FDA Approves Leucovorin for Cerebral Folate Transport Deficiency

The FDA has approved expanded use of leucovorin calcium tablets (Wellcovorin) for the treatment of adult and pediatric patients with cerebral folate transport deficiency associated with confirmed variants in the folate receptor 1 (FOLR1) gene. The regulatory decision marks the first FDA-approved therapy specifically indicated for this rare genetic neurological condition.¹

According to the agency, the approval was supported by a systematic review of published literature that included case reports with patient-level data as well as mechanistic evidence supporting the biological rationale for leucovorin therapy.

“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,” Marty Makary, MD, MPH, commissioner of the FDA, said in a statement.¹ “This action may benefit some individuals with FOLR1-related cerebral folate transport deficiency who have developmental delays with autistic features.”

The FDA worked with GlaxoSmithKline, the new drug application holder for Wellcovorin, to update the drug’s labeling to include information supporting safe and effective use in patients with FOLR1-related cerebral folate transport deficiency.¹ The approval was issued through a supplemental new drug application for the existing product.²

Leucovorin treatment is generally well tolerated but can be associated with adverse reactions including pruritus, rash, urticaria, dyspnea, rigors, and impaired thermoregulation. Rare but serious hypersensitivity reactions, including anaphylaxis, may occur and require immediate medical attention.

“This approval 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 statement.¹ “It also provides an example of how observational or real-world evidence can support an approval when a treatment shows clear clinical benefit compared with the natural history of disease.”

Leucovorin, also known as folinic acid, is a reduced form of folate that can bypass certain metabolic barriers and restore folate availability in tissues. In patients with FOLR1-related deficiency, leucovorin may help replenish folate levels in the brain and improve neurological function by circumventing impaired receptor-mediated transport.

Cerebral folate transport deficiency occurs when mutations in the FOLR1 gene impair the transport of folate into the central nervous system. Folate is a critical vitamin involved in DNA synthesis, neuronal development, and brain function. Patients with the disorder often experience severe neurological manifestations, including developmental delay, seizures, movement disorders, and autistic features.¹

The FDA noted that pediatric study requirements for the indication have been fulfilled and that the therapy may be used in both adult and pediatric populations with confirmed FOLR1-related disease.²

Overall, the decision addresses a significant unmet need in a rare neurological disorder for which treatment options have historically been limited to supportive care. With regulatory approval now in place, leucovorin represents the first therapy specifically indicated for patients with genetically confirmed cerebral folate transport deficiency.

REFERENCES
1. FDA approves first treatment for patients with cerebral folate transport deficiency. U.S. Food and Drug Administration. News Release. March 10, 2026. Accessed March 10, 2026.
2. U.S. Food and Drug Administration. Supplement approval NDA 018342/S-15: Wellcovorin (leucovorin calcium) tablets for treatment of cerebral folate transport deficiency in patients with FOLR1 variants. March 9, 2026.