A BRIEF REVIEW ON CLINICAL ASSESSMENT OF GENE THERAPIES FOR HEMOPHILIA A AND HEMOPHILIA B

Hemophilia A is an X-linked, recessive disorder caused by deficiency of functional plasma clotting factor VIII (FVIII), which may be inherited or arise from spontaneous mutation. The development of inhibitory alloantibodies to FVIII can severely complicate the treatment of genetic cases. Rarely, development of autoantibodies to FVIII results in acquired hemophilia A. In the early-phase hemophilia B trials of the currently licensed products, data has shown durable expression for periods of up to 8 years, with observation ongoing. This gives reasonable confidence that this bar can be met, at least for hemophilia B. To date, the only clinical dataset showing long-term expression (>10 years) is one for hemophilia B, in a trial that started in 2010. However, hemophilia A has not yet been shown to exhibit consistent long-term expression at stable levels above 30%, and predictability remains a problem for all licensed gene treatments for hemophilia (all three are AAV vectors that drive liver-specific expression of the clotting factor). The fact that there are already two authorized gene treatments for hemophilia B makes it unique. Both products are non-inferior and superior to routine prophylaxis in terms of ABR; they both demonstrated mean FIX activity levels well into the mild hemophilia range, with Hemgenix levels slightly higher than Beqvez (34% vs. 26.9% by one stage assay); and nearly two-thirds of phase 3 trial participants experienced no bleeding episodes during the follow-up periods.