Interim Results from a Dose Escalating Study of AMT-060 (AAV5-hFIX) Gene Transfer in Adult Patients with Severe Hemophilia B

Introduction: The development of gene transfer for hemophilia is advancing rapidly and offers the potential to shift the disease severity from severe to mild with a single treatment. AMT-060 consists of an AAV5 vector with a gene cassette containing an LP1 liver specific promoter and codon-optimized wild type hFIX gene that has previously been shown to result in durable increases in FIX activity of at least 4 years¹. This phase 1/2 study aims to investigate the safety and efficacy of AMT-060 in adult patients with severe hemophilia B.

Methods: This is a multi-national, multi-center, open-label, dose-escalating study in patients with FIX activity ≤ 2% of normal, and a severe bleeding phenotype. To be eligible, patients had to require either prophylactic exogenous FIX, or on-demand exogenous FIX with more than 4 bleeds per year or suffer from hemophilic arthropathy. Ten patients were treated in two subsequent, escalating dose cohorts, with AMT-060 5x 10¹² gc/kg (n=5) or 2x 10¹³ gc/kg (n=5). Patients received AMT-060 via a single intravenous infusion over 30 minutes. Efficacy assessments include endogenous FIX activity, measured at least 10 days after the most recent administration of exogenous FIX; reduction of exogenous FIX use; and annualized spontaneous bleeding rates. Safety assessments include treatment related adverse events and immunological assessments, including T-cell response to capsid antigens.

Results: There were no screen failures for pre-existing antibodies against AAV5. The age of enrolled patients ranged from 33 to 72 years. At enrollment, nine patients were on FIX prophylaxis, and one patient in the high dose cohort used on-demand FIX therapy. At the time of submission, all ten patients have received AMT-060. The mean of all endogenous FIX activity values after cessation of prophylaxis in the low-dose cohort was 5.4% (95% CI 5.0-5.8%, range 3.1-6.7%; n=4), and stable during the 39 weeks of follow-up. Four out of five patients in the low-dose cohort were able to stop FIX prophylaxis. These patients demonstrated a mean reduction in annualized total FIX usage of 82% after treatment with AMT-060. For all five patients in the low-dose cohort, the mean annualized total FIX usage declined 75% after treatment with AMT-060. Following AMT-060 administration, one patient in the lower dose cohort had a mild, asymptomatic, elevation of ALT at week 10 that resolved with a seven weeks course of tapering prednisolone. No change in FIX activity, and no T-cell response or other possibly associated immunogenicity or inflammatory abnormalities were seen during the ALT elevation. Efficacy and safety results will be updated up to 52 weeks of follow up for the low-dose cohort. Initial efficacy and safety results from the higher-dose cohort up to 26 weeks of follow up will also be presented.

Conclusions: Follow up of patients with severe hemophilia B who received either the low or higher dose of AMT-060 is ongoing. A single infusion of AMT-060 was generally well-tolerated. FIX activity increased to levels sufficient to provide endogenous prophylaxis in four of five patients in the low-dose cohort, relieving them from the need for exogenous FIX prophylaxis and resulting in marked decrease of FIX usage.

¹Nathwani et al. NEJM 2014; 371:1994-2004