Achievement of Normal Circulating Factor VIII Activity Following Bmn 270 AAV5-FVIII Gene Transfer: Interim, Long-Term Efficacy and Safety Results from a Phase 1/2 Study in Patients with Severe Hemophilia a

Background: As an X-linked single gene disorder of Factor VIII (FVIII), hemophilia A (HA) is an ideal candidate for gene therapy. To date, extended follow-up of multiple subjects in multiple dose cohorts following successful gene transfer in HA patients has not been reported.

Aim: We present results from an ongoing Phase 1/2 study of AAV5-FVIII gene transfer in patients with severe HA receiving BMN 270. Data is reported herein from the two highest dose cohorts: 6E13 vg/kg and 4E13 vg/kg.

Methods: 13 subjects (6E13 vg/kg, n=7; 4E13 vg/kg, n=6) received a single intravenous (IV) dose of an AAV5 vector containing the B-domain-deleted F8 gene (BMN 270). Safety, efficacy, immunogenicity, and other clinically relevant endpoints are being evaluated.

Results: Data are current as of July 28, 2017. FVIII activity over time is presented herein as median levels over 4-week intervals. In the 6E13 vg/kg cohort, FVIII activity plateaued by 20 weeks post-BMN 270, with median levels between Weeks 20 to 64 in the normal range (86-122 IU/dL); at Week 64, median FVIII activity was 86 IU/dL (interquartile range [IQR] 65-107 IU/dL). In the 4E13 vg/kg cohort, median [IQR] FVIII activity levels continue to steadily increase toward the normal range (Week 20 [n=6]: 34 [28-40] IU/dL; Week 32 [n=3]: 51 [48-54] IU/dL). Median [IQR] annualized FVIII infusions in the 6E13 and 4E13 vg/kg cohorts declined from 139 [122-157] and 156 [112-183] to 0 [0-0] and 0 [0-0], respectively, 4 weeks post-BMN 270 infusion through the last follow-up visit. Median [IQR] annualized bleeding rate for subjects previously on prophylactic therapy (n=6 in both the 6E13 and 4E13 vg/kg cohorts) declined from 17 [1-24] and 8 [1-15] before dosing to 0 [0-0] and 0 [0-0], respectively, 4 weeks post-BMN 270 infusion through the last follow-up visit, with 5 subjects in each cohort self-reporting no bleeding episodes. Mild, grade 1, asymptomatic alanine aminotransferase (ALT) increases were reported in all 7 and 4 of 6 subjects in the 6E13 and 4E13 vg/kg cohorts, respectively. Peak ALT levels ranged from 44-141 U/L (upper limit of normal=43 U/L). All but 1 subject (in 4E13 vg/kg cohort) currently have a normal ALT level, and all but 1 subject (in 4E13 vg/kg cohort) are off of corticosteroid therapy (dose being tapered in 1 subject).

Conclusions: AAV5-FVIII gene transfer in subjects with severe HA has resulted in sustained, clinically relevant FVIII activity that profoundly reduced self-reported bleeding and exogenous FVIII use >1.2 years post-gene transfer in the 6E13 vg/kg cohort. FVIII activity levels in the 4E13 vg/kg cohort continue to steadily rise, reaching the lower end of the normal range >0.6 years post-gene transfer. BMN 270 was well-tolerated. Efficacy and safety data up to 1.5- and 1-year follow-up for all subjects in the 6E13 and 4E13 cohorts, respectively, will be presented. Both doses appear to enable achievement of long-term normalization of FVIII activity in severe HA patients and complete protection against hemophilia-related bleeding, with a favorable safety profile. Optimal dosing of BMN 270 will be further evaluated in upcoming Phase 3 clinical trials.