Reduction in Annualized Bleeding and Factor IX Consumption up to 2.5 Years in Adults with Severe or Moderate-Severe Hemophilia B Treated with AMT-060 (AAV5-hFIX) Gene Therapy

Abstract Introduction: AMT-060 consists of an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized wildtype human factor IX (FIX) gene under control of a liver-specific promoter. We have previously reported on the safety and efficacy of AMT-060 gene therapy at 2 dose levels in adults with moderate-severe or severe hemophilia B with up to 1-year follow-up. Here we present longer-term follow-up data on reductions in annualized bleed rates and FIX consumption up to 2.5 years post-treatment. Methods: Multi-national, open-label, dose-escalating study in participants (pts) with FIX activity ≤2 % of normal, and a severe bleeding phenotype (NCT02396342). Pts received either 5x1012 gc/kg (Cohort 1, n=5) or 2×1013 gc/kg (Cohort 2, n=5) of AMT-060 iv. Duration of follow-up was 2.5 and 2 years in Cohort 1 and Cohort 2, respectively. Efficacy assessments include FIX activity (measured ≥10 days after use of exogenous FIX), reduction of FIX use, and annualized total bleeding rates. Bleeds were counted for each individual patient starting after discontinuation of prophylaxis post-AMT-060. For Cohort 1, exogenous FIX use and bleeds for "year 3" are presented as a calculated annualized mean using data captured between 2 and 2.5 years. Safety assessments include treatment-related adverse events, immunological and inflammatory biomarkers. Results: Nine pts with severe (FIX <1 %) and 1 with moderate-severe (FIX 1.5 %) hemophilia B were enrolled and received AMT-060. Nine were receiving exogenous FIX prophylaxis and one was receiving on-demand exogenous FIX. Mean FIX activity over the course of follow up was 4.9 % in Cohort 1 and 7.4% in Cohort 2. Disease severity improved in all pts: from severe to mild (n=6), severe to moderate (n=3), and moderate to mild (n=1). Eight of nine pts on FIX prophylaxis at study entry discontinued use after AMT-060 infusion. In Cohort 1, annualized exogenous FIX use (excluding use for surgeries) decreased from a pre-treatment cumulative total of 1,562,000 IU by 85%, 96% and 93% for years 1, 2 and 3 of follow-up (n=4, excluding patient who remained on prophylaxis post-treatment). In Cohort 2, exogenous FIX use was reduced from a pre-treatment cumulative total of 866,000 IU by 78% and 93% for years 1 and 2 of follow-up (n=5). Mean annualized total bleeds decreased from 14.4 in the year prior to AMT-060 to 7.6, 2.8 and 7.8, in years 1, 2, and 3 of follow-up in Cohort 1. Among the three patients with FIX activity >5% in Cohort 1, a single bleed was reported in year 2 and no bleeds were reported to data cut-off in year 3. For the two patients with FIX activity <5%, one patient with mean FIX activity of 4-4.3% reported 4 bleeds for year 2 and 4 bleeds to data cutoff in year 3, while the patient remaining on prophylaxis reported 8 and 9 bleeds during the same period. In Cohort 2, mean annualized total bleeds were reduced from a pre-therapy mean of 4.0 to 1.5 and 0.5 in years 1 and 2, respectively. One pt in Cohort 2 was not included in the calculation as historical bleed data was not available; he experienced one traumatic bleed approximately 7.5 months after the discontinuation of prophylaxis. No pts developed inhibitors to FIX and there were no detectable signs of sustained AAV5 capsid-specific T-cell activation. Fourteen treatment-emergent adverse events were reported in the first 3.5 months after treatment, including three patients who experienced transient mild elevations in alanine aminotransferase as previously disclosed. There were no additional treatment-related adverse events reported during this additional follow-up period up to 2.5 years post-treatment. Conclusions: Stable endogenous FIX concentrations >4% have now been observed out to 2.5 years post-treatment with AMT-060. In addition, we have observed continued reductions in annualized bleeds to near zero with the higher dose of AMT-060, and a 78-93% reduction in exogenous FIX use. The lack of additional safety concerns or treatment-related adverse events over the longer study period, including no recurring changes in ALT, support the continued development and transition of AMT-060 to AMT-061, which will use the same AAV5 vector to deliver the 2×1013 gc/kg dose with the enhanced Padua transgene, which is anticipated to increase FIX activity 6-8 fold. Disclosures Leebeek: CSL Behring: Research Funding; Uniqure: Research Funding; Baxalta/Shire: Research Funding. Meijer:BMS: Honoraria; Aspen: Honoraria; Boehringer Ingelheim: Honoraria; Pfizer: Research Funding; Sanquin: Honoraria, Research Funding; Bayer: Honoraria, Other: Travel support, Research Funding; UniQure: Research Funding. Coppens:Bayer: Honoraria, Other: Non-financial support, Research Funding; CSL Behring: Honoraria, Other: non-financial support, Research Funding; Uniqure BV: Research Funding. Kampmann:Uniqure BV: Research Funding. Klamroth:Baxalta (Shire), Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Shire, and SOBI: Consultancy; Baxalta (Shire), Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Shire, and SOBI: Research Funding. Schutgens:Baxalta/Shire: Research Funding; Novo Nordisk: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Pfizer: Research Funding; Uniqure BV: Research Funding. Seifried:Medac: Other: BSD owns IP and is contract manufacturer; Uniqure BV: Research Funding. Schwaeble:UniQure BV: Research Funding. Bonig:Kiadis Pharma: Consultancy. Sawyer:Uniqure BV: Employment. Miesbach:Bayer, Shire, Biotest, pfizer, Octapharma, LFB, CSL Behring, SOBI, Biogen, BPL: Consultancy; UniQure BV: Research Funding; Novo Nordisk: Consultancy, Research Funding.