FDA approves Wellcovorin to treat cerebral folate deficiency

The FDA approved Wellcovorin (leucovorin calcium; GSK) to treat cerebral folate deficiency in adult and pediatric patients on March 10, 2026.¹

Patients with this rare condition are given leucovorin as a first-line treatment, highlighting how this approval expands options for patients with severe unmet needs. It is also the first treatment approved for patients with a confirmed variant in the FOLR1 gene (CFD-FOLR1).

“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,” said FDA Commissioner Marty Makary, MD, MPH.

Potential benefits for developmental delays

According to Makary, the approval may benefit patients with FOLR1-related cerebral folate transport deficiency presenting with developmental delays with autistic features. The drug’s labeling was also updated to include essential clinical data that will help make use safe and effective among CFD-FOLR1 patients of all ages.

In these patients, the transportation of folate, which is an essential vitamin for brain health, is adversely impacted. This increases the risks of seizures, movement disorders, severe developmental delays, and other severe neurological complications.

The use of Wellcovorin to prevent these outcomes was supported by data from a systematic review of published literature, including case reports with patient-level information and mechanistic data. Adverse events related to Wellcovorin use have been reported, including pruritus, rash, urticaria, dyspnea, rigors, and impaired thermoregulation.

The FDA noted anaphylaxis as a severe, potentially fatal adverse reaction of Wellcovorin use that requires immediate medical attention. Overall, the approval of Wellcovorin was highlighted as addressing a critical unmet need in adults and children with CFD-FOLR1.

"The approval of leucovorin…demonstrates the FDA’s commitment to rapidly identifying effective treatments for ultra rare diseases while maintaining the same evidentiary standards for approval,” said Tracy Beth Hoeg, MD, PhD, acting director of the FDA’s Center for Drug Evaluation and Research.

Diagnostic signs and early intervention

The clinical signs and treatment outcomes of cerebral folate deficiency have been highlighted by the National Organization for Rare Disorders (NORD).² According to NORD, development often begins in the first year of life, with children losing mental and motor skills at approximately aged 2 years.

Symptoms of cerebral folate deficiency used in diagnosis include hypotonia, ataxia, unsteady walking, and small head circumference. Irregular subcortical white matter may also be identified through MRI, and electrical brain activity can be recorded through electroencephalography. Unusual arrays may have high amplitude and irregular waves.

In patients with mutations in the FOLR1 gene, a diagnosis may be confirmed using molecular genetic testing. NORD supports leucovorin calcium treatment in patients with a positive diagnosis, noting that the age at which the treatment is initiated may influence outcomes, with earlier treatment leading to better outcomes.

Dietary considerations and inheritance risk

Treatment should not be supplemented with folic acid, as this increases the risk of seizures. Additionally, a milk-free diet in combination with calcium treatment has been linked to improved symptoms, especially if used in the disease’s early stages.

Finally, NORD highlighted the odds of patients developing mutations in the FOLR1 gene leading to cerebral folate deficiency. These mutations are inherited as an autosomal recessive genetic condition, with a 25% risk of 2 carrier parents both passing the altered gene to an affected child.

“The risk to have a child who is a carrier like the parents is 50% with each pregnancy,” wrote NORD. “The chance for a child to receive normal genes from both parents is 25%.”

References

1. FDA approves first treatment for patients with cerebral folate transport deficiency. News release. FDA. March 10, 2026. Accessed March 10, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-cerebral-folate-transport-deficiency
2. Cerebral folate deficiency. National Organization for Rare Disorders. Updated August 22, 2019. Accessed March 10, 2026. https://rarediseases.org/rare-diseases/cerebral-folate-deficiency/