FDA approved leucovorin for cerebral folate deficiency, a rare genetic neurological condition.

The decision stopped short of a broader approval for autism, marking a significant retreat from expectations set by senior government official’s last fall.²

The approval allows for GSK's Wellcovorin (leucovorin calcium) to be used for the treatment of cerebral folate deficiency in patients with a confirmed variant in the folate receptor 1 gene (CFD-FOLR1), marking the first FDA-approved treatment for the condition.¹

The approval covers both adult and pediatric patients, and (in an unorthodox process) was based on a systematic review of published literature and case reports rather than clinical trial data.¹ According to FDA, the approach was necessary given the extreme rarity of the disease, with only 20 to 50 documented cases.¹

What is Leucovorin?

Leucovorin, also known as folinic acid, is a decades-old form of vitamin B9 currently used in chemotherapy patients.¹ GSK no longer manufactures the drug, but the expanded approval applies to all generic versions, and the FDA said it is encouraging manufacturers to increase production.

How is this approval different from what was promised?

The approval is considerably narrower than what the Trump administration signaled in September, when FDA Commissioner Marty Makary, President Trump, and Health Secretary Robert F. Kennedy Jr. held a White House press conference promoting leucovorin as a potential treatment for autism symptoms more broadly.³ Kennedy called it an "exciting therapy that may benefit large numbers of children who suffer from autism."²

Following the press conference, a study published in the Lancet found that leucovorin prescriptions in children spiked 71% in the months following the press conference.²

The FDA acknowledged the shift, with a senior official saying the agency narrowed its scope as it worked through the available scientific data, "Right now, we don't have sufficient data to say that we could establish efficacy for autism more broadly."²

Why wasn't a broader autism approval granted for Leucovorin?

Leucovorin’s broader approval was dependent on small studies suggesting many children with autism have autoantibodies that block folate from entering the brain, producing a deficiency similar to CFD-FOLR1.²

However, scientists have consistently called for large, randomized trials, and the American Academy of Pediatrics does not recommend leucovorin's routine use in autism patients, citing insufficient evidence.

The FDA says its review team was able to examine the available autism data thoroughly but could not find enough evidence to support a broader indication at this time.

"Right now, we don't have sufficient data to say ​that we could establish ⁠efficacy for autism more broadly. The review team did an amazing job really looking at the data for autism in general that's available, and was really able to show why we don't have the evidence at now for a broader approval," said an FDA official.²

What is CFD-FOLR1 and why does Leucovorin’s approval matter?

Cerebral folate deficiency is a neurological condition in which folate transport into the brain is impaired, leading to severe developmental delays, movement disorders, seizures, and other serious neurological complications.

Patients with the FOLR1 variant often present with autistic features, which contributed to early hopes that leucovorin could address autism more widely.

FDA Commissioner Makary called the approval a significant milestone for a patient population that has had no approved treatment options, saying, "Today's approval represents a significant milestone for patients living with cerebral folate transport deficiency due to the FOLR1 variant, a rare genetic condition that has had no FDA-approved treatment options until today. This action may benefit some individuals with FOLR1- related cerebral folate transport deficiency who have developmental delays with autistic features.”

How was this approval different from the standard process?

The FDA's approval of leucovorin was notable not just for what it approved, but for how. Rather than relying on the randomized controlled trial data that underpins most drug approvals, the agency based its decision on a systematic review of published literature, case reports, and mechanistic data.¹

The FDA claims a traditional clinical trial was not feasible given the extreme rarity of the condition as there are only 20 to 50 documented cases worldwide, making the process of assembling a patient population large enough to power a controlled study effectively impossible.²

The approach reflects a growing willingness at the agency to apply flexible evidentiary standards for ultra-rare diseases, as Tracy Beth Hoeg, acting director of the FDA's Center for Drug Evaluation and Research, said the decision demonstrates how real-world evidence can support an approval when a drug shows clear clinical benefit against the natural history of a disease, while maintaining the same evidentiary standards applied to all approvals.¹

“It also provides a good example of how observational or ‘real world’ evidence can lead to an FDA approval when the product is shown to provide clear clinical benefit compared with what is seen with the natural history of the disease,” said Hoeg.

Sources

1. FDA Approves First Treatment for Patients with Cerebral Folate Transport Deficiency U.S. Food and Drug Association March 10, 2026 https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-cerebral-folate-transport-deficiency
2. US FDA approves leucovorin for ultra- rare genetic disorder causing autism-like symptoms Reuters March 10, 2026 https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-approves-leucovorin-ultra-rare-genetic-disorder-causing-autism-like-2026-03-10/
3. President Trump, Secretary Kennedy Announce Bold Actions to Tackle Autism Epidemic U.S. Department of Health and Human Services September 22, 2025 https://www.hhs.gov/press-room/hhs-trump-kennedy-autism-initiatives-leucovorin-tylenol-research-2025.html#:~:text=HHS%20Press%20Office-,President%20Trump%2C%20Secretary%20Kennedy%20Announce%20Bold%20Actions%20to%20Tackle%20Autism,folate%20deficiency%20and%20autistic%20symptoms.