FDA Approves Expanded Use of Leucovorin For Cerebral Folate Transport Deficiency

The FDA approved the expanded use of leucovorin calcium (Wellcovorin) tablets as the first-ever treatment for adult and pediatric patients with cerebral folate transport deficiency caused by a confirmed FOLR1 gene variant. This regulatory milestone addresses a critical unmet need for individuals with this rare neurological condition, which previously had no FDA-approved therapeutic options.¹

For pharmacists, this approval formalizes the clinical application of high-dose leucovorin—also known as folinic acid—in managing a condition where the brain lacks essential folate despite normal systemic levels.²

"The approval of leucovorin for FOLR1-related cerebral folate transport deficiency demonstrates the FDA’s commitment to rapidly identifying effective treatments for ultra-rare diseases while maintaining the same evidentiary standards for approval,” Tracy Beth Hoeg, MD, PhD, acting director of the FDA’s Center for Drug Evaluation and Research, said in a news release. “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.”

Cerebral folate transport deficiency, specifically the CFD-FOLR1 variant, is an autosomal recessive disorder resulting from a loss of function in the folate receptor alpha protein. This protein is responsible for transporting folates across the blood-choroid plexus-cerebrospinal fluid (CSF) barrier. Without it, patients experience progressive neurological deterioration, including severe developmental delays, movement disorders, and intractable seizures. Clinical literature suggests that while untreated individuals can survive into adulthood, they often face profound cognitive impairment and immobility.²

Pharmacists should note that the approval was supported by a systematic review of published literature and case reports, illustrating a real-world evidence approach to evaluating treatments for ultra-rare diseases. Data indicates that early intervention with leucovorin can substantially improve neurological findings and, in some cases, prevent the onset of symptoms in asymptomatic younger siblings of diagnosed patients. The therapeutic objective is to restore CSF folate concentrations to a normal range for the patient's age.^1,2

The safety profile for leucovorin includes potential adverse effects such as pruritus, rash, urticaria, dyspnea, and impaired thermoregulation. Rare and serious allergic reactions like anaphylaxis require immediate medical intervention. Pharmacists should also be aware of potential drug interactions with antiseizure medications. For instance, leucovorin may decrease the serum concentration of phenobarbital or primidone, and some anti-seizure drugs like valproate can interfere with folate metabolism.^1,2,3

This approval follows a period of heightened public interest and shifting prescribing patterns for leucovorin. In late 2025, a surge in outpatient prescriptions was observed following public discussions regarding the drug's potential use in broader neurodevelopmental contexts, such as autism spectrum disorder. This increased demand contributed to a national shortage of leucovorin calcium tablets in November 2025. With the formal FDA approval for CFD-FOLR1, pharmacists will play a vital role in ensuring this medication is prioritized for patients with the confirmed genetic variant while managing expectations for off-label use.⁴

In September 2025, President Donald J. Trump and US Health and Human Services (HHS) Secretary Robert F. Kennedy Jr announced efforts to address autism spectrum disorder, which has been a focus of the current administration in the health care space. The FDA published a Federal Registry that outlined label updates for leucovorin for cerebral folate transport deficiency, which has been associated with autism. With the label change, state Medicare programs would be able to cover leucovorin for indications of autism, according to the news release. However, this recent approval covers cerebral folate transport deficiency with no mention of autism spectrum disorder.⁵

“A growing body of evidence suggests that some children suffering from autism are folate deficient within the brain—a problem that can be treated with leucovorin,” FDA Commissioner Marty Makary, MD, said in a statement.⁴ “Given the extent of the current autism epidemic, physicians should immediately have this treatment option available for candidate children. We are also sharing new information about the potential risks of acetaminophen so patients can make a more informed decision with their health care provider.”

Senior FDA officials told AP News that the review of the drug was narrowed to focus on the strongest evidence, which only included cerebral folate transport deficiency. The officials also stated that the study supporting the drug’s use for autism spectrum disorder was retracted earlier in 2026.⁶

READ MORE: FDA Updates

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REFERENCES

1. FDA approves first treatment for patients with cerebral folate transport deficiency. News release. FDA. March 10, 2026. Accessed March 12, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-cerebral-folate-transport-deficiency

2. Goldman ID. FOLR1-Related Cerebral Folate Transport Deficiency. 2024 Jan 11 [Updated 2025 Dec 18]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK599286/

3. Mayo Clinic. Leucovorin (oral route, intravenous route, injection route). Updated February 1, 2026. Accessed March 12, 2026. https://www.mayoclinic.org/drugs-supplements/leucovorin-oral-route-intravenous-route-injection-route/description/drg-20064503

4. Faust JS, Barnett ML. Changes in paracetamol and leucovorin use after a White House briefing. Lancet. Published online March 5, 2026. doi:10.1016/S0140-6736(26)00243-6

5. President Trump, Secretary Kennedy announce bold actions to tackle autism epidemic. News release. HHS. September 22, 2025. Accessed March 12, 2026. https://www.hhs.gov/press-room/hhs-trump-kennedy-autism-initiatives-leucovorin-tylenol-research-2025.html

6. Perrone M. FDA finds little evidence that a drug touted by Trump can help people with autism. AP News. March 10, 2026. Accessed March 12, 2026. https://apnews.com/article/autism-fda-drug-leucovorin-trump-kennedy-97a1b5092de76b7956f778f374189a0c