Sanofi's Once-Weekly Extended Half-Life Factor VIII Therapy Efanesoctocog Alfa (BIVV001) Granted Breakthrough Therapy Designation by China CDE

By | Sunshine

On July 13, Sanofi's recombinant human coagulation factor VIII Fc–von Willebrand factor–XTEN fusion protein for injection (efanesoctocog alfa, rFVIIIFc-VWF-XTEN, BIVV001) was designated as a breakthrough therapy by the CDE. The proposed indications are for adults and children with hemophilia A: (1) routine prophylaxis to reduce the frequency of bleeding episodes; (2) on-demand treatment of bleeding; and (3) management of perioperative bleeding.

Hemophilia is an inherited bleeding disorder. Currently, there are approximately 136,000 patients in China, with Hemophilia A being the most common type, accounting for approximately 80% to 85% of all hemophilia cases. Among all patients with Hemophilia A, approximately 70% to 80% of those with severe disease and 90% to 95% of those with moderate to mild disease are negative for Factor VIII inhibitors. For a long time, standard prophylactic treatment for Hemophilia A has required intravenous infusions of FVIII two to three times per week, amounting to approximately 104 to 183 injections annually, with a treatment burden that is self-evident. Frequent intravenous injections not only exacerbate the risk of bleeding in hemophilia patients, but have also become one of the major limiting factors for prophylactic treatment.

von Willebrand factor (vWF) can form a complex with factor VIII (FVIII) to stabilize and protect FVIII from degradation and clearance; however, degradation of vWF results in the simultaneous degradation of FVIII, limiting the maximum half-life of FVIII to only 15–19 hours.

BIVV001 is an investigational novel coagulation factor VIII replacement therapy comprising a recombinant FVIII Fc fusion protein linked to a specific region of VWF (the FVIII-binding D’D3 domain) and two unstructured XTEN polypeptides. By overcoming the limitation imposed by VWF on FVIII half-life extension, it enables hemophilia A prophylaxis to be administered once weekly or less frequently.

A Phase I/IIa clinical trial, codenamed 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 demonstrated that BIWV001 was well tolerated, with no hypersensitivity reactions or clinically significant treatment-related adverse events observed during the study. In the 65 IU/kg dose cohort, a single administration of BIVV001 achieved an FVIII half-life of 43 hours, more than three times longer than the 13-hour half-life of conventional recombinant FVIII. Following a single infusion of BIWV001, mean Factor VIII activity levels remained ≥51% (within the normal range) over a 4-day period. Seven days post-infusion, Factor VIII activity levels were 17%.

In the 25 IU/kg cohort, a single dose of BIVV001 achieved an FVIII half-life of 38 hours, representing a 4-fold increase compared to the 9-hour half-life of injected rFVIII, with mean factor activity levels of 5% at 7 days post-infusion.

On February 18 of this year, the FDA granted Fast Track Designation (FTD) to this therapy for the treatment of Hemophilia A. BIVV001 is currently being evaluated in a Phase III XTEND-1 study designed to assess the efficacy and safety of BIVV001 in previously treated patients aged 12 years and older (n=150) with severe Hemophilia A.

BIVV001 was initially developed based on Amunix’s XTEN technology. In 2011, Biogen partnered with Amunix to co-develop BIVV001. On August 9, 2016, Biogen spun off its hemophilia business to establish a new company, Bioverativ. On January 22, 2018, Sanofi acquired Bioverativ for $11.6 billion ($105 per share), obtaining its marketed hemophilia products Eloctate (recombinant Factor VIII Fc fusion protein) and Alprolix (recombinant Factor IX Fc fusion protein), along with the investigational product BIVV001.