The death this week of a teenager receiving Sarepta Therapeutics’ gene therapy Elevidys for Duchenne muscular dystrophy is a tragic reminder of the stakes involved in cutting-edge biotech innovation.
While gene therapies like Sarepta’s offer an opportunity to treat and even cure diseases, that benefit carries risks. And although Elevidys has been used by more than 800 patients according to Sarepta, the recent death reflects concerns experts had with the therapy prior to its accelerated FDA approval in 2023 and full nod last year.
Despite a failed late-stage trial, Sarepta pointed to the treatment’s effect on secondary evidence of a functional mechanism of action. And Dr. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, ultimately overruled regulatory staff and a review team when he expanded the therapy’s label to treat a wider range of patients.
The 16-year-old boy whose death was reported this week suffered from acute liver failure. While liver injury has been listed as a possible side effect of Elevydis and other gene therapies, no previous reaction was this severe, the company said, noting that the patient may have been at higher risk due to a recent viral infection.
Gene therapy, while particularly promising as a means to address diseases with few alternatives, can’t quite shake a history of patient deaths. As biotechs wrestle with the risk-benefit profile of these therapies, the death could once again shape the way researchers and regulators evaluate the hazards of continuing along that path.
Early setback
In 1999, 18-year-old Jesse Gelsinger was the first reported patient to die following treatment with an experimental gene therapy. Born with a rare metabolic disorder called ornithine transcarbamylase deficiency syndrome, Gelsinger suffered multiple organ failure from an immune response after receiving the therapy in a trial at the University of Pennsylvania.
The university and individual researchers settled with the U.S. Justice Department over allegations that the early-stage safety study continued despite signs it should have been terminated, according to a University of Pennsylvania archive.
Following Gelsinger’s death, all U.S. gene therapy trials were put on hold until the FDA could review ongoing studies, leading to the development in 2000 of a Gene Therapy Clinical Trial Monitoring Plan for better oversight, as well as the Gene Transfer Safety Symposia to share data around adverse events.
As the field advanced and the first gene therapy Kymriah from Novartis was approved for lymphoblastic leukemia in 2017, researchers have continued to approach the treatments with caution.
But the potential for unexpected fatal side effects is still inherent in the gene therapy equation, even after precautions have grown more prevalent.
The latest gene therapy death from Sarepta also underscores the particular challenges of treating DMD, which primarily affects young boys.
Pfizer, once a fellow developer of a DMD gene therapy, pulled the plug on its program last year following a failed phase 3 study. During development, a child died from cardiac arrest following treatment with Pfizer’s gene therapy. Prior to that, another patient died in an earlier study, temporarily halting the program to install new safeguards.
This week’s patient death was the first reported by Sarepta and knocked more than 25% off of the biotech’s share price Tuesday.
A risky track record
Gene therapies continue to gather praise when they reach regulatory approval, and advocacy groups have pushed for flexibility in the process so more patients can receive the benefit they provide. But deaths remain a part of the picture.
In 2022, Novartis reported that two children died from acute liver failure after receiving the gene therapy Zolgensma, which treats the rare disease spinal muscular atrophy. Approved by the FDA in 2019 following clinical trials that didn’t result in any cases of acute liver failure or death, Zolgensma had been used in more than 2,300 patients by the time the children died.
A Novartis spokesperson said at the time that the deaths were not a new safety signal and that Zolgensma’s risk-benefit profile remained favorable. The company updated the label to reflect acute liver failure.
A gene therapy from Neurogene designed to treat Rett syndrome was linked to the death of a young girl last year. Like Gelsinger and other patients receiving therapies that use adeno-associated viral vectors, the girl died of a severe immune response that was unforeseen due to direct delivery to the central nervous system.
Still, Neurogene and independent neurologists said the gene therapy’s risk-benefit profile remained viable due to four other participants showing improvement with no serious adverse events.
As the field advances, drug developers continue to learn from serious adverse events.
Following the deaths of four boys under the age of 5 with the rare neuromuscular disease X-linked myotubular myopathy in a clinical trial run by Astellas Pharma, researchers looked for underlying causes for their liver dysfunction, and the company lowered the dose.
“It is imperative that the scientific community work together with full transparency and cooperation to learn from these tragedies to assure that we can deliver safe and effective treatments to individuals living with rare genetic diseases,” said Dr. James Wilson, formerly a gene therapy pioneer at the University of Pennsylvania, in a report from Genetic Engineering & Biotechnology News.
Wilson also led the trial in which Gelsinger died but has continued to research and support gene therapy innovation in the ensuing decades.
