Folic Acid

FDA Commissioner Marty Makary speaks at a White House press conference on September 22, 2025. / Joyce N. Boghosian, White House 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 a complete response letter (CRL) but also public criticism from FDA officials for attempting to win approval based on an externally controlled pivotal trial. RENENXBIO, Biohaven and Capricor Therapeutics have also 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.”

WEDNESDAY, March 11, 2026 — The U.S. Food and Drug Administration (FDA) has approved a generic drug for a very rare brain disorder, but said it should not be considered a treatment for autism . On Tuesday, the agency cleared leucovorin for people with a genetic condition that prevents enough folate, a form of vitamin B, from reaching the brain. The FDA estimates the disorder affects fewer than 1 in a million people in the United States. The decision follows months of ambiguity after officials said the drug might help people with autism. In September, President Donald Trump and FDA Commissioner Dr. Marty Makary said the medication was being reviewed as a possible treatment for autism. “It might be 20, 40, 50% of kids with autism,” Makary said at the time. But FDA officials said Monday that the agency later focused only on the strongest scientific evidence. That evidence only supported the drug’s use for people with the rare genetic mutation affecting folate in the brain. Officials also noted that one study supporting the drug’s use for autism was retracted earlier this year. Autism researchers say the drug has not been proven to help most people with the condition. “There is no evidence to say that leucovorin will help most people with autism, and there’s certainly no evidence to say it’s safe,” Dr. Alycia Halladay of the Autism Science Foundation, told The Associated Press in an interview. Leucovorin is a lab-made form of folate that doctors have used for years to reduce side effects from certain chemotherapy medications and to treat a rare blood disorder. People with the condition targeted by Tuesday’s approval may develop movement problems, seizures and other neurological symptoms that can sometimes resemble autism. But major medical groups are cautious about using leucovorin for autism. The American Academy of Pediatrics does not recommend its use for children with autism, including those with a condition called cerebral folate deficiency. But despite the uncertainty, prescriptions for leucovorin have increased. A recent study in The Lancet found that prescriptions for children ages 5 to 17 rose 71% in the three months following the White House announcement last September. “We’ve seen huge increases in leucovorin prescriptions for autism because of the initial premature and ill-informed announcement that it can treat autism symptoms,” David Mandell , an autism expert at the University of Pennsylvania, told The AP . "Now families are experiencing whiplash about what constitutes best practice for their children," Mandell added. Some families have also reported difficulty filling prescriptions recently due to supply shortages. FDA officials said the agency is allowing foreign manufacturers to help with supply. The drug’s original maker, GSK, does not plan to relaunch its version. Halladay warned that parents should be careful about trying the drug for autism. Reports have linked the medication to side effects such as irritability, aggression and hyperactivity in some patients. “If parents are insistent on trying this they should know that it may cause harm and it may do no good,” Halladay said. Researchers say autism likely results from a mix of genetic and environmental factors, and there is still no single known cause. Sources The Associated Press, March 10, 2026