AMT-060 Gene Therapy in Adults with Severe or Moderate-Severe Hemophilia B Confirms Stable FIX Expression and Sustained Reductions in Bleeding for up to 5 Years

Objective Gene therapy aims to provide long-term therapeutic benefit from a single administration. AMT-060, an adeno-associated virus serotype 5 (AAV5) vector with a codon-optimized wildtype human factor IX (FIX) gene and liver-specific promoter, is being evaluated in 10 adults with severe/moderate-severe hemophilia B. over 5 years. Aim: To describe efficacy and safety outcomes from an analysis up to 5-years post-AMT-060 (Phase 1/2 study, NCT02396342).

Material and Methods Adult males with FIX activity ≤2 % and a severe bleeding phenotype received a single intravenous infusion of AMT-060 (5x10^12 gc/kg, Cohort 1, n = 5) or (2×10^13 gc/kg, Cohort 2, n = 5). Assessments include FIX activity, FIX replacement use, annualized bleeding rate (ABR) and treatment-related adverse events (TRAE) up to 5 years (Cohort 1) and 4.5 years (Cohort 2).

Results As of November 2019, mean FIX activity was 5.1 % at 4.0 years for Cohort 1 versus 4.4 % in Year 1; 6.8 % in Year 2; 7.3 % in Year 3 and 7.0 % in Year 4. Mean FIX activity for Cohort 2 was 7.5 % versus 7.1 % in Year 1; 8.4 % in Year 2; 7.9 % in Year 3; and 7.4 % in Year 4. Mean ABR during the last 12, and 6 months of observation, was 3.3 for Cohort 1 and 0.0 for Cohort 2, respectively, representing a 77 % and 100 % reduction in the year prior to treatment. During the same period, FIX replacement therapy consumption declined 90 % (Cohort 1) and 100 % (Cohort 2). Eight of 9 participants using prophylaxis at baseline were able to discontinue.

No participants developed FIX inhibitors or signs of sustained AAV5 capsid-specific T-cell activation. As previously reported, TRAE were mainly reported in the first 3.5 months after treatment, including three participants who experienced transient mild elevations in alanine aminotransferase. One additional TRAE (joint swelling post-exercise) was observed during the last 12 months of observation post-treatment. Updated data, up to 5-years of observation, will be presented.

Conclusion Durable, stable endogenous FIX activity and reductions in ABR and FIX replacement use were maintained over several years following a single treatment with AMT-060. There were no additional safety concerns with longer term follow-up. This data supports the ongoing Phase 3 study of the enhanced construct etranacogene dezaparvovec (AMT-061), which encodes the highly active Padua FIX variant.

Publication History

Article published online:
18 June 2021