AMT-060 Gene Therapy in Adults with Severe or Moderate-Severe Hemophilia B Confirm Stable FIX Expression and Durable Reductions in Bleeding and Factor IX Consumption for up to 5 Years

Background: Gene therapy aims to provide long-term therapeutic benefit from a single administration. AMT-060 is an adeno-associated virus serotype 5 (AAV5) vector with a codon-optimized wildtype human factor IX (FIX) gene and liver-specific promoter. AMT-060 is being evaluated in an ongoing study of 10 participants with severe/moderate-severe hemophilia B (Phase 1/2 study, NCT02396342) over 5 years.

Aim: To describe efficacy and safety outcomes from an analysis at up to 5-years post-AMT-060.

Methods: Adult males with FIX activity ≤2% and a severe bleeding phenotype received a single intravenous infusion of AMT-060 (5x10¹² gc/kg, Cohort 1, n=5) or (2×10¹³ gc/kg, Cohort 2, n=5). Assessments included FIX activity, FIX replacement use, annualized bleeding rate (ABR), treatment-related adverse events (TRAE), immunological and inflammatory biomarkers up to 5 years (Cohort 1) and 4.5 years (Cohort 2).

Results: As of November 2019, for Cohort 1 the mean FIX activity (at 4.0 years) was 5.1% as compared to 4.4% in the first year, 6.8% in the second year, 7.3% in the third year and 7.0% in the fourth year. Mean FIX activity for Cohort 2 was 7.5% as compared to 7.1% in the first year, 8.4% in the second year 7.9% in the third year, and 7.4% in the fourth year. Eight of 9 participants using prophylaxis at baseline were able to discontinue use. During the last 12, and 6 months of observation respectively, the mean annualized bleed rate (ABR) was 3.3. for Cohort 1 and 0.0 for Cohort 2. These represent, respectively, a reduction in mean ABR to the year prior to treatment of 77% and 100% for Cohort 1 and Cohort 2. During this same period the consumption of FIX replacement therapy declined 90% and 100% relative to pre-treatment, respectively for Cohort 1 and Cohort 2. 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 for the first time.

Conclusions: Long-term stable endogenous FIX activity and reductions in ABR and FIX replacement use were sustained over multiple 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.