FDA Moves to Approve Leucovorin for Cerebral Folate Deficiency (2025)

Table of Contents

1. What the FDA Did in September 2025
2. What Cerebral Folate Deficiency Is, in the FDA’s Words
3. The Evidence the FDA Says It Reviewed
4. The Tablet Application: Approved 1983, Withdrawn 1999, Approved Again 2025
5. What the Action Was Set to Change: A Relabeling
6. The Broader Group the FDA Says Needs More Study
7. What the Action Does Not Do
8. What FDA Officials Said
9. Dates and Status as of 11 October 2026
10. How It Fits the FDA’s Other 2025 Actions
11. Primary Documents
12. Key Research Papers
13. Connections

1. What the FDA Did in September 2025

The action came in two documents, two days apart.

• 22 September 2025 — FDA news release. The agency said it had “initiated the approval of leucovorin calcium tablets for patients with cerebral folate deficiency (CFD).” It said it was working with the holder of the original leucovorin tablet application — the drug company that first brought the tablets to market — on a process to add “the essential scientific information needed for the safe and effective use of these drug products for adults and pediatric patients with CFD,” and that the company had “preliminarily agreed to work with the FDA on this relabeling effort.”
• 24 September 2025 — Federal Register notice. Titled “Approval of Previously Withdrawn New Drug Application for [the original brand of] (Leucovorin Calcium) Tablets,” the notice announced approval of new drug application (NDA) 018342 for leucovorin calcium tablets in two strengths, equivalent to 5 milligrams and 25 milligrams of leucovorin base. It states that the FDA was “initiating this action on the basis of new data.” The notice was signed by the FDA’s Deputy Commissioner for Policy, Legislation, and International Affairs and filed on 22 September 2025.

Two terms explain the paperwork. A new drug application (NDA) is the file a drug’s sponsor submits and the FDA approves before a medicine can be sold in the United States; each NDA carries a number. The Federal Register is the U.S. government’s daily journal of rules and notices, and a docket is the public file number under which a notice and any related material are kept; this one is FDA-2025-N-3959.

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2. What Cerebral Folate Deficiency Is, in the FDA’s Words

The September 2025 release describes cerebral folate deficiency as “a neurological condition that affects folate (a vitamin essential for brain health) transport into the brain.”

The FDA lists what has been observed in people with the condition:

• developmental delays with autistic features — the release gives “challenges with social communication, sensory processing, and repetitive behaviors” as examples;
• seizures;
• problems with movement and coordination.

The Federal Register notice is more specific about the genetic form of the condition, caused by variants in the FOLR1 gene. The patients described in the published case reports had, in the notice’s words, “heterogenous clinical symptoms that included global developmental delays with autistic features and psychomotor regression, intractable epilepsy, and cerebellar ataxia” — that is, delayed development with loss of previously gained skills, seizures that are hard to control, and unsteady movement arising from the cerebellum. The March 2026 FDA release adds that people with the genetic form “often have severe developmental delays, movement disorders, seizures, and other serious neurological complications.”

Folate itself, its forms and the blood tests used to measure it are covered on the site’s Folate for Methylation & Homocysteine and Folate Test pages.

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3. The Evidence the FDA Says It Reviewed

No new clinical trial was run for this action. Both FDA documents say the agency carried out “a systematic analysis of literature published between 2009-2024,” including published case reports with information on individual patients, and mechanistic data. The release says this “supports a finding that leucovorin calcium can help individuals suffering from CFD.”

The Federal Register notice gives the details:

• The published case reports provided patient-level data on “over 40 patients, including both adults and pediatric patients, with genetically confirmed CFD due to variants in the FOLR1 gene who were treated with oral leucovorin.”
• In some patients, the leucovorin dose was adjusted according to symptoms or according to levels of 5-methyltetrahydrofolate (5-MTHF) — the form of folate measured — in the cerebrospinal fluid (CSF), the fluid surrounding the brain and spinal cord.
• There was no randomized comparison group. Outcomes were compared with “the known natural history of CFD due to variants in the FOLR1 gene as historic control” — what is known about how the untreated condition usually progresses.
• The notice states that “the majority of patients demonstrated substantial improvement of symptoms of CFD that would not be expected when compared to the natural history” of the condition.
• For the mechanistic data, the notice reports “a normalization in CSF 5-MTHF levels in 80% of patients who had CSF samples available for analysis following administration of leucovorin.”

On this basis the notice states that the information “supports a finding that orally administered leucovorin calcium tablets improve certain symptoms in adults and pediatric patients with cerebral folate deficiency (CFD).”

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4. The Tablet Application: Approved 1983, Withdrawn 1999, Approved Again 2025

The Federal Register notice sets out the history of NDA 018342:

1. 8 July 1983 — the application for leucovorin calcium tablets, 5 mg and 25 mg base, was first approved. Its most recently approved labeling stated that the tablets were indicated “to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists” — that is, as a rescue medicine when methotrexate or similar folate-blocking drugs build up in the body.
2. 22 September 1999 — the FDA announced in the Federal Register that it was withdrawing approval of the application, after the holder told the agency the tablets were no longer marketed and asked for the withdrawal.
3. 28 April 2017 — the FDA announced in the Federal Register its determination that these tablets “were not withdrawn from sale for reasons of safety or effectiveness.”
4. 24 September 2025 — the FDA announced approval of the previously withdrawn application.

The legal basis cited is 21 CFR 314.160, a federal drug regulation which, in the notice’s summary, provides that the FDA, “on its own initiative or upon request of an applicant, may, on the basis of new data, approve an application or abbreviated application which it had previously refused, suspended, or withdrawn approval.” The notice says the FDA was “required to publish notice of approval of an NDA for which the Agency had previously withdrawn approval,” which is why the step appeared in the Federal Register.

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5. What the Action Was Set to Change: A Relabeling

The September 2025 notice reinstated the application; it did not itself add cerebral folate deficiency to the label. It describes the next step: after the approval, the FDA “intends to request” that the application holder “submit a prior approval supplemental NDA to revise the prescribing information” to include “the essential scientific information needed for the safe and effective use of these drug products for the treatment of CFD in adults and pediatric patients.”

A prior approval supplement is a request to change an already-approved drug’s application — here, its prescribing information, the official label that tells clinicians what a drug is approved to treat — that the FDA has to approve before the change takes effect. The press release described the same process as a “relabeling effort” to which the holder had “preliminarily agreed.”

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6. The Broader Group the FDA Says Needs More Study

Both September 2025 documents draw a line between the genetic condition and a much larger group. The press release states:

“CFD has also been reported in a broader patient population with neuropsychiatric symptoms, including autistic features, and detectable serum autoantibodies to the folate receptor alpha; however, there are limitations on the available data for the use of leucovorin in this population and additional studies are needed to assess safety and efficacy.”

Autoantibodies are antibodies the body makes against one of its own proteins; the folate receptor alpha is a protein that helps carry folate into the brain. The Federal Register notice says the same in shorter form: data on leucovorin “is limited in this population and additional studies are needed.” Published research on these autoantibodies in autism, and a randomized placebo-controlled trial of folinic acid in autistic children with language impairment, are listed under Key Research Papers below.

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7. What the Action Does Not Do

• It is not an approval of leucovorin as a treatment for autism. The September 2025 documents concern cerebral folate deficiency, and the FDA states that data for the broader group with autistic features and folate-receptor autoantibodies are limited. The indication approved in March 2026 is limited to cerebral folate deficiency in patients with a confirmed variant in the folate receptor 1 gene (see section 9).
• The September 2025 Federal Register notice did not itself add the cerebral folate deficiency indication. It reinstated the 1983 application; the new use was to come through a separate label supplement.
• It is not based on a new randomized trial. The FDA describes its evidence as a systematic review of published literature, case reports and mechanistic data, compared with the condition’s known natural history.
• It did not create a public comment period. The notice is an announcement of an approval, not a proposed rule; it invites no comments.

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8. What FDA Officials Said

The September 2025 release quoted two officials.

• The FDA Commissioner: “We have witnessed a tragic four-fold increase in autism over two decades. Children are suffering and deserve access to potential treatments that have shown promise. We are using gold standard science and common sense to deliver for the American people.”
• The Director of the FDA’s Center for Drug Evaluation and Research at the time: “This effort reflects the FDA’s commitment to identify opportunities to repurpose drugs to treat chronic diseases. The FDA remains committed to finding and treating the root causes of autism.”

The March 2026 release quoted the Commissioner calling the approval “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,” and adding: “This action may benefit some individuals with FOLR1-related cerebral folate transport deficiency who have developmental delays with autistic features.” The Acting Director of the Center for Drug Evaluation and Research said the 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.”

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9. Dates and Status as of 11 October 2026

• 22 September 2025 — FDA news release: approval process for cerebral folate deficiency initiated.
• 24 September 2025 — Federal Register notice: previously withdrawn tablet application approved again (final action).
• 10 March 2026 — later status. The FDA approved expanded use of leucovorin calcium tablets for the treatment of cerebral folate deficiency in adult and pediatric patients with a confirmed variant in the folate receptor 1 gene (CFD-FOLR1), calling leucovorin “the first treatment for the rare genetic condition of cerebral folate deficiency.” The release says the approval rested on a systematic review of the published literature, including case reports with patient-level information, and mechanistic data. It lists possible side effects as itching (pruritus), rash, hives (urticaria), shortness of breath (dyspnea), rigors (a sudden feeling of cold with shivering) and impaired temperature regulation, and describes anaphylaxis — a severe, rapid and potentially fatal allergic reaction — as a serious side effect requiring immediate medical attention.
• 10 April 2026 — later status. A further Federal Register notice (91 FR 18472, FR Doc. 2026-06911, Docket No. FDA-2026-N-0707) withdrew approval of NDA 018342, “and all amendments and supplements thereto,” as of 10 April 2026. The notice states that the application holder told the FDA in writing that the tablets were “no longer marketed” and asked for the withdrawal, and that withdrawal under this procedure is “without prejudice to refiling.” Tablets already in inventory on that date “may continue to be dispensed until the inventories have been depleted or the drug products have reached their expiration dates.” The notice does not discuss cerebral folate deficiency.

Status as of 11 October 2026: the September 2025 reinstatement was a final action, and the cerebral folate deficiency indication (CFD-FOLR1) was approved on 10 March 2026. According to the Federal Register, the approval of the application that carried that indication was then withdrawn at the holder’s request on 10 April 2026. The FDA documents reviewed for this page do not say how, or whether, the indication carries over to other leucovorin products.

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10. How It Fits the FDA’s Other 2025 Actions

The leucovorin release came out on 22 September 2025, the same day the FDA announced that it had begun a label change for acetaminophen use in pregnancy, citing studies of a possible association with autism and ADHD in children; that action is described on the FDA Starts an Acetaminophen-in-Pregnancy Label Change (2025) page. Both actions concern autism, but they are separate: one is a label warning for a widely used pain and fever medicine, the other a new use for an old folate drug in a rare condition.

Other drug-label actions of the year are listed on the FDA Actions of 2025 hub, including the ADHD stimulant label change for children under 6 and the opioid long-term-use label changes.

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11. Primary Documents

1. U.S. Food and Drug Administration (2025). FDA Takes Action to Make a Treatment Available for Autism Symptoms. FDA News Release, 22 September 2025 — fda.gov press announcement
2. Food and Drug Administration, HHS (2025). Approval of Previously Withdrawn New Drug Application for [the original brand of] (Leucovorin Calcium) Tablets. Federal Register 90:45944–45945, 24 September 2025. Docket No. FDA-2025-N-3959 — FR Doc. 2025-18510 (official PDF, govinfo.gov)
3. U.S. Food and Drug Administration (2026). FDA Approves First Treatment for Patients with Cerebral Folate Transport Deficiency. FDA News Release, 10 March 2026 (later status) — fda.gov press announcement
4. Food and Drug Administration, HHS (2026). [Application holder]; Withdrawal of Approval of a New Drug Application for [the original brand of] (Leucovorin Calcium) Tablets, EQ 5 mg Base and EQ 25 mg Base. Federal Register 91:18472, 10 April 2026. Docket No. FDA-2026-N-0707 (later status) — FR Doc. 2026-06911
5. Food and Drug Administration, HHS (2017). Determination that a meperidine injectable and other drug products, including these leucovorin calcium tablets, were not withdrawn from sale for reasons of safety or effectiveness. Federal Register 82:19735, 28 April 2017 — FR Doc. 2017-08582
6. Food and Drug Administration, HHS (1999). Withdrawal of Approval of 18 New Drug Applications and 44 Abbreviated New Drug Applications. Federal Register 64:51325, 22 September 1999 — FR Doc. 99-24595

Brand and company names that appear in the official titles are replaced with bracketed generic descriptions, following the site’s rule of naming no company or product.

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Key Research Papers

1. Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J (2005). Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. New England Journal of Medicine 352(19):1985-1991 — PubMed PMID: 15888699
2. Steinfeld R, Grapp M, Kraetzner R, Dreha-Kulaczewski S, Helms G, Dechent P, Wevers R, Grosso S, Gärtner J (2009). Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. American Journal of Human Genetics 85(3):354-363 — PubMed PMID: 19732866
3. Grapp M, Just IA, Linnankivi T, Wolf P, Lücke T, Häusler M, Gärtner J, Steinfeld R (2012). Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. Brain 135(Pt 7):2022-2031 — PubMed PMID: 22586289
4. Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA (2013). Cerebral folate receptor autoantibodies in autism spectrum disorder. Molecular Psychiatry 18(3):369-381 — PubMed PMID: 22230883
5. Frye RE, Slattery J, Delhey L, Furgerson B, Strickland T, Tippett M, Sailey A, Wynne R, Rose S, Melnyk S, Jill James S, Sequeira JM, Quadros EV (2018). Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Molecular Psychiatry 23(2):247-256 — PubMed PMID: 27752075
6. Rossignol DA, Frye RE (2021). Cerebral folate deficiency, folate receptor alpha autoantibodies and leucovorin (folinic acid) treatment in autism spectrum disorders: a systematic review and meta-analysis. Journal of Personalized Medicine 11(11):1141 — PubMed PMID: 34834493

The 2021 review is the subject of a published correction (Journal of Personalized Medicine 2022;12(5), PubMed PMID: 35629273). Papers 1, 4, 5 and 6 concern the broader group with folate-receptor autoantibodies that the FDA says needs more study; papers 2 and 3 concern the genetic FOLR1 form covered by the 2026 approval.

PubMed Topic Searches

1. PubMed: cerebral folate transport deficiency and FOLR1
2. PubMed: folinic acid and cerebral folate deficiency
3. PubMed: folate receptor alpha autoantibodies and autism

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Connections

• FDA Actions of 2025
• FDA and Regulation
• FDA Starts an Acetaminophen-in-Pregnancy Label Change (2025)
• FDA Label Change for Extended-Release ADHD Stimulants Under Age 6 (2025)
• FDA Requires New Opioid Labeling on Long-Term Use (2025)
• Vitamin B9
• Folate for Methylation & Homocysteine
• Folate Test
• Autism
• Autism Spectrum Disorder (ASD)

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