Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B

Hemophilia B gene therapy aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno-associated virus-5 (AAV5) vector with a liver-specific promoter driving expression of a codon-optimized wild-type human FIX gene. This multi-national, open-label study included ten adults with hemophilia B (FIX ≤2% of normal) and severe-bleeding phenotype. No participants tested positive for AAV5-neutralizing antibodies using a green-fluorescent protein-based assay and all 10 were enrolled. A single dose of 5x1012 or 2x1013 genome copies of AMT-060/kilogram was administered to five-participants each. In the low-dose cohort, mean endogenous FIX activity increased to 4.4 IU/dL. Annualized FIX use was reduced by 81%, and mean annualized spontaneous bleeding rate (ASBR) decreased from 9.8 to 4.6 (53%). In the higher-dose cohort, mean FIX activity increased to 6.9 IU/dL. Annualized FIX use decreased by 73%, and mean ASBR declined from 3.0 to 0.9 (70%). There was no reduction in traumatic bleeds. FIX activity was stable in both cohorts and eight of nine participants receiving FIX at study entry stopped prophylaxis. Limited, asymptomatic, and transient alanine aminotransferase elevations in the low-dose (n=1) and higher-dose (n=2) cohorts, were treated with prednisolone. No decrease in FIX activity or capsid-specific T-cell responses were detected during transaminase elevations. A single infusion of AMT-060 had a positive safety profile and resulted in stable and clinically-important FIX activity increases, a marked reduction in spontaneous bleeds and FIX concentrate use, without detectable cellular-immune responses against capsids. Registered to www.ClinicalTrials.gov as NCT0239634