A Phase II Open-Label Study Evaluating Hemostatic Activity, Pharmacokinetics and Safety of Recombinant Porcine Factor VIII (OBI-1) in Hemophilia A Patients with Alloantibody Inhibitors Directed Against Human FVIII.

Abstract

Development of inhibitors to human FVIII (hFVIII) is a significant complication in the reversal and prevention of bleeding events in hemophilia A patients. Porcine FVIII (pFVIII) possesses low cross reactivity to anti-hFVIII antibodies. OBI-1, a recombinant B-domain deleted pFVIII, has recently been tested in a Phase II trial in patients with congenital hemophilia A and inhibitors experiencing a non-life/non-limb threatening bleed. In patients with a measurable anti-pFVIII antibody titer, dosing was initiated with a loading dose (LD) followed by up to 8 doses of 50 to 150 U/kg of OBI-1 administered at 6 hour intervals until the bleed was controlled. The PK profile of OBI-1 was assessed for the first OBI-1 infusion of each patient. FVIII levels were measured 30 minutes after each infusion. Inhibitor titers were evaluated for a minimum of 6 months after the first OBI-1 infusion. A total of 25 bleeding episodes in 9 patients were treated successfully with OBI-1. The median time from bleeding onset to treatment was 7 hours (range: 3 20 hr). OBI-1 showed a cumulative efficacy of 72% after 1 injection, 84% after 2 injections or less, 92% after 3 injections or less, and 100% after 8 or less injections. In over 40 infusions, OBI-1 was well tolerated and no drug related SAEs were observed. One case of pruritus rated as mild was easily controlled with diphenhydramine. FVIII levels measured 30 minutes after each OBI-1 infusion ranged from < 0.5% to 226%. They were generally lower with higher anti-pFVIII titers although all bleeds were successfully controlled. Follow up inhibitor titers are still being monitored and final results will be presented and discussed. Other investigative parameters, including vital signs and laboratory variables did not show treatment related abnormalities. OBI-1 can be given as a short infusion. It was effective in controlling all bleeds which occurred in this study and was well tolerated. The results suggest that a LD is not needed with OBI-1 treatment, and in some instances patients may have been over treated. Given the promising results in this study, additional studies are planned to optimize dose range for OBI-1 and to confirm the long term safety and efficacy of OBI-1 in the treatment of bleeds in a larger cohort of individuals with hemophilia A complicated by the presence of hFVIII inhibitors.