FDA Clears Trial Hold on Late-Onset Pompe Disease Gene Therapy AT845

Ha Tran, MD

This content originally appeared on our sister site, CGTLIVE.

Recently, the FDA lifted a clinical hold on Astellas Pharma's phase 1/2 FORTIS clinical trial (NCT04174105) assessing its investigational agent AT845 for the treatment of adults with late-onset Pompe disease (LOPD).¹ FORTIS is the first-in-human trial of the gene replacement therapy, which is designed to use the adeno-associated virus vector 8 to deliver a functional copy of the GAA gene under a muscle-specific promoter.

FORTIS formerly was placed on hold because of a case of a serious adverse event (AE) of peripheral sensory neuropathy.³ The AE was classified as grade 1 and mild although it was serious because of medical significance. Therefore, the FDA told Astellas that there was not enough information for assessing the risks of the participants and that more information is needed about the incidence of neuropathy.

Previously, positive interim safety data from FORTIS on 4 participants were presented by Astellas Pharma at the 18th Annual WORLDSymposium, February 7-11, 2022.² The follow-up data observed 2 patients dosed at 3 x 1013 vg/kg in Cohort 1, and preliminary data with 2 patients dosed at 6 x 1013 vg/kg in Cohort 2. All told, the therapy was well-tolerated with a positive safety profile, and no serious AEs observed.

"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 trial is a multi-center, dose-ascending, open-label study that primarily evaluates 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 for 4 years for long-term safety monitoring. Follow-ups will assess GAA activity and protein level in patients’ muscles, as well as efficacy, measured by change in muscle GAA protein expression, and enzyme activity. Secondary endpoints include improvements in respiratory, endurance, and quality of life measures.

READ MORE: FDA Defers Action on AT-GAA Treatment for Pompe Disease

"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."

Currently, the only approved therapy for Pompe disease is enzyme replacement therapy (ERT). In August 2021, the FDA granted approval for Sanofi's avalglucosidase alfa-ngpt (Nexviazyme) for patients aged 1 year and older with LOPD. In late 2020, the biologics license application for the long-term ERT was originally accepted for review  after receiving breakthrough therapy and fast track designations. This therapy method depends solely on tissue uptake of GAA from plasma and delivered via biweekly with IV infusions, based on the recommended dose according to body weight—20 mg/kg for patients weighing 30 kg or heavier, and 40 mg/kg for those patients under 30 kg—and administered in increments via IV infusion.^4,5

“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.”

REFERENCES
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. https://finance.yahoo.com/news/astellas-announces-hold-lifted-fda-060000239.html
2. 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. https://www.biospace.com/article/releases/astellas-announces-positive-safety-data-from-the-fortis-study-of-at845-in-adults-with-late-onset-pompe-disease/
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. https://www.biospace.com/article/releases/astellas-announces-positive-safety-data-from-the-fortis-study-of-at845-in-adults-with-late-onset-pompe-disease/
4. FDA approves Nexviazyme® (avalglucosidase alfa-ngpt), an important new treatment option for late-onset Pompe disease. News release. Sanofi Genzyme. August 6, 2021. Accessed February 8, 2022. https://www.sanofi.com/en/media-room/press-releases/2021/2021-08-06-17-42-21-2276588
5. FDA grants priority review for avalglucosidase alfa, a potential new therapy for Pompe disease. News release. Sanofi. November 18, 2020. Accessed February 8, 2022. http://www.news.sanofi.us/2020-11-18-FDA-grants-priority-review-for-avalglucosidase-alfa-a-potential-new-therapy-for-Pompe-disease