Over the past several years, drugmakers have inundated the Food and Drug Administration with scores of applications to begin clinical trials of experimental gene therapies for a wide array of inherited diseases.
The wave of submissions reflects a research boom that's brought two gene therapies to market in the U.S. and numerous others into later stages of testing. Awash in funding, new gene therapy biotechs have proliferated and, with them, a pipeline that by one count now exceeds 300 would-be treatments.
Yet, while gene therapy has made huge strides since its emergence in the late 1980s, many scientific questions remain, particularly now that more and more patients are being treated in clinical trials.
To help answer some of those questions, the FDA has asked a panel of gene therapy experts to evaluate an array of safety risks to the complex and cutting-edge treatments.
The meeting, which will be held virtually Thursday and Friday, could help the agency set new guardrails for running gene therapy trials and for monitoring participants afterwards. And for a field that's advancing quickly, the discussion could serve as a reminder of the risks of treatments often characterized by their potential for dramatic benefit.
Here's what to expect:
What will the committee be discussing?
The FDA is focusing the discussion on the safety risks presented by one of the more commonly studied types of gene therapy, namely treatments delivered by a harmless virus called adeno-associated virus, or AAV.
AAVs are a popular tool for shuttling functional copies of genes into the cells that need them. Luxturna, a blindness treatment developed by Spark Therapeutics that became the first gene therapy approved in the U.S., uses AAV, as does Zolgensma, a therapy for spinal muscular atrophy sold by Novartis. Many other gene therapies that are still in testing do as well.
Over the course of the two days, the panel will discuss the cancer risk posed by AAV gene therapy, as well as toxicity to the liver and brain that's been observed in animal testing and in humans.
FDA officials and researchers from top academic centers will present on each safety concern, after which the panel will debate how best to assess that risk and whether it can be prevented or mitigated by better treatment or study design.
The roster of speakers is headlined by Jim Wilson, a star gene therapy researcher with the University of Pennsylvania. Wilson led the gene therapy trial that resulted in the 1999 death of study volunteer Jesse Gelsinger. Since that tragedy, however, he's become a pioneer in the development of AAV vectors, forming multiple biotechs like RegenxBio and Passage Bio in the process.
But as use of AAV vectors has become more widespread and developers test higher and higher doses, Wilson has also been a voice of caution. A paper his group at UPenn published three years ago described liver and nerve damage in animal experiments, a finding his team used to call for researchers to do more monitoring. Wilson will deliver two separate presentations at the meeting, respectively focused on liver or neurological side effects in preclinical studies.
The meeting will feature talks from other gene therapy researchers and investigators as well. Ronald Crystal, the chair of genetic medicine at Weill Cornell who has worked on gene therapy since 1987, will discuss the use of AAV vectors in the brain. Lindsey George, a Children's Hospital of Philadelphia investigator involved in multiple hemophilia gene therapy trials, will talk about liver toxicity observed in human studies.
Only one industry representative, from Novartis, will present to the panel. That talk will center around three cases of a rare clotting syndrome that were observed in post-marketing surveillance of Zolgensma last year. A warning alerting doctors of the potentially serious side effect, known as thrombotic microangiopathy, is now in Zolgensma's prescribing information.
Why is this meeting being held?
Safety concerns have dogged gene therapy ever since a series of setbacks two decades ago temporarily halted research and chilled further investment. Improved delivery tools, such as AAV, have helped address some of those concerns, and AAVs are now used in dozens of clinical trials.
But as the use of AAVs widened, more serious side effects have been reported, reviving safety questions and grabbing the attention of regulators.
The FDA cited recent research, for instance, that found roughly a third of AAV gene therapy trials had a "treatment-emergent serious adverse event."
Some of those have led to tragic results, or to significant patient concerns. In a clinical trial of an Audentes Therapeutics gene therapy for a rare neuromuscular disease, liver-related side effects lead to the death of three patients. Immune-related side effects have occurred in testing of Duchenne muscular dystrophy gene therapies from Solid Biosciences and Pfizer as well as of a vision loss treatment from Adverum Biotechnologies.
A participant in a study of a UniQure gene therapy for hemophilia, meanwhile, was diagnosed with liver cancer, though the biotech later concluded its gene therapy was "highly unlikely" to be the cause.
Worrisome findings have been found in animal tests with AAV vectors as well, which, taken together, has led to "questions about causality and risk mitigation," the FDA said.
What could come of the meeting?
Advisory committee meetings are just that. The FDA uses them as a sounding board for issues it's wrestling with, but it's not required to follow the advice given by the assembled experts.
In gene therapy, though, the FDA and drugmakers are both learning as they go. The agency has firmed up its thinking on a number of topics, finalizing a slate of six guidance documents early last year, but it's still developing the rules of the road.
The questions the FDA posed to its advisers cover a lot of ground and many are open-ended. But they give clues to the direction the agency is thinking.
Several of the questions ask the experts whether the FDA should set an upper limit on the size of gene therapy doses due to the risk of serious brain and liver toxicity, both of which have been associated with higher doses in several instances.
With liver toxicity, the FDA wants to know if there are patient factors other than weight that should be considered when determining a dose, a line of inquiry that could impact how clinical trials are run.
Other questions suggest the FDA is particularly interested in whether animal studies could be better designed to assess the risk of cancer or liver damage before testing in humans starts.