A group of gene therapy experts called for better research tools and more careful monitoring of side effects to treatment, but stopped short in a high-profile meeting Thursday of advocating for major changes to how studies in the fast-growing field are conducted.
The committee, which the Food and Drug Administration convened for advice on the risks to gene therapy, proposed a number of ways research could potentially be made safer, such as by improving how patients are screened for clinical trials. None of the panel members, though, suggested slowing research in any significant fashion, rejecting, for instance, the idea of imposing an upper limit on gene therapy doses to lower risks.
"While the meeting was an excellent update on pre-clinical and clinical adverse events in the field, it largely left untouched what measures might actually be taken to help future-proof this field," said Anthony Davies, founder and CEO of Dark Horse Consulting, which specializes in gene therapy.
Experts said that inconsistent standards in how gene therapies are produced, and how certain safety risks are assessed, made it difficult to come up with recommendations that could be broadly applied.
The meeting, which will continue Friday, comes after a series of safety incidents in gene therapy clinical trials resurfaced some longstanding concerns, as well as new worries about the use of high treatment doses. The deaths last year of three children in a study of a neuromuscular disease therapy, in particular, appear to have spurred the FDA to seek the experts' advice.
"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 Thursday. "The greatest risks in drug development fall on the patients who receive an investigational product."
Weighing cancer risk
The FDA split the first day of the meeting into two sessions, focusing the first on the persistent worry that injecting genes into cells might eventually spur cancer, and the second on the liver injury that can be caused by treatment. The committee will discuss brain toxicity Friday.
In discussing the risk of cancer, experts spent considerable time weighing findings from testing in animals, some of which dates back more than 20 years. Results have shown that a commonly used delivery tool, the adeno-associated virus or AAV, can fuse itself into the genomes of certain animals and, at least in mice, that integration is associated with liver cancer.
Concerns around whether this risk can play out similarly in humans grew earlier this year when a patient given an experimental hemophilia gene therapy developed by the biotech company UniQure was diagnosed with liver cancer.
UniQure has since exonerated its gene therapy, and experts at the FDA panel noted the risk remains theoretical. Other research in larger animals and in humans haven't replicated the worrisome findings in mice. A study following dogs given a hemophilia gene therapy and presented at the meeting by University of Pennsylvania researcher Denise Sabatino, for example, showed AAV did get into the genome but didn't lead to cancer.
"[T]his is something that will need to be monitored very carefully, [but] so far, the signal in the clinic doesn't seem to be very strong," said Christopher Breuer, the director of the center for regenerative medicine at Nationwide Children's Hospital, a top gene therapy hub.
Pfizer, which has invested heavily in gene therapy, argued companies shouldn't have to run more studies looking for integration events in animals until there is "clear causality in humans," according to a public comment filed with the FDA. Pfizer claimed additional experiments using human cell lines to assess risk would be more relevant.
FDA panelists, meanwhile, said longer animal tests might more effectively capture any cancer risk of AAV, as will tracking the health of the more than 800 children who have so far received the Novartis spinal muscular atrophy treatment Zolgensma. Experts also suggested closer scrutiny of gene therapy components.
But several were hesitant to make broad recommendations to the FDA as there aren't set rules for every aspect of how gene therapies are made.
"We are starting to get a sense of the scientific issues that are out there, but we need to start to drive towards some type of standardization," said Taby Ahsan, the head of biologics analytical development at MD Anderson Cancer Center. "Understanding that will help us give solid recommendations for preclinical study design as we move forward."
While the cancer risk of AAV gene therapy in humans remains theoretical, liver toxicity is one of the most common side effects reported in clinical testing to date and, in a few cases, has led to serious health problems.
In a study of a gene therapy developed by Audentes Therapeutics, for instance, three young children given a very high dose developed liver damage and later died, although the exact link between their deaths and the treatment is still unclear. Two cases of acute liver failure have also been reported in patients treated with Zolgensma, and many hemophilia patients across several gene therapy studies have experienced significant increases in liver enzyme counts, a potentially worrisome sign.
"I think that a lot of the studies have missed opportunities to involve hepatologists early on," said Theo Heller, a liver specialist at the National Institute of Diabetes and Digestive and Kidney Diseases, at the meeting. "Hepatotoxicity is such a common side effect of this therapy."
Experts did call on researchers to more comprehensively assess and screen for preexisting liver conditions, which they said might affect how side effects develop.
"We do need careful screening," said Lisa Butterfield, the meeting's chair and vice president of the Parker Institute for Cancer Immunotherapy at the University of California, San Francisco. "We need to focus on more than just fluctuations in blood work."
The committee made few other concrete recommendations on how best to manage the risk of liver problems, though. In particular, they opposed placing an upper limit on the gene therapy doses that could be tested, although research suggests the worst health consequences to liver toxicity only emerge at higher doses.
A major sticking point, some members noted, was the difficulty in characterizing the make-up of gene therapy doses, which can contain extraneous material alongside the therapeutic DNA.
"It confounds this question of toxicity and toxic side effects of AAV perhaps because, again, going back, we don't have reference standards for the field," said Charles Venditti, a senior investigator with the National Human Genome Research Institute.