AT845 Gene Therapy Showing Safety in Ongoing FORTIS Trial

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by Patricia Inacio PhD |

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AT845 gene therapy | Pompe Disease News | illustration of clinical trials

Acceptable safety is being seen to date in four adults with late-onset Pompe disease (LOPD) given the one-time gene therapy  AT845 in the FORTIS Phase 1/2 trial, its developer, Astellas Gene Therapies, announced.

Interim study data in these four enrolled patients, as of the Dec. 3 cutoff date, shows treatment safety and tolerability with no serious adverse events reported. Two patients were given AT845 at a low dose of 3 x 1013 vector genomes per kilogram of weight (vg/kg) and two others at a high dose of 6 x 1013 vg/kg, the company announced in a press release.

People in the low-dose group have been followed for up to 24 weeks (about six months) post-treatment.

“We are pleased that AT845 has been well-tolerated so far in the four adults with LOPD who have received treatment,” said Weston Miller, MD, senior medical director, Clinical Development, at Astellas. “These safety data are encouraging, and the program continues to enroll participants.”

These findings were presented at the 18th annual WORLD Symposium 2022 running through Feb. 11.

FORTIS (NCT04174105), which began dosing in April 2021, may be actively recruiting patients at its eight sites in the U.S., Germany, and the U.K. Information on trial sites and contacts is available here.

Pompe disease is caused by the lack of working acid alpha-glucosidase (GAA) — an enzyme that breaks down a large sugar molecule called glycogen — due to mutations in the GAA gene. As a result, patients accumulate toxic levels of glycogen in several tissues, mainly in the muscle.

AT845 delivers a healthy working copy of the GAA gene directly to muscle cells.

The Phase 1/2 open-label trial is assessing the safety and tolerability of AT845 at either low or high dose, administered as an intravenous (IV, into-the-vein) injection in eight LOPD patients ages 18 to 80. The therapy uses an adeno-associated virus, called the AAV8 vector, to deliver the working gene copy to target cells that include skeletal and cardiac muscles.

Post-treatment, patients are being regularly examined for one year to determine safety, along with measures that can support the therapy’s potential effectiveness. Such clinical and biochemical efficacy measures include changes in GAA protein expression and enzyme activity in muscles relative to their levels at the study’s start.

Secondary trial goals (endpoints) will also evaluate respiratory, endurance, and quality of life measures.

Enrolled adults must be on enzyme replacement therapy (ERT) for at least two years to enter the study and at a stable dose for at least six months.

“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 [immune response] of ERT,” said Tahseen Mozaffar, MD, a professor of neurology at the University of California Irvine and a trial investigator. “AT845 has the potential to be a best-in-class approach as a muscle-directed gene therapy.”

While no serious side effects have been reported, one patient had elevated transaminases, enzymes that indicate possible liver inflammation, after being infused with AT845, Astellas reported, and the patient responded to steroid treatment.

“Elevated transaminases … is considered a common immune-mediated treatment response based on the time of onset after dosing, its presentation during steroid taper initiation and its reversal with steroid re-initiation,” Miller said.

Researchers in the U.K. recently reported the dosing of a first patient at that country’s sole site, the John Walton Muscular Dystrophy Research Centre jointly run by the Newcastle Upon Tyne Hospitals and Newcastle University.

“The enrolment of the first European patient in this Phase 1/2 gene therapy programme is a great achievement for the Pompe community and we are very pleased to contribute to innovative research in the pursuit of future therapies,” Jordi Díaz-Manera, MD, PhD, a principal trial investigator, said in a separate press release.

“This is the first gene therapy program for a neuromuscular disease affecting adults which poses a new investigative treatment opportunity for our entire clinical research team. I’m very proud to be leading the UK arm of this global study,” Díaz-Manera added.

FORTIS is expected to fully conclude in January 2027.