AT845 Gene Therapy Shows Stable Muscle, Respiratory Function in Early Pompe Disease Trial

Investigational gene replacement therapy AT845, designed to deliver the human acid alpha-glucosidase (GAA) gene to muscle tissue, showed an acceptable safety profile and stabilization of respiratory and functional outcomes in adults with late-onset Pompe disease (LOPD). The findings come from an interim analysis of the ongoing multicenter, open-label, ascending-dose phase 1/2 FORTIS trial (NCT04174105).

FORTIS Study Design

The FORTIS Study, led by Tahseen Mozaffar, MD, director of the UCI Health ALS & Neuromuscular Center in Orange Claifornia, enrolled 11 with LOPD who received a single intravenous infusion of AT845. Participants were treated at doses of 3 × 10¹³ vector genomes (vg)/kg (cohort 1; n = 2) or 6 × 10¹³ vg/kg (cohort 2; n = 9). At baseline, patients ranged in age from 24 to 70 years (median, 52 years) and had received enzyme replacement therapy (ERT) for a median of 11 years (range, 2–17).

Follow-up ranged from 24 weeks to 4 years at the July 22, 2025 data cutoff. Overall, results showed that all participants demonstrated increases in vector copy number in muscle within 3 months of dosing, although GAA protein expression and enzyme activity levels varied.¹

Safety Findings

Elevations in liver enzymes were the most common adverse events (AEs), occurring in 9 of 11 participants 4 to 8 weeks after dosing. Three serious AEs were reported, including grade 3 alanine aminotransferase/aspartate aminotransferase elevations (n = 2) and grade 4 gamma-glutamyl transferase elevation (n = 1). All cases were asymptomatic and managed with corticosteroids. In the higher-dose cohort, 1 participant experienced medically significant grade 2 peripheral sensory neuropathy.¹

Discontinuation and Functional Outcomes

Of the 11 total participants, 9 discontinued ERT between 10 and 48 weeks after receiving AT845 (median, 17 weeks). At the time of data cutoff, 5 participants remained off ERT for 1 to more than 3.5 years, while 2 participants continued ERT throughout follow-up.¹

Functional and respiratory measures remained largely stable following treatment with AT845. At 48 weeks, median change from baseline in percent-predicted upright forced vital capacity was 2.4 in cohort 1 and –3.0 in cohort 2. Median changes in percent-predicted 6-minute walk test were −0.19 and −1.03 in cohorts 1 and 2, respectively. of note, these outcomes remained generally stable for up to 4 years after dosing.¹

Clinical Context

Pompe disease is a rare lysosomal storage disorder caused by deficiency of acid alpha-glucosidase, leading to progressive glycogen accumulation in skeletal and respiratory muscles. Current management typically involves lifelong enzyme replacement therapy, although treatment burden and variable clinical response have prompted investigation of gene therapy approaches.²

Previous Results

Previously reported data from the phase 1/2 FORTIS clinical trial displayed promising efficacy for AT845 in LOPD.³ Among the 4 patients initially treated with the gene therapy, 3 had ceased treatment with their prior standard of care treatment, ERT.

Patient 1, a 52-year-old male patient with 68 weeks of follow-up, withdrew from ERT at 17 weeks post-treatment with AT845; Patient 3, a 66-year-old male patient with 54 weeks of follow-up, withdrew from ERT at 10 weeks post-treatment; and Patient 9, a 49-year-old female patient with 43 weeks of follow-up, withdrew from ERT at 24 weeks. Patient 2, a 48-year-old female patient with 78 weeks of follow-up, did not withdrawn from ERT. Patient 2 and Patient 1 received a dose of 3.0x10¹³ vg/kg of AT845 and Patient 3 and Patient 9 received a dose of 6.0x10¹³ vg/kg of AT845.³

REFERENCES
1. Mozaffar T, Longo N, Walzer M, et al. Update on FORTIS: A phase 1/2 open-label clinical trial on AT845 gene replacement therapy for late-onset Pompe disease. Presented at: Muscular Dystrophy Association (MDA) Clinical and Scientific Conference; March 8-11 2026; Orlando, Florida
2. van der Ploeg AT, Reuser AJJ. Pompe’s disease. The Lancet. 2008;372(9646):1342-1353. doi:10.1016/S0140-6736(08)61555-X.
3. Diaz-Manera J, Mozaffar T, Longo N, et al. AT845 gene replacement therapy for late onset Pompe disease: An update on safety and preliminary efficacy data from FORTIS, a phase I/II open-label clinical study. Presented at WORLDSymposium 2023, held February 22-26, in Orlando, Florida. Abstract #95