AT845 Gene Therapy Trial to Restart Now That FDA Has Lifted Hold
The experimental therapy targets adults with late-onset Pompe disease
FORTIS, a Phase 1/2 clinical trial of an experimental gene therapy called AT845, is due to restart in adults with late-onset Pompe disease (LOPD), thanks to a decision by the U.S. Food and Drug Administration (FDA).
The trial was put on hold mid-2022 after one of its participants developed mild, yet serious, peripheral sensory neuropathy, a type of damage to the network of nerves that connects the brain and spinal cord to the rest of the body. Astellas Gene Therapies, the company developing AT845, continued to closely monitor this and other participants and was requested to provide additional information on reported side effects.
The FDA now has lifted its hold on the trial, and the company is crossing off all clinical and regulatory activities before dosing of AT845 can be resumed.
“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, MD, who is Astellas’ executive medical director, said in a press release.
“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,” Tran added.
Pompe disease is caused by mutations in GAA, the gene that contains instructions for making an enzyme that breaks down a complex sugar molecule called glycogen into a simpler sugar called glucose.
When glycogen is allowed to build up, it can damage tissues in the body. Because this happens particularly in the muscle tissues, some of the main symptoms of Pompe are weak muscles, difficulty breathing, and an enlarged heart that fails to pump blood as well as it should.
In the late-onset type of the disease, these symptoms may not become apparent until later in childhood or later in life
The only specific treatment available is enzyme replacement therapy, which involves the regular administration of the faulty or missing enzyme into a patient’s vein. This can make treatment expensive, inconvenient, and time-consuming for the patient.
AT845 is a one-time gene therapy that delivers a healthy copy of the GAA gene using a harmless virus called AAV8 as a vector. The vector also carries a muscle-specific promoter, a sequence of DNA t0 drive activity of the therapeutic gene specifically in muscle cells.
Goals of FORTIS clinical trial
FORTIS (NCT04174105) is testing how safe AT845 is when given at one of three different doses and how well it is tolerated by up to 12 adults with LOPD. The trial is open-label, meaning that everyone involved knows what the participants are receiving as a treatment.
Another of the trial’s primary goals is to measure the amount of active enzyme in muscle tissues. Secondary goals include testing whether AT845 may bring about improvements in endurance, breathing, and quality of life.
While testing positive for antibodies against AAV8 above a specified threshold was a criterion for exclusion in FORTIS, the company has bought the rights to develop a medication that may be used along with AT845 to reduce the possibility of an immune response against the AAV8 vector.
Such an immune response can make a gene therapy ineffective. The medication, known as IdeXork or Xork, may one day allow the company to test its AT845 in a larger number of people with LOPD, according to Astellas.