FDA Approves Expanded Use of Wellcovorin for Cerebral Folate Transport Deficiency

The Food and Drug Administration (FDA) has approved the expanded use of Wellcovorin (leucovorin calcium; GlaxoSmithKline [GSK], London, United Kingdom), a form of folic acid, for the treatment of adults and children who have cerebral folate transport deficiency associated with a confirmed pathogenic variant of the folate receptor 1 gene (FOLR1-CFTD). FOLR1-CFTD, an extremely rare neurogenetic condition, impairs the delivery of folate across the blood-brain barrier (BBB), resulting in a range of serious neurological symptoms, including severe developmental delay, movement disorders, and seizures.

Given the rarity of FOLR1-CFTD and the unlikelihood of a large-scale clinical trial, the FDA approved the new indication based on a novel regulatory approach: a systematic review of the published literature and mechanistic action rather than a traditional prospective clinical trial. Across 26 published case reports and case reviews through 2024, 46 patients with FOLR1-CFTD who received leucovorin were identified

Key details from the FDA’s review and approval include the following:

• The FDA approval was supported by published literature including observational data and case reports, which demonstrated clinical improvement in individuals treated with Wellcovorin vs natural history.
• Twenty-seven of the 46 individuals reported receiving Wellcovorin orally, 24 of which reported improvements in neurologic outcomes including reduced severity or number of seizures and improvements in motor function, communication, or behavior.
• GSK collaborated with the FDA to update the Wellcovorin prescribing information with guidance on safe and effective use for individuals with FOLR1-CFTD.
• Adverse reactions listed in the new prescribing information include pruritus, rash, urticaria, dyspnea, hypersensitivity reactions, rigors, and temperature change.

“[The Wellcovorin approval] 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 Tracy Beth Hoeg, MD, PhD, Acting Director of the FDA’s Center for Drug Evaluation and Research.

Sources: US Food and Drug Administration. FDA approves first treatment for patients with cerebral folate transport deficiency. Press release. Published March 15, 2026. Accessed March 15, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-cerebral-folate-transport-deficiency

GlaxoSmithKline. Wellcovorin (leucovorin calcium) tablets, for oral use: Full Prescribing Information [package insert]. NDA 018342/S-015. Durham, NC: GlaxoSmithKline; March 2026. Accessed March 16, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/018342s015lbl.pdf.