A young boy enrolled in a clinical trial testing an experimental gene therapy died last week after developing abnormal liver function following treatment, the study's sponsor, Astellas Pharma, said in a brief statement Tuesday.
The boy's death is the fourth to occur in the trial, which is studying Astellas' gene therapy as a treatment for a rare and fatal neuromuscular condition known as X-linked myotubular myopathy. The trial had been halted after the first three deaths, which happened in May, June and August last year.
Following the trial's suspension, Astellas lowered the treatment dose, which was one of the highest being tested in any gene therapy study, by more than half. The Food and Drug Administration subsequently allowed Astellas to resume the trial in December 2020, only for the company to pause it again Sept. 1 after tests showed abnormal liver function in the boy who died last week.
He was the first and only participant treated following the restart, Astellas said. The cause of death is still pending and the company continues to gather more information.
"We will investigate and review all findings with our independent data monitoring committee, our expert liver advisory panel and the ASPIRO site investigators," said Nathan Bachtell, head of gene therapy, medical and development at Astellas, in the Tuesday statement. ASPIRO is the name of Astellas' trial.
The information disclosed to date, however, appears to share similarities with what Astellas reported about three other study participants who died last year. Each developed signs of liver damage following treatment with the high dose of Astellas' therapy, which later progressed to liver failure. The cause of death in two of the participants was sepsis and in the third, gastrointestinal bleeding.
The trial's tragedy is a serious blow to gene therapy research, confronting both Astellas and the broader field with weighty questions on the safety of these gene-based treatments, particularly those involving higher doses.
"This is clearly a call to action for the field," said Nicole Paulk, an assistant professor at the University of California, San Francisco who works on gene therapy but doesn't have ties to Astellas. "We all need to start looking at the clinical data we already have, but also to set up preclinical modeling in mice or non-human primates and try to figure it out."
Earlier this month, the FDA convened a panel of expert advisers to discuss gene therapy safety in a closely followed two-day meeting that touched on the then three deaths that had occurred in Astellas' study. Experts made several recommendations for how to better screen participants and suggested lower doses might help manage side effects. But they didn't call for upper limits to gene therapy doses, citing inconsistencies in how dose size is measured, among other points.
Signs of liver toxicity, but not patient deaths, have been reported in trials of other gene therapies for hemophilia and spinal muscular atrophy. In those cases, however, the liver-related side effects were either more benign, or effectively managed with steroid treatment.
Intravenously administered gene therapies, like other drugs, are processed by the liver as blood flows through the organ. While factors like dose size and underlying patient conditions are clearly important, it's still unclear exactly what else may have contributed to make Astellas' gene therapy so toxic for the four trial volunteers who died.
"This brings up more questions than answers," said Paulk. She noted, however, that it seems "there is clearly something to do with this background of preexisting and/or active liver disease."
Audentes Therapeutics, the original biotech developer of the therapy that Astellas bought in late 2019, has previously been criticized for not sharing more information on the first three patient deaths.
In a letter to the patient community dated Sept. 13, Astellas' Bachtell said all other enrolled study participants will be followed closely and asked parents to reach out to trial investigators with any questions. The company is awaiting a formal clinical hold letter from the FDA after receiving notice the agency would officially halt further study via a Sept. 3 email.
"Following receipt of the official FDA clinical hold letter, Astellas will review its contents and have further dialogue with regulators on the path forward," the company said in its statement.
To date, two dozen boys have been treated with Astellas' therapy, which is known as AT-132. Seventeen were given the high dose that was suspended last year, and seven received the lower dose.
X-linked mytobular myopathy, or XLMTM, is a fatal disease of the muscles, caused by mutations in a gene known as MTM1. As the disease is inherited via the X chromosome, it occurs almost exclusively in boys. Progressive muscle weakness limits patients' ability to stand, walk and sit. When severe, breathing and eating can also be affected.
AT-132 is designed to treat the disease by delivering a functional copy of the MTM1 gene to muscle cells via a special type of virus commonly used in gene therapy.