Development of a universal gene therapy for hemophilia A or B with or without inhibitors

Summary/Abstract Hemophilia is an inherited bleeding disorder caused by a deficiency of the functional clotting factor FVIII (hemophilia A) or FIX (hemophilia B) in the contact activation pathway of the coagulation cascade. Current treatment by protein replacement therapy is constrained by the short half-life of the clotting factors, requiring repeated infusions at relatively large doses. The development of inhibitors (alloantibodies to clotting factors) remains the single most important obstacle to managing hemophilia with protein therapy. Approximately 20–30% of patients with hemophilia A and 5% of patients with hemophilia B develop inhibitors after protein replacement therapy. In patients with inhibitors, the administration of clotting factors is ineffective, and poor control of hemorrhagic episodes increases complications associated with the disease. Bispecific Factor IXa and X-directed antibodies can be given to hemophilia A patients with or without inhibitors and are an improvement over infusions. However, 47% of patients still require infusions for breakthrough bleeds. Hemophilia A gene therapies using Adeno-associated virus (AAV) to deliver FVIII, either approved or in development, for non-inhibitor patients have demonstrated limited durability of effect after a single infusion. Importantly, to date there have been no approved AAV based gene therapies in development for hemophilia patients with inhibitors. GeneVentiv is directly addressing this critical unmet need through the development of GENV-HEM, the first designed to treat inhibitor patients. GENV-HEM is an AAV8 vector encoding human FVa (hFVa) driven by a liver- specific promoter. Within the coagulation pathway, FVa functions downstream as a co-factor of activated Factor X (FXa) to amplify thrombin generation. FVa acts in the common coagulation pathway and can generate thrombin via the prothrombinase complex without FVIII or Factor IX, or in the presence of anti-FVIII or anti-FIX antibodies. Because of the position of FVa in the coagulation cascade, GENV-HEM offers a potential platform (universal) therapy that can treat all types of hemophilia. We have demonstrated proof-of-concept of GENV-HEM in mouse models of hemophilia A or B with or without inhibitors. The next major steps toward commercialization of this innovative technology are encompassed in the following Specific Aims: (1) Optimization of lead GENV-HEM candidate in a mouse model of hemophilia to reduce the minimum effective dose; (2) Manufacture GLP-grade GENV-HEM for IND-enabling studies; (3) Demonstrate efficacy of GENV-HEM in a canine model of hemophilia; and (4) Develop bioanalytical methods in nonhuman primates in preparation for IND-enabling pharmacology/toxicology studies. This application requests supplemental TABA funding to provide Regulatory support and guidance to prepare for our FDA INTERACT meeting and additional IP filing resulting directly from the parent Phase II SBIR. As an early-stage startup, our regulatory and IP budget is limited for these critical activities towards completing a successful round of financing and eventual commercialization. Support for regulatory and IP filing activities will increase the ultimate value of our enterprise.