Background:
Gene transfer for hemophilia offers the potential to convert the disease from a severe to mild phenotype with a single treatment. AMT-060 consists of an AAV5 vector containing a codon-optimized wildtype hFIX gene under control of a liver-specific promoter.
Objective:
This phase 1/2 study investigates the safety and efficacy of AMT-060 at 2 dose levels in adults with moderate-severe or severe hemophilia B.
Methods:
Multi-national, open-label, dose-escalating study in patients with factor IX (FIX) activity ≤2% of normal, and a severe bleeding phenotype (prophylactic exogenous FIX; or ondemand exogenous FIX, plus ≥4 bleeds/year or hemophilic arthropathy). Patients received either 5x1012 gc/kg (n=5) or 2×1013 gc/kg (n=5) of AMT-060 iv. Efficacy assessments include endogenous FIX activity (measured ≥10 days after use of exogenous FIX); reduction of exogenous FIX use; and annualized spontaneous bleeding rates. Safety assessments include treatment related adverse events, immunological and inflammatory biomarkers.
Summary:
There were no screening failures due to AAV5 neutralizing antibodies. Mean FIX activity in the lower dose cohort was 5.2% (min-max, 3.0-6.8%; n=4; 1 patient remaining on prophylaxis excluded) during 1 year of follow-up, and 6.9% (min-max, 3.1-12.7%; n=5) in the higher dose cohort during 26 weeks follow-up. Eight of 9 patients on FIX prophylaxis discontinued use after AMT-060 infusion. Follow-up to up to 1.5 years will be presented, with annualized reduction of exogenous FIX use and spontaneous bleeding rates. Mild, temporary elevations in ALT were observed in 3 patients with higher mean FIX activity (6.3-12.7%; 1 in the lower and 2 in the higher dose cohort). Each received a tapering course of prednisolone. ALT elevations were not associated with changes in FIX activity or a capsid-specific T-cell response.
Conclusions:
Patients continue to show sustained clinical benefit and endogenous FIX activity with no T-cell activation ≥1 year after a single infusion of AMT-060.