Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A

Abstract

BACKGROUND Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ. METHODS We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years. RESULTS Three years after infusion, two participants (one who had received 6×10 12 vector genomes [vg] per kilogram of body weight and one who had received 2×10 13 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×10 13 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×10 13 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. 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. CONCLUSIONS Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×10 13 vg per kilogram or 6×10 13 vg per kilogram of the gene therapy.

Assessing the potential cost-effectiveness of a gene therapy for the treatment of hemophilia A

“…We developed an individual-based, state-transition microsimulation model for assessing the likely cost-effectiveness of valoctocogene roxaparvovec compared to FVIII prophylaxis (referred to as the comparator). To reflect the valoctocogene roxaparvovec trial population, we simulate a hypothetical cohort of males who are 30 years of age (phase 2 clinical trial median age), have a severe phenotype of hemophilia A, previously received prophylactic FVIII therapy, and have no history of inhibitors to FVIII protein 20 . The following outcomes are considered: total costs (incurred by treatment with FVIII, bleed management, and other medical costs), total number of FVIII infusions, total number of bleeding events (joint and nonjoint), life-years gained, and quality-adjusted life-years (QALYs) gained.…”

“…For the valoctocogene roxaparvovec arm, we simulated a patient-specific, time-invariant annual bleed rate (ABR) to reflect the mean ABRs and proportion of patients that are bleed-free reported at Year 3 of the clinical trial 20 . Of the individuals who were administered valoctocogene roxaparvovec, 20% were assumed to experience bleeds even while responding to valoctocogene roxaparvovec and were assigned ABRs drawn from a normal distribution (mean 5, SD 1) and 80% were assumed to experience zero bleed events while responding to valoctocogene roxaparvovec.…”

The Unusual Properties of the AAV Inverted Terminal Repeat

“…In addition, for safety considerations, generally, it is considered desirable that vectors were not be able to replicate. Over time additional studies on the fate of AAV and AAV vectors after infection enabled modifications in the construction of vectors to the point that AAV vectors have been developed that have enabled apparent cures for several monogenic human diseases, including a form of Leber's disease (congenital blindness), [28][29][30][31] hemophilia (A and B), [32][33][34][35][36] lipoprotein lipase deficiency, 37 and spinal muscle atrophy. 38 A major reason that AAV has found favor as a vector for human gene therapy is that until recently there has been no known association with human disease.…”

My Pathway to Adeno-Associated Virus and Adeno-Associated Virus Gene Therapy: A Personal Perspective

“…Also, the manufacturing group at BioMarin built an in-house commercial facility to manufacture AAV vectors at 2,000 L scale. The pivotal trials 17 have now led to recent filings, in both Europe and the United States, for approval of the AAV hemophilia A product that is now known as valoctocogene roxaparvovec.…”