Late-Onset Pompe Disease Gene Therapy Shows Promise in Phase 1/2 Study


Following treatment with AT845 gene therapy, 3 of 4 patients withdrew from their previous enzyme replacement therapy.

Astellas Pharma’s AT845, an investigational adeno-associated virus (AAV) vector-based gene replacement therapy intended to treat late-onset Pompe disease (LOPD) has demonstrated encouraging efficacy in interim data from the phase 1/2 FORTIS clinical trial (NCT04174105).1,2 The data were presented at the WORLDSymposium 2023, held February 22-26, in Orlando, Florida.

AT845 is intended to deliver a functional copy of the acid alpha-glucosidase (GAA) gene with a muscle-specific promotor via an AAV8 vector with tropism to muscle tissue. Among the 4 patients treated with AT845 in the FORTIS trial so far, 3 have ceased treatment with their prior standard of care treatment, enzyme replacement therapy (ERT). Patient 01, a 52-year-old male patient with 68 weeks of follow-up, withdrew from ERT at 17 weeks post-treatment with AT845; Patient 03, a 66-year-old male patient with 54 weeks of follow-up, withdrew from ERT at 10 weeks post-treatment; and Patient 09, a 49-year-old female patient with 43 weeks of follow-up, withdrew from ERT at 24 weeks. Patient 02, a 48-year-old female patient with 78 weeks of follow-up, has not withdrawn from ERT. Patient 02 and Patient 01 received a dose of 3.0x1013 vg/kg of AT845 and Patient 03 and Patient 09 received a dose of 6.0x1013 vg/kg of AT845.

All patients showed stable forced vital capacity over time following treatment with AT845, including after ERT withdrawal (when applicable). Similarly, the patients’ performance on the 6-Minute Walk Test remained stable over time post-treatment, including after ERT withdrawal. On the Patient-Reported Outcomes Measurement Information System (PROMIS) Item Bank v1.0 Fatigue-Short Form 8a, Patients 02, 01, and 03 showed stable scores post-treatment, while Patient 09’s score trended towards improvement from baseline. Furthermore, on PROMIS scales for ability to participate in social roles and activities, sleep disturbance, and physical function, the 4 patients also showed stability over time. The patients also showed stability on measures of ability to perform daily activities and social participation on the Rasch-built Pompe-specific Activity instrument scale following treatment with AT845.

In terms of safety, most treatment-emergent adverse events (AEs) were grade 1 and deemed unrelated to AT845. One participant experienced an infusion-related reaction which was resolved with oral diphenhydramine and acetaminophen. In addition, 3 of the 4 patients experienced cases of transaminitis during their steroid taper which were deemed related or possibly related to AT845. All of these cases resolved with modifications to the steroid taper.

Notably, 1 patient experienced a case of grade 2 peripheral sensory polyneuropathy, prompting the FDA to put a clinical hold on the trial in June of last year. The hold was lifted in January 2023. Anti-GAA antibodies were not detectable in 3 of the patients prior to treatment with AT845; at approximately 1 year following infusion, these patients continue to have no detectable anti-GAA antibodies. Patient 01 has shown varying levels of anti-GAA antibodies since his initial screening; however, at 1 year of follow-up, he showed no increase in anti-GAA antibodies from the time of infusion.

“We are excited to share these new findings from the ongoing FORTIS clinical study of AT845,” Ha Tran, executive medical director, Astellas Pharma, said in a statement.2 “These data, along with our recent announcement of the clinical hold lift of the FORTIS clinical trial, are very positive developments for the program. The preliminary data presented are encouraging. We look forward to continuing the FORTIS clinical trial as we advance towards our goal of developing innovative gene therapies and bringing new potential treatments to patients with high unmet need.”

Click here to read more coverage of WORLDSymposium 2023.


1. 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
2. Astellas announces update on preliminary safety and efficacy data from FORTIS study of investigational AT845 in adults with late-onset Pompe disease. News release. Astellas Pharma Inc. February 22, 2023. Accessed February 24, 2023. 
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