Update on FORTIS: A phase 1/2 open-label clinical trial on AT845 gene replacement therapy for late-onset Pompe disease


Topic:

Clinical Trials

Poster Number: 440 O

Author(s):

Tahseen Mozaffar, MD, University of California, Irvine, Nicola Longo, MD, PhD, University of California Los Angeles, Mark Walzer, PhD, Astellas Pharma Global Development, Gurunadh Chichili, PhD, Astellas Pharma Global Development, Sean Yiu, PhD, Astellas Pharma Limited, David Viskochil, MD, PhD, University of Utah, Chieri Hayashi, MD, PhD, Astellas Pharma Global Development, Jordi Diaz-Manera, MD, PhD, John Walton Muscular Dystrophy Research Centre, Newcastle University, UK

In Pompe disease, acid alpha-glucosidase (GAA) deficiency leads to lysosomal glycogen accumulation. FORTIS (NCT04174105) is an ongoing multicenter, open-label, ascending-dose phase 1/2 trial evaluating the safety/tolerability/preliminary efficacy of AT845, a gene replacement therapy that expresses human GAA in muscles, in adults with late-onset Pompe disease (LOPD). Eleven participants received intravenous AT845 with subsequent monitoring at a single dose of 3×10^13 vg/kg (n=2, cohort 1) or 6×10^13 vg/kg (n=9, cohort 2), with 24 weeks–4 years follow-up at data cutoff (July 22, 2025). At baseline, participants were aged 24–70 years (median 52), with median 11 years enzyme replacement therapy (ERT; range: 2–17). All participants had increases in vector copy number in muscle within 3 months; GAA protein and enzyme activity levels were variable. At data cutoff, 9/11 participants had discontinued ERT 10–48 weeks (median 17) after AT845 dosing, with 5 remaining off ERT between 1 and >3.5 years; 2 never discontinued. Liver enzyme elevations (4–8 weeks onset) were the most common AE, reported in 9/11 participants including 3 SAEs (grade 3 ALT/AST elevations, n=2; grade 4 GGT, n=1). All were asymptomatic and managed with corticosteroids. One participant in cohort 2 experienced a medically significant grade 2 peripheral sensory neuropathy. At 48 weeks, median change from baseline in % predicted upright forced vital capacity was 2.4 (range: −1.0–5.7; n=2) for cohort 1 and –3.0 (−13.0–7.3; n=7) for cohort 2; median change from baseline in % predicted 6-minute walk test was −0.19 (–0.9–0.5; n=2) for cohort 1 and –1.03 (–13.5–4.3; n=6) for cohort 2. These outcomes remained mainly stable ≤4 years post-dosing. Treatment with AT845 was generally safe and demonstrated stabilized muscle and respiratory function in a small cohort of LOPD patients who discontinued ERT. These findings were previously disclosed at WORLDSymposium 2026.