Phase 2b Trial of AMT-061 (AAV5-Padua hFIX): Translation into Humans of an Enhanced Gene Transfer Vector for Adults with Severe or Moderate-severe Hemophilia B

Scientific Research Question: We have previously reported steady state factor IX (FIX) activity levels of 3–13% following a Phase I/II trial of AMT-060, an investigational gene therapy consisting of an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized wildtype human FIX gene under control of a liver-specific promoter. AMT-061 consists of the same AAV5 vector and liver-specific promoter as AMT-060, but with a codon-optimized Padua variant of the human FIX (hFIX) gene resulting from a single nucleotide change from arginine to leucine at R338L. This variant of FIX has been reported to enhance specific activity ~7–9 fold compared with the wildtype variant. AMT-061 demonstrated an ~6.5-fold increase in FIX activity over AMT-060 in head-to-head comparisons in nonhuman primate studies.

The primary aim of this ongoing trial (NCT03489291) is to confirm that a single dose of AMT-061 will provide a minimum therapeutic response of FIX activity levels ≥5% at six weeks after dosing in patients with severe or moderately severe hemophilia B. Secondary endpoints include safety and efficacy outcomes.

Methodology: Phase 2b, open-label, single-dose, single-arm, multi-center trial to confirm the FIX activity level following AMT-061 administration to three adults with FIX < 2%. Participants (pts) receive 2 × 10¹³ gene copies (gc)/kg of AMT-061 intravenously. Pts will be followed for 52 weeks, with weekly visits for the first 12 weeks, bi-weekly from Week 12 to Week 26, and every month from Week 26 to Week 52. Primary efficacy will be assessed by FIX activity at 6 weeks after dosing. Secondary endpoints include e-diary recordings of bleedings and FIX concentrate use, laboratory parameters (including FIX protein levels and inhibitors), assessment of joint health, and patient-reported outcome questionnaires on general and disease-specific quality-of-life. Safety will be assessed by adverse events (AEs), physical examination, and laboratory testing.

Findings: This abstract reflects interim data from the 6-week follow-up of three treated patients, which will primarily determine the efficacy of AMT-061 in terms of FIX activity. Both efficacy and safety data will be presented.

Conclusions: These data will confirm the expected increase in FIX activity relative to AMT-060 in humans based on observations from nonhuman primate studies, with an expected minimum increase ≥5% in FIX activity following AMT-061 (AAV5-Padua hFIX) in the first 6-weeks of the 1-year study.