001 was 38 hours, which is four times the 9-hour half-life observed with rFVIII, and the mean factor activity level at 7 days after infusion of BIVV001 was 5%.

References:

[1] New England Journal of Medicine publishes positive final results from Phase 1/2a study of BIVV001 in people with severe hemophilia A. Retrieved September 10, 2020, from https://www.sanofi.com/en/media-room/press-releases/2020/2020-09-10-07-00-00

[2] Konkle et al., (2020). BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A. NEJM, DOI: 10.1056/NEJMoa2002699

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