FDA Initiates Approval of Leucovorin for Patients With Cerebral Folate Deficiency

The FDA announced they have initiated the approval of leucovorin calcium tablets (Wellcovorin; GSK) for patients with cerebral folate deficiency (CFD), which the agency claims can cause developmental delays with features of autism spectrum disorder (ASD).

The action is based on an FDA-conducted systematic review of published literature between 2009 and 2023, including published case reports and mechanistic data.¹ The autistic features cited by the FDA include seizures and problems with movement and coordination.

GSK, the manufacturer of leucovorin calcium and the holder of the medicine’s new drug application, is working with the FDA on a process to include information needed for the safe use of the drug in patients with CFD on its label. It is unknown how long the approval process may take for leucovorin calcium.¹

What is Cerebral Folate Deficiency?

CFD is a neurological syndrome that begins to impact development at age 2. Low levels of 5-methyltetrahydrofolate, an essential B-vitamin, in the brain can cause CFD. Children may lose some mental and motor skills, while others may experience intellectual disability, difficulty speaking, or recurrent seizures. Motor issues, including tremors or ataxia, can become severe as the disorder progresses. Some research has demonstrated that cerebral folate receptor alpha (FRα) antibodies can be observed in ASD.^2-4

According to the Department of Health and Human Services, autoimmune forms of CFD are the most common presentations. In this form, autoantibodies mistakenly attack the body’s folate transport system, which yields severe neurological symptoms.

It is critical to note that not every individual with ASD harbors FRα autoantibodies. One analysis found that the pooled prevalence of ASD in individuals with CFD was 44%, while the pooled prevalence of CFD in ASD was 38%, with significant variation across included studies. Another found that FRα autoantibodies were identified in 58% to 76% of children with ASD.^3,5,6

What is Leucovorin?

Leucovorin, also known as folinic acid, helps bypass the defective folate transport system and deliver the active form of folate directly to the brain. It is typically used in the treatment of methotrexate toxicity and chemotherapy regimens, while also occasionally used as an alternative agent for megaloblastic anemia when oral intake of folic acid is not possible. It first received FDA approval in 2002.⁷

According to the FDA’s meta-analysis, which encompassed 23 publications over 15 years, leucovorin demonstrated effectiveness in reducing the symptoms of CFD. FDA investigators found that 85% of patients experienced some form of clinical benefit, including improved communication capabilities. Furthermore, efficacy data on the use of leucovorin specifically for the autoimmune presentation of CFD suggest benefits, but the FDA cautions that the data must be replicated in future research.^3,5,7

Some adverse effects are possible with leucovorin but are generally mild in nature. One analysis reported common effects, including aggression, excitement or agitation, headache, insomnia, and increased tantrums. However, these authors concluded that leucovorin appears safe and generally well-tolerated. The FDA stated that leucovorin is generally well-tolerated based on its established safety profile in other approved indications.^3,5,7

What Can Pharmacists Do?

Pharmacists stand to be critical harbingers of trusted, up-to-date medical information in the wake of this announcement. HHS noted in their fact sheet that off-label use of leucovorin has increased substantially in recent years; however, it is critical for pharmacists to explain that ingesting folate through over-the-counter supplements has not been approved by the FDA and may be harmful. Even if a patient presents as using leucovorin, a pharmacist should evaluate their medication history and ensure there are no drug-drug interactions or contraindications that may harm the patient.⁵

Research on this topic is ongoing. The FDA explained in their news release that there are limitations on available data for the use of leucovorin in this population. Pharmacists should counsel patients that, although the FDA is initiating its approval process, leucovorin may not be a stand-alone cure for autistic symptoms. Parents and caregivers of children with ASD should ensure that, above all, the well-being of their child is of top priority, and that novel treatments should be rigorously examined before use.¹

Pharmacists should monitor the approval process of leucovorin and ensure they are prepared to educate patients if and when the drug is made available.

REFERENCES

1. FDA. FDA takes action to make a treatment available for autism symptoms. News Release. Released September 22, 2025. Accessed September 23, 2025. https://www.fda.gov/news-events/press-announcements/fda-takes-action-make-treatment-available-autism-symptoms

2. Cerebral folate deficiency. National Organization for Rare Disorders. Updated August 22, 2019. Accessed September 23, 2025. https://rarediseases.org/rare-diseases/cerebral-folate-deficiency/

3. Rossignol DA, Frye RE. Cerebral folate deficiency, folate receptor alpha autoantibodies and leucovorin (folinic acid) treatment in autism spectrum disorders: A systematic review and meta-analysis. J Pers Med. 2021;11(11):1141. doi:10.3390/jpm11111141

4. Frye RE, Sequeira JM, Quadros EV, et al. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2012;18(3):369-381. doi:10.1038/mp.2011.175

5. Frye RE, Rossignol DA, Scahill L, et al. Treatment of folate metabolism abnormalities in autism spectrum disorder. Seminars in Pediatric Neurology. 2020;25:100835. doi:10.1016/j.spen.2020.100835

6. Department of Health and Human Services. Autism announcement fact sheet. Released September 22, 2025. Accessed September 23, 2025. https://www.hhs.gov/press-room/autism-announcement-fact-sheet.html

7. Hedge VS, Nagalli S. Leucovorin—StatPearls [Internet]. National Library of Medicine. Last Updated July 3, 2023. Accessed September 23, 2025. https://www.ncbi.nlm.nih.gov/books/NBK553114/