FDA Places Hold on Astellas’ Gene Therapy Trial in Adults with Late-Onset Pompe Disease

The U.S. Food and Drug Administration (FDA) has placed a clinical hold on Astellas Gene Therapies’ FORTIS phase 1/2 trial evaluating AT845, an investigational adeno-associated virus (AAV) gene replacement therapy in adults with late-onset Pompe disease, following the occurrence of a serious adverse event of peripheral sensory neuropathy in one of the trial participants.

Photo: Weston Miller, senior medical director, Clinical Development at Astellas Gene Therapies

Pompe disease is a rare, severe, autosomal recessive metabolic disease characterized by progressive muscular degeneration. The disease is caused by mutations in the alpha-glucosidase (GAA) gene that prevent the production and function of a protein called acid alpha-glucosidase (GAA). GAA is responsible for metabolizing glycogen, and dysfunction or absence of this protein results in the accumulation of glycogen in tissues, primarily in the skeletal and cardiac muscles, where it causes damage to tissue structure and function. Currently, the only approved treatment for Pompe is enzyme replacement therapy, which is a chronic treatment delivered in bi-weekly infusions and relies solely on tissue uptake of GAA from plasma.

Astellas is developing AT845, a novel gene replacement therapy using an AAV8 vector under a muscle-specific promotor to deliver a functional copy of the GAA gene, for the treatment of late-onset Pompe disease. AT845 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.

FORTIS is a multicenter, open-label, ascending dose phase 1/2 first-in-human clinical trial to determine if AT845 is safe and tolerable in adults with late-onset Pompe disease. The primary endpoints of the trial are safety and tolerability, as well as efficacy measures, including change in muscle GAA protein expression and enzyme activity from baseline. Secondary endpoints evaluate improvements in respiratory, endurance and quality of life measures.

The FDA informed Astellas that it did not have sufficient information to assess the risks to subjects and requires additional information about the recently reported serious adverse event (SAE). To date, the SAE has been classified by the site investigator as Grade 1 (mild in severity) and deemed serious due to medical significance. A written explanation for the basis of the hold will be issued by the FDA and sent to Astellas within the next 30 days.

Astellas is working with the site investigator to closely follow the patient’s clinical course and will continue to gather and review all relevant data. All currently enrolled participants will continue to be monitored closely per the study protocol.

“Patient safety is our top priority, and we are working closely with the FDA to determine appropriate next steps,” said Weston Miller, senior medical director, Clinical Development at Astellas Gene Therapies. “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.”

Author: Rare Daily Staff