FDA Places Clinical Hold on FORTIS AT845 Gene Therapy Trial

Somi Igbene, PhD avatar

by Somi Igbene, PhD |

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The U.S. Food and Drug Administration (FDA) has placed a clinical hold on the FORTIS Phase 1/2 trial of AT845, a single-dose gene therapy for adults with late-onset Pompe disease (LOPD).

The decision was due to a study participant developing peripheral sensory neuropathy — nerve damage outside the brain and spinal cord, usually affecting hands and feet. Although graded as mild, the adverse event was deemed serious because of its medical implications.

As it considers that existing data is insufficient to properly assess risks to participants, the FDA is requiring more information and will provide the therapy’s developer, Astellas Pharma, with a written explanation for the hold. Meanwhile, Astellas is closely monitoring the patient and all others enrolled in the study and adhering to study protocol.

“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 of clinical development at Astellas Gene Therapies, said in a press release. “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.”

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Pompe disease is caused by GAA gene mutations that lead to a lack of the working version of an enzyme called acid alpha-glucosidase (GAA). This enzyme breaks down a complex sugar molecule called glycogen; without it, glycogen builds up in tissues, especially in muscles, causing severe damage.

The only treatment approach currently approved for Pompe is enzyme replacement therapy — available in the U.S. as Lumizyme and Nexviazyme — which involves infusions every two weeks. In contrast, AT845 is a single-dose gene therapy designed to deliver a healthy copy of the GAA gene directly to muscle cells. It uses an adeno-associated virus, called the AAV8 vector, to deliver the working gene.

FORTIS (NCT04174105), being conducted at sites in the U.S., Germany, and the U.K., will evaluate the safety and efficacy of AT845 given intravenously (into the vein) to adults with LOPD. It will also investigate the change in GAA protein expression levels and function from the study’s start to 12 weeks after treatment, as well as treatment safety. Secondary goals include evaluations of respiratory function, endurance, and quality of life.

Study participants will receive one of three doses of AT845. Dose escalation will be based on assessments of safety and in consultation with an independent data monitoring committee. The patients will be monitored for 48 weeks and then followed up every six months for up to five years.

Preliminary data from four patients showed that AT845 was well-tolerated, with no serious adverse events reported.