Nearly five months after U.S. Department of Health and Human Services Secretary Robert F. Kennedy Jr. touted leucovorin at a White House press conference as an “exciting treatment that could benefit millions of children suffering from autism,” the FDA approved the decades-old drug for a rare genetic disorder with “autistic features” that affects a small percentage of people with autism.
The FDA has approved GSK’s leucovorin calcium tablets, Welcovorin, as a treatment for cerebral folate deficiency (CFD), but only in patients with a confirmed mutation in the folate receptor 1 (FOLR1) gene.
CFD-FOLR1 is an extremely rare genetic form of CFD that is present in some children with autism spectrum disorders and affects fewer than 1 in 1 million people, according to FDA officials. CFD is a neurological disease characterized by the inability of folic acid to cross the blood-brain barrier, leading to symptoms such as seizures, movement disorders, and intellectual disability. Besides FOLR1 mutations, other causes of CFD include autoantibodies that block folate receptors.
limited indications
The patient population with CFD-FOLR1, or FOLR1-related cerebral folate transport deficiency, is much smaller than the broader patient population that U.S. health leaders initially touted as candidates for leucovorin.
FDA Commissioner Marty McCully, M.D., said at a White House press briefing on September 22, 2025, that the FDA is changing the labeling of leucovorin so that “hundreds of thousands of children” with autism can benefit. The FDA commissioner also highlighted a study showing that “two-thirds of children with autism symptoms showed improvement, with some significant improvement” after receiving leucovorin.
However, following bold claims from U.S. health leaders, the American Academy of Pediatrics announced that it no longer recommends routine use of leucovorin in children with autism, saying the evidence supporting its use in the broader autism population is “too limited.”
The medical association maintained language in its latest guidance, updated on February 13, 2026, that further research in larger trials is needed to determine whether leucovorin is safe and effective in autism and in which subgroups it is most effective.
The Federation of Autism Scientists also noted that there is a lack of scientific evidence showing that leucovorin is an effective treatment for autism.
McCurry said in a March 10 statement that leucovorin’s approval could benefit “some individuals with FOLR1-related cerebral folate transport deficiency who have developmental delays with autistic features.”
The FDA considered whether existing data supported a broad classification of autism, but after a “systematic review,” FDA reviewers determined that the FOLR1 subpopulation had the “highest quality data,” a senior FDA official told reporters at a press conference.
“We zeroed in on that population because we felt it was the most powerful we could use to overcome some of the limitations of the data source, both in terms of scientific basis and maximum treatment effect,” she added.
Because leucovorin is a small molecule, it falls under the purview of the FDA Center for Drug Evaluation and Research (CDER), directed by Acting Director Tracy Beth Hogue, MD.
To approve leucovorin as a first-line treatment for CFD-FOLR1, the FDA took some very unusual steps.
FDA’s unusual move
Instead of clinical trials, the FDA based its decision on published literature, including actual case reports and the mechanism of leucovorin.
In a historical data set, the clinical response rate for CFD-FOLR1 patients taking leucovorin was 87%, supported by 80% normalization of laboratory levels of 5-MTHF, the bioavailable form of folic acid in cerebrospinal fluid, another senior FDA official said at a press conference.
Leucovorin itself is a type of folic acid that can cross the blood-brain barrier and has the potential to address folate deficiency in the central nervous system, FDA officials said.
Although unconventional, the FDA has issued approvals in the past based on real-world evidence. In 2019, based on data from electronic health records and postmarketing reports on real-world use, the FDA approved Pfizer’s Ibrance (palbociclib) as part of a regimen for patients with HR-positive, HER2-negative male breast cancer. In 2021, the FDA approved Astellas Pharma’s Prograf (tacrolimus) as part of a combination therapy to prevent organ rejection in patients undergoing lung transplants. This approval is based on real-world data from the National Scientific Transplant Recipient Registry.
Randomized controlled clinical trials generally provide the strongest scientific evidence, but conducting such studies in an ultra-rare disease like CFD-FOLR1 is extremely difficult, the first FDA official said at a press conference.
“We were also willing to leverage this data because we know there is a strong scientific and mechanistic basis for why leucovorin is expected to be effective in this condition,” the official added. “And from what we’ve seen and heard in the literature, we felt that very large and substantial improvements were being reported with treatment with leucovorin.”
Other senior officials on the conference call explained that the lack of clinical trials fits into the FDA’s newly announced plausible mechanistic pathway, which is aimed at enabling the approval of personalized treatments primarily based on gene editing.
“This drug directly addresses the deficiencies seen in this disease, but the response we saw to administering the drug was actually different from what we see in the natural history of this disease,” the officials said, while also noting that conducting a placebo-controlled clinical trial in such an ultra-rare disease “would be unethical.”
The plausible mechanistic pathways described by the FDA are aimed at tailored treatments that address the underlying causes of disease and use natural history data to demonstrate clinical benefit. Leucovorin is never customized to individual patients.
The Center for Biologics Evaluation and Research (CBER), the FDA’s sister arm of CDER, has come under fire for its coverage of treatments for rare diseases, even those that appear to meet some criteria for plausible mechanistic pathways. UniQure’s Huntington’s disease gene therapy has been rejected by CBER, despite targeting a clear genetic cause, showing clinical efficacy in several patients, and using a well-characterized natural history control group.
In explaining his decision to reject uniQure’s proposal to compare Phase 1/2 results with natural history data to support the application, CBER Director Vinay Prasad, MD, previously pointed out to Fiers that uniQure’s treatment is not tailored to each individual and is not amenable to plausible mechanistic pathways.
In another unusual step in approving leucovorin, the FDA aggressively lobbied GSK. GSK originally developed Welcovorin for other uses such as reducing certain anemias and the toxic side effects of chemotherapy. At the FDA’s request, the UK pharmaceutical company submitted case report data identified by the FDA to enable label updates.
However, GSK has long stopped manufacturing Welcovorin, and a GSK spokesperson confirmed to Fierce Pharma that the company will no longer manufacture Welcovorin after the latest approval.
Still, other generic leucovorin versions are also available. Absent intellectual property restrictions, the FDA’s approval of Welcovorin in CFD-FOLR1 applies equally to all generic Leucovorins, as generic drugs must maintain the same labeling as the originator drug.
Despite warnings from the scientific community, leucovorin prescriptions for children ages 5 to 17 jumped 71% in the approximately 11 weeks following the September White House event, according to a study published in The Lancet.
“While we cannot claim causation, the observed association is consistent with the impact of new FDA recommendations on clinical decisions,” the researchers noted.
One senior FDA official said at a news conference that the FDA allows imports of leucovorin from other manufacturers outside the United States, and the drug is not currently on the agency’s shortage list.
“We are in talks with other companies to allow imports or allow existing manufacturers to increase production if demand continues to increase,” she said.
