Adeno-associated virus (AAV)-mediated gene therapy is a promising treatment option for patients with hemophilia A. Up-to-date 3 years follow-up on the efficacy and safety of a single administration of AAV5-hFVIII-SQ are available. Fifteen subjects, older than 18 years, affected by severe hemophilia A (factor VIII level, ≤1 IU per deciliter) were treated with a single infusion of AAV5-hFVIII-SQ at various doses. Several laboratory and clinical parameters including factor VIII level, annualized rate of bleeding events, need of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years. At three years after infusion, two subjects had factor VIII expression of less than 1 IU per deciliter. Seven patients had a median factor VIII expression of 20 IU per deciliter; the median annualized treated bleeding events were absent, and the median need of exogenous factor VIII was reduced. Bleeding in target joints resolved in five of six participants. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed. Main study results showed that gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A was able to determine clinically relevant benefits in terms of substantial reduction in annualized bleeding rates and complete discontinuation of prophylactic factor VIII use.
Reference:
Pasi KJ, Rangarajan S, Mitchell N, Lester W, Symington E, Madan B, Laffan M, Russell CB, Li M, Pierce GF, Wong WY.Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. N Engl J Med. 2020 Jan 2;382(1):29-40.