Biotech developers of gene therapies were shown a yellow light last week by advisers to the Food and Drug Administration, who over two days of closely watched meetings proposed little that would significantly change the course of research in the fast-advancing field.
The advisers, convened by the FDA to discuss the safety risks of gene therapy, made several recommendations for longer testing in animals, more comprehensive screening of clinical trial participants and follow-up monitoring of treated patients. While they had concerns over serious side effects recently reported in several studies, they stopped short of suggesting testing be curtailed or somehow limited by the FDA.
Analysts on Wall Street who cover the companies were accordingly confident that clinical development will proceed apace. "We don't anticipate any immediate impact to the industry," wrote Danielle Brill, an analyst at Raymond James, in a note to clients titled "The sky is not falling."
Yet, despite analysts' optimism, there are ample signs the FDA remains wary about gene therapy's safety, the latest being a clinical hold placed on testing of an experimental treatment for the rare disease phenylketonuria. The treatment's maker, BioMarin Pharmaceutical, reported it had observed cases of liver cancer in mice treated with a high dose of its gene therapy — one of several side effects singled out in the meeting as of particular concern.
Shares in UniQure, a leading gene therapy developer, rose by more than 10% in Tuesday morning trading, as did those of Solid Biosciences. Shares in BioMarin, Sarepta Therapeutics, Rocket Pharmaceuticals and Ultragenyx, however, fell.
During the meeting, advisers wrestled with the question of whether gene therapy could spur cancer, but agreed the link remained theoretical as worrisome findings in mice have not been replicated in larger animals or in humans. Without a better sense of how animal studies may be predictive of human risk, however, the FDA appears to be erring on the side of caution.
Many of the side effects discussed at last week's meeting, including liver and brain toxicity as well as blood abnormalities, have previously been the cause of clinical holds ordered by the FDA over the past two years. A study testing a spinal injection of Novartis' approved spinal muscular atrophy treatment Zolgensma, for instance, was on pause for more than 18 months due to signs of nervous system inflammation in animal tests. Trials of therapies being developed by UniQure and Bluebird bio, meanwhile, were briefly paused this year after reports of cancer in patients enrolled in each. The developers later showed their treatments were likely not to blame.
Liver toxicity leading to the tragic deaths of three children in an Astellas Pharma study led to a halt as well and likely played a role in the FDA's decision to seek outside advice from its expert panel.
Scientists in academic and drugmakers' labs are working to better understand how gene therapy infusions can lead to these types of serious side effects, with advisers hearing last week from several of the field's top researchers. But the meeting discussion made clear that much remains uncertain, as the experts debated what factors in the construction and production of gene therapies might cause later safety problems.
Advisers also highlighted the inconsistent methods and tools used to assess these risks, making it harder to generalize recommendations across development programs.
"Our enthusiasm for this field must be balanced by caution," said Wilson Bryan, director of the FDA's Office of Tissues and Advanced Therapies, in a presentation opening the meeting last week. "The greatest risks in drug development fall on the patients who receive an investigational product."
FDA officials have indicated on several occasions that they expect to be approving between 10 and 20 cell and gene therapies a year by 2025, although a division chief recently suggested the effects of the COVID-19 pandemic could result in a number on the lower end of that range.