Interim results from a dose escalating study of AMT-060 (AAV5-hFIX) gene transfer in adult patients with severe haemophilia B

W. Miesbach8, M. Tangelder1, K. Meijer2, G. Castaman3, F. Cattaneo4, M. Coppens1, P. Kampmann5, R. Klamroth6, R. Schutgens7, E. Seifried8, J. Schwaeble8, (1Amsterdam, The Netherlands, 2Groningen, The Netherlands, 3Florence, Italy, 4Parma, Italy, 5Copenhagen, Denmark, 6Berlin, Germany, 7Utrecht, The Netherlands, 8Frankfurt, Germany)

Innovation and Novelty
Date: 16.02.2017,
Time: 14:00 - 15:15

Objective: Gene transfer for haemophilia offers the potential to shift the disease severity from severe to mild with a single treatment. AMT-060 consists of an AAV5 vector containing a liver-specific promoter and codon-optimized wildtype hFIX gene. Here, we investigate the safety and efficacy of AMT-060 in adults with severe haemophilia B.

Methods: This is a Phase 1/2, multi-national, multi-center, open-label, dose-escalating study. Patients had to have FIX ≤2% of normal and require either prophylactic exogenous FIX, or on-demand exogenous FIX with either ≥4 bleeds/year or haemophilic arthropathy. Patients received AMT-060 at either 5x10^12 gc/kg (n=5) or 2x10^13 gc/kg (n=5) via a single intravenous infusion over 30 minutes. Assessments include endogenous FIX activity, measured >10 days after the most recent administration of exogenous FIX; reduction of exogenous FIX use; annualized spontaneous bleeding rates; treatment related adverse events; and immunological assessments.

Results: There were no screen failures for pre-existing anti-AAV5 antibodies. Ten patients enrolled (33-72 years of age) and received AMT-060; 9 were on FIX prophylaxis and 1 in the higher-dose cohort used on-demand FIX therapy. At the time of submission, mean endogenous FIX activity 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 39 weeks of follow-up. Four of 5 patients in the low-dose cohort were able to stop FIX prophylaxis, reducing their annualized total FIX usage by a mean of 82%. One patient in the low-dose cohort had a mild, asymptomatic elevation of ALT at week 10 post-AMT-060 that resolved with a 7 weeks course of tapering prednisolone. No change in FIX activity, T-cell response, or other immunogenicity/inflammatory abnormalities were seen during the ALT elevation. Results will be updated up to 52 weeks for the low-dose cohort. Initial results up to 26 weeks will be presented for the higher-dose cohort.

Conclusion: Follow up of patients with severe haemophilia B who received 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 4/5 patients in the low-dose cohort, relieving them from the need for exogenous FIX prophylaxis and resulting in marked decrease of FIX usage.