Objective:
As a single gene disorder of Factor VIII (FVIII), hemophilia A (HA) is an ideal candidate for gene therapy. We present results from an ongoing Phase 1/2 study of valoctocogene roxaparvovec (BMN 270; AAV5-FVIII-SQ) gene transfer in patients with severe HA.
Methods:
As of 16 April 2018, 13 subjects (6E13 vg/kg, n=7; 4E13 vg/kg, n=6) received a single intravenous dose of valoctocogene roxaparvovec, an AAV5 vector containing a B-domain-deleted FVIII gene. Safety, efficacy, immunogenicity, and other endpoints are being evaluated.
Summary:
FVIII activity is presented as median levels over 4-week intervals. In the 6E13 cohort, FVIII activity plateaued by Week 20 post-valoctocogene roxaparvovec, with median levels between Weeks 20-104 in the non-hemophilic range ([range] 46-122 IU/dL); Week 104 median FVIII activity was 46 IU/dL ([range] 6-145 IU/dL). In the 4E13 cohort, median [range] FVIII activity increased to just below the normal range (NR) at Week 52 [n=6]: 32 [3-59] IU/dL. Prior FVIII prophylaxis subjects had median [interquartile range, IQR] annualized FVIII infusions decline from 139 [122-157] (6E13) and 156 [126-183] (4E13) to 0 [0-0.4] and 0 [0-1] 4 weeks post-infusion through last follow-up; median [IQR] annualized bleeding rates post-infusion were 0 [0-0] in both cohorts (no bleeding episodes in 5 subjects in each cohort). Mild, grade 1, asymptomatic alanine aminotransferase (ALT) increases were reported in six of seven 6E13 and four of six 4E13 subjects; one 4E13 subject had a grade 2 ALT increase. Peak ALT levels ranged from 44-141 U/L (upper limit of normal=43 U/L). All subjects had a normal ALT level at last follow-up and all subjects were off of corticosteroid therapy. No subjects developed inhibitors to FVIII.
Conclusions:
Gene transfer with valoctocogene roxaparvovec in subjects with severe HA resulted in sustained, clinically relevant FVIII activity that reduced self-reported bleeding and exogenous FVIII use 2 years post-infusion in the 6E13 cohort. FVIII activity in the 4E13 cohort was maintained at the upper range of mild HA 1 year post-infusion. Both doses enabled achievement of long-term therapeutic levels of FVIII activity and prevention of hemophilia-related bleeding with a favorable safety profile.