Although FDA Commissioner Marty Makary promised “an exciting treatment” for autism, what the agency delivered was a label expansion for leucovorin to treat the ultrarare cerebral folate deficiency. The regulatory process, which relied on a literature review rather than new evidence, stands in contrast to recent rare disease rejections in which the FDA cited a need for more rigorous evidence.
FDA observers have noted a disconnect between what agency officials say about the need for regulatory flexibility when considering therapeutics for rare diseases, and a string of rejections of just such candidates. UniQure, for example, has weathered not only negative feedback from the FDA but also public criticism from agency officials for attempting to win approval based on an externally controlled pivotal trial. Meanwhile, RENENXBIO, Biohaven and Capricor Therapeutics have received CRLs over the past year. Sen. Ron Johnson (R-WI) has launched an investigation into such rejections.
In sharp contrast to these stories, the FDA last week touted its expansion of leucovorin—long approved to ameliorate the effects of certain cancer therapies—to treat cerebral folate deficiency (CFD) linked to a particular genetic variant, an action it said “reflects the agency’s commitment to accelerating cures and expanding treatment options including for patients with serious and unmet needs.”
Notably, the expansion was initiated not by a drug company but by the FDA itself after Commissioner Marty Makary promoted leucovorin as a treatment for autism. Agency staffers mined the literature for evidence of leucovorin’s effectiveness in CFD. Unsurprisingly for a disease that has been diagnosed in fewer than 50 people worldwide, that evidence does not include a randomized, controlled trial.
The apparent discrepancy in evidence standards “can’t be rationalized in a coherent sense, other than that leucovorin is a drug that is being shaped to fit RFK’s agenda around autism and it’s outside the reach of Vinay Prasad and [the Center for Biologics Evaluation and Research],” Holly Fernandez Lynch, a bioethics and law professor at the University of Pennsylvania, wrote in an email to BioSpace. “This is exactly the sort of thing that makes the public not trust FDA’s decisions, as this is not based in science, it’s based in politics.”
The decision “is highly unusual—maybe unprecedented—and I think it’s good and bad,” said Paul Kim, principal at Kendall Square Policy Strategies and a former FDA counsel to the late Senator Edward Kennedy and Congressman Henry Waxman. While the regulatory approach of mining real-world evidence could benefit other rare diseases, Kim agreed there is a political story behind the expansion.
A Tenuous Autism Link
On Sept. 22, 2025, as part of a White House press conference in which President Donald Trump and members of his administration alleged a link between autism and Tylenol exposure in utero, FDA chief Marty Makary took the podium to deliver what he called good news.
“Today, the FDA is filing a federal register notice to change the label on an exciting treatment called prescription leucovorin so that it can be available to children with autism,” he said. “We have a duty to let doctors and the public know. . . . Hundreds of thousands of kids, in my opinion, will benefit.”
This came after then–Center for Drug Evaluation and Research Director George Tidmarsh had asked FDA staff in August to look into finding a way to approve leucovorin for autism, STAT News later reported. The drug, a form of folic acid, was originally sponsored by GSK and used to ameliorate the effects of cancer drugs such as methotrexate and fluorouracil. It’s been used off-label to treat CFD since 2009, an expert on the condition told CNN. GSK no longer makes the drug, but some generic suppliers do.
CFD has some overlap in symptoms with autism, and a few small studies have explored leucovorin’s use in the more common condition. But according to the American Academy of Pediatrics, “Current evidence is insufficient to support prescribing leucovorin for autism in the absence of CFD.”
Tidmarsh and FDA staffers ultimately compromised with a plan to submit leucovorin for approval in CFD rather than autism, STAT reported. GSK reviewed the case reports provided by the FDA and submitted the supplemental New Drug Application to update the indication, a company spokesperson told BioSpace in an email, though it does not plan to resume making or marketing the brand-name version of the drug.
At the September press conference, Makary blurred the distinction between CFD and autism and discussed a possible mechanistic link between folate and autism.
Policy and regulatory consultant Steven Grossman speculated that leucovorin’s approval for CFD may make the drug materially easier to access for autism as well.
“[If] you’re a pediatrician and you’re under pressure from parents—and I’m sure they are—to prescribe leucovorin [for autism] because of the noises coming out of HHS,” the drug’s recent label expansion may make it easier to justify, he suggested. It would still be an off-label prescription but it would be for a drug that’s approved for a pediatric disease and not just for cancer.
“While there may be more going on,” Grossman said, “the whole deal looks very much like a gigantic ‘wink-wink’ from the administration.”
A Glimpse of What Could Be
As Kim sees it, with the press conference and what followed, “we get this highly unsatisfactory, patient-adverse lifting of expectations and crashing of them with the announcement on CFD.” Yet for him, the episode points to what’s possible, namely that “many, many very rare diseases . . . could benefit from this approach” of mining real-world evidence.
With more research funding and needed infrastructure in place, “I would be not surprised to see multiple approvals of very rare disorder therapies like leucovorin, either repurposed or novel ones, and a real renaissance,” Kim said—one that is not dependent on the financial markets or emerging company formation but rather taps into the ongoing work of academics and clinicians.
As it stands, he said, the leucovorin label expansion is “like hanging a Christmas ornament high on the tree, but there’s nothing else on the tree.”
Correction (March 17): This story originally stated, incorrectly, that uniQure had received a CRL from the FDA. BioSpace regrets the error.
