WALTHAM, Mass.—Bioverativ Inc., a Sanofi company that is focused on therapeutics for rare blood disorders, on May 21 presented at the World Federation of Hemophilia 2018 World Congress initial clinical data for BIVV001 (rFVIIIFc-VWF-XTEN), a novel and investigational von Willebrand factor (VWF)-independent factor VIII therapy for people with hemophilia A. Notably, the data indicate that a single low dose of BIVV001 extended the half-life of factor VIII to 37 hours with high factor activity levels.
“For decades, scientists have been trying to overcome the von Willebrand factor ceiling, which imposes a limit on the half-life of factor VIII, and these data demonstrate that BIVV001 has finally broken through that ceiling,” said Joachim Fruebis, senior vice president of development at Bioverativ. “Importantly for the hemophilia community, the factor levels seen in this study are unparalleled in hemophilia A, and we are excited about the potential for BIVV001 to transform the treatment paradigm for patients and physicians.”
In addition to the VWF ceiling breakthrough, the preliminary safety and pharmacokinetic data from the ongoing EXTEN-A Phase 1/2a study also indicated that the drug was generally well tolerated.
Factor replacement therapy is fundamental in the treatment of hemophilia A, as it naturally provides what is missing in the body (clotting factor VIII), and it has a consistent and well-characterized safety and efficacy profile. BIVV001 is an investigational factor VIII therapy that has the potential to provide comprehensive protection in all treatment scenarios, including management of acute bleeds, perioperative care, emergency situations and prophylactic use. The role of factor VIII also goes beyond the coagulation cascade and may have a role to play in joint and bone health for hemophilia patients.
EXTEN-A is an open-label, multicenter study of BIVV001 in both a low-dose and high-dose cohort of subjects aged 18 to 65 years with severe hemophilia A. In the recently presented data, four adult males from the low-dose cohort received a single dose of rFVIII (25 IU/kg) followed, after a washout period, by a single low dose of BIVV001 (25 IU/kg). Primary endpoints include occurrence of adverse events and development of inhibitors. Secondary endpoints related to pharmacokinetic parameters were also presented. Key findings included (cut-off 20 April 2018):
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A single, low dose of BIVV001 extended the half-life of factor VIII to 37 hours, a substantial increase over the 13 hours seen with rFVIII
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Average factor VIII activity for the four subjects was 13 perent at five days and 5.6 percent at seven days post infusion with a single low dose of BIVV001
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BIVV001 was generally well tolerated, with no development of inhibitors
In news from just several days earlier, Bioverativ also announced that the U.S. Food and Drug Administration (FDA) had accepted the Investigational New Drug (IND) application for BIVV003, a gene-edited cell therapy candidate for the treatment of people with sickle cell disease. Bioverativ and Sangamo Therapeutics are developing BIVV003 as part of an exclusive worldwide collaboration to develop and commercialize gene-edited cell therapies for sickle cell disease and beta thalassemia.
“This acceptance marks the second IND for this gene-editing approach in less than a year, and the first for a gene-edited therapy in sickle cell disease,” said Dr. Ken Huttner, vice president of clinical development at Bioverativ. “It represents our commitment to advancing cutting-edge science and offers hope to the many people who have been waiting generations for an effective way to treat sickle cell disease. We look forward to advancing the program into clinical trials.”
“Sickle cell disease is a lifelong blood disorder with serious, painful and debilitating complications, and patients deserve new, more effective treatment options,” added Dr. Ed Conner, chief medical officer at Sangamo. “Gene-edited cell therapy has the potential to provide patients living with sickle cell disease a lifelong treatment with a single administration. We believe the precision, efficiency and specificity of zinc finger nuclease technology differentiate BIVV003 from other genomic therapies in development.”
BIVV003 is a non-viral approach utilizing zinc finger nuclease gene-editing technology. By modifying a short sequence of the BCL11A gene in a patient’s red blood cell precursors, sickle hemoglobin production is suppressed, and the production of fetal hemoglobin is reactivated to levels that may protect patients against the progression of their sickle cell disease.
This IND enables Bioverativ to initiate a Phase 1/2 clinical trial to assess the safety, tolerability and efficacy of BIVV003 in adults with sickle cell disease, and Bioverativ expects to open several clinical sites across the United States this year. Currently, Sangamo is enrolling patients with transfusion-dependent beta thalassemia in a Phase 1/2 trial evaluating the safety, tolerability and efficacy of ST-400, which uses the same gene-editing approach as BIVV003.
