Could relaxed regulations boost gene therapy for ultra-rare diseases?

Last year saw the creation and success of the first-ever personalized CRISPR gene-editing therapy. This year, the FDA wants to make it easier to create and market treatments like this for ultra-rare diseases.

On Dec. 4, the agency cut the default number of required clinical trials for approval from two to one. On Feb. 23, it released draft guidance outlining how individualized therapies for ultra-rare diseases can get approval through current pathways. The new guidance—dubbed the plausible mechanism framework—says that a clinical trial with just one participant whose symptoms significantly improve could be enough.

Experts told Healthcare Brew the traditional approval pathway wasn’t built for drugs that treat ultra-rare diseases, which affect so few patients—fewer than 1 in 50,000, according to some researchers’ definitions—and that a large clinical trial sometimes doesn’t make practical or financial sense. These FDA moves could inspire more innovation in the pharmaceutical industry, they say, particularly the struggling gene therapy market that has seen less investor interest over the last few years compared to trendier drugs like GLP-1s. But this new pathway still needs guaranteed guardrails.

“The key is making sure innovation in regulatory pathways is paired with innovation in evidence generation rather than simply running smaller or weaker trials,” Farid Vij, CEO and co-founder of Citizen Health, an AI-powered patient advocacy organization geared toward rare disease patients, told Healthcare Brew via email.

Enthusiasm builds. This FDA draft proposal popped up after a “string of rejected applications” for rare disease drugs over the last few months, Washington Healthcare Policy Analyst Chris Meekins of financial services firm Raymond James wrote in a Feb. 24 analyst note. Many in the rare disease drug industry are skeptical of the FDA right now over “mixed signals,” despite this proposed pathway, Stat reported.

This draft guidance also isn’t binding, and public comments are being accepted until April 27. Still, some gene-editing startup leaders are feeling inspired. 

Biotech Prime Medicine said in a March 3 press release it would apply for accelerated approval for its individualized gene-editing therapy for chronic granulomatous disease, an ultra-rare genetic immune disorder affecting about 1 in 200,000 people.

The company tested this therapy with two patients in a clinical trial launched in October 2024. It saw promising results but couldn’t afford to test further, the New York Times reported in September.

Prime CEO Allan Reine told us via email that the plausible mechanism framework “provided important context” that inspired the company’s decision to apply for accelerated approval based on just those two patients’ results.

“Prime Medicine believes the FDA’s plausible mechanism pathway has the potential to meaningfully expand patient access to therapies for rare genetic diseases,” he said.

A new company, Aurora Therapeutics, officially launched on Jan. 9 with plans to create personalized CRISPR-based therapies for rare metabolic disorder phenylketonuria, which affects 1 in 15,000 US babies. A press release announcing its launch said its goals “align closely with the US Food and Drug Administration’s recently announced plausible mechanism pathway.” (The pathway had been announced but the official draft guidance hadn’t been shared at that point in time.) Aurora did not respond to a request for comment.

Concerns remain. However, this excitement may butt up against practical concerns, Stacey Lee, a professor of health law and ethics at Johns Hopkins University’s Carey Business School, told us.

For one, there’s no guarantee health insurers will get on board in covering individualized treatments even if they are approved, she said. And relaxing the premarket evaluation process puts a lot more responsibility on postmarket surveillance to ensure treatments are working.

Postmarket surveillance sometimes uncovers new issues that weren’t revealed during preapproval clinical trials, and those issues don’t always lead to pulling a drug from the market.

For instance, the FDA gave the Sarepta Therapeutics drug for Duchenne muscular dystrophy, Elevidys, accelerated approval with a requirement to conduct a postmarketing confirmatory trial. The trial failed to achieve its prespecified endpoint, but the drug was approved anyway. It was later linked to two patient deaths, and the FDA suspended sales until the company added a new safety warning to the drug.

“I think the draft guidance is going in the right direction. I have a lot of concerns about the postmarket surveillance,” Lee said.