Late-Onset Pompe Disease Gene Therapy Cleared to Continue Trial


The FDA has lifted a clinical hold placed in the summer of 2022 due to a mild but medically significant case of peripheral sensory neuropathy.

The FDA has lifted the clinical hold on Astellas Pharma’s phase 1/2 FORTIS trial (NCT04174105) of AT845 in patients with late-onset Pompe disease (LOPD). Astellas is working to resume dosing in the trial.1

"With that same spirit and focus on patient safety, we look forward to resuming the FORTIS clinical trial and the continued development of AT845 as an important potential new treatment for adults living with LOPD," Ha Tran, executive medical director, Astellas, said in a statement.1 "As always, we are grateful to the patients participating in the FORTIS clinical trial and we remain committed to developing novel therapies for those with a high unmet medical need."

The gene therapy AT845 uses the adeno-associated virus vector 8 to deliver a functional copy of the GAA gene under a muscle-specific promoter. The multi-center, dose-ascending, open-label FORTIS study is primarily evaluating the therapy for safety in participants with LOPD. Participants receive a 1-time peripheral intravenous (IV) infusion of AT845 and are followed for 1 year for safety, clinical, and biochemical endpoints and then 4 years of long-term safety monitoring. Follow-up will assess GAA activity and protein level in patients’ muscles. The study is also evaluating efficacy as measured by change in muscle GAA protein expression and enzyme activity from baseline. Secondary endpoints include improvements in respiratory, endurance, and quality of life measures.

FORTIS was previously placed on hold due to the incidence of a serious adverse event (AE) of peripheral sensory neuropathy.2 The AE was classified as grade 1 and mild but was serious due to medical significance. The FDA told Astellas that there is not enough information to assess the risks to study participants and that more information is needed about the incidence of neuropathy.

READ MORE: Pompe Disease mRNA Therapy Receives FDA Orphan Drug Designation

"Patient safety is our top priority, and we are working closely with the FDA to determine appropriate next steps," Weston Miller, MD, senior medical director, clinical development, Astellas Gene Therapies, said in a statement.2 "We remain committed to the safe and effective development of AT845 and will keep the scientific and patient communities informed with updates as we learn more."

FORTIS had enrolled 4 participants as of December 3, 2021, dosed with 3 x 1013 vg/kg or 6 x 1013 vg/kg of AT845.3 The therapy was well-tolerated with no serious AEs observed at that time.

“There is significant unmet need for patients with Pompe disease due to the short half-life, inefficient uptake in the key tissues affected by the disease and the immunogenicity of ERT,” Tahseen Mozaffar, MD, professor of neurology, pathology, and orthopedic surgery; and director, Division of Neuromuscular Diseases, Neurology School of Medicine, UC Irvine, said in a previous statement.3 “AT845 has the potential to be a best-in-class approach as a muscle-directed gene therapy using an AAV8 capsid serotype. It is being investigated to determine whether it can deliver a functional GAA gene that is efficiently transduced to express GAA directly in tissues affected by the disease, including skeletal and cardiac muscle.”

1. Astellas Announces Hold Lifted by FDA on FORTIS Clinical Trial of AT845 Investigational Treatment for Adult Patients with Late-Onset Pompe Disease. News release. Astellas Pharma. January 20, 2023.
2. Astellas announces FDA update on the FORTIS clinical trial of AT845 in adults with late-onset Pompe disease. News release. Astellas Pharma. June 26, 2022.
3. Astellas announces positive safety data from the FORTIS study of AT845 in adults with late-onset Pompe disease. News release. February 7, 2022. Accessed February 8, 2022.
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