In response to safety concerns, including the death of a young boy with a rare neuromuscular disease, the U.S. Food and Drug Administration (FDA) held a two-day public meeting in September with outside experts to discuss managing the potentially serious side effects associated with gene therapies.
Since the summer of 2020, four boys under the age of 5 have died in a clinical trial run by Astellas after developing liver dysfunction in the weeks after treatment. The most recent death occurred after the trial was allowed to resume after three other children died following treatment with the same therapy, AT132.
The company is still investigating the latest death, but suspects that certain patients with X-linked myotubular myopathy are especially susceptible to liver damage because of their underlying disease. So far, they have found no evidence suggesting an immune reaction to the virus delivering the healthy gene is at fault, said Nathan Bachtell, MD, head of gene therapies at Astellas.
Because most gene therapies pass through the liver before arriving at their intended cell targets, high doses are known to cause liver damage. Recent studies have also found a potential long-term cancer risk in mice and dogs treated with gene therapies. However, said Henry Fuchs, MD, president of research and development at BioMarin, "liver cancer as a result of gene therapy has never been observed in a human, and so at this point it remains a theoretical concern, not an observed risk."
"One of the reasons you're hearing about all these [setbacks] is that the scale of these trials is going up exponentially because the therapies are all working so well," said Nicole Paulk, PhD, assistant professor of biochemistry and biophysics at the University of California, San Francisco. "With that increase in numbers, there will be increases in growing pains."
BioMarin faced an even bigger setback last year when the FDA unexpectedly refused to approve BioMarin's gene therapy for the bleeding disorder hemophilia, saying it wanted more detailed, long-term data before allowing the therapy on the market. "That surprise was a year-long setback," Dr. Fuchs said.
BioMarin expects in the coming months to have two years of study data that the FDA requested and to file for approval in 2022, Dr. Fuchs said. The company has said available data indicate the therapy is effective for at least five years, but won't be a lifetime cure.
Read more about progress and setbacks in gene therapy in the May 2021 issue of ASH Clinical News, "Gene Therapy: The Comeback Kid of Hematology Treatments?"