The hold comes after a serious AE of peripheral sensory neuropathy.
The FDA has placed a clinical hold on Astellas Pharma’s phase 1/2 FORTIS study (NCT04174105) evaluating the AT845 gene-replacement therapy for the potential treatment of late-onset Pompe disease (LOPD) after the incidence of a serious adverse event (AE) of peripheral sensory neuropathy.1
"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.1 "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."
The serious AE has been classified as grade 1 and mild but serious due to medical significance. The FDA will send a letter to Astellas within the next 30 days with a written explanation of the hold. So far, the FDA has informed 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.
Astellas is following the affected participant closely and is gathering and reviewing relevant data. The company will continue to monitor other treated participants as well and is reviewing the potential financial impact of the clinical hold.
The FORTIS study has enrolled 4 patients as of December 3, 2021.2 The latest data from the study were positive and were presented at the 18th Annual WORLDSymposium. At that time, there had been no serious AEs in the participants and 1 incidence of elevated transaminases.
The study is primarily evaluating the safety of AT845 in participants in LOPD. It 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. Participants in the FORTIS study 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.
“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.2 “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.”
The FORTIS study is the second of Astellas’ trials that have recently stalled, following the phase 1/2/3 ASPIRO trial (NCT03199469) the company voluntarily paused in September 2021 after a patient death.3 ASPIRO is evaluating the AT132 gene therapy in patients with X-linked myotubular myopathy and the death occurred in a patient that experienced a previously reported liver-related serious AE. The ASPIRO trial was previously placed on hold in 2020 and 3 other participants have died throughout the study.