Tacrolimus

To approve leucovorin as the first treatment for CFD-FOLR1, the FDA took several highly unusual steps. About five months after U.S. Department of Health and Human Services Secretary Robert F. Kennedy Jr. touted leucovorin as “an exciting therapy that may benefit large numbers of children who suffer from autism” during a White House press conference, the FDA has approved the decades-old drug for a rare genetic condition with “autistic features” that represents a small subset of autism patients.The FDA has approved GSK’s brand-name leucovorin calcium tablets, Wellcovorin, to treat cerebral folate deficiency (CFD) but only in patients who have a confirmed variant in the folate receptor 1 (FOLR1) gene.CFD-FOLR1 is an ultrarare genetic form of CFD, which is present in some children with autism spectrum disorder, affecting, according to a senior FDA official, less than 1 in a million people. CFD is a neurological condition characterized by the inability of folate to cross the blood-brain barrier, leading to symptoms such as seizures, motor issues and intellectual disability. Besides FOLR1 mutation, other causes of CFD include autoantibodies blocking the folate receptor. A limited indication The patient population for CFD-FOLR1, or FOLR1-related cerebral folate transport deficiency (FOLR1-CFTD), is far smaller than the broad group originally touted by U.S. health leaders as potential candidates for leucovorin.The FDA was changing the label of leucovorin to make it available so “hundreds of thousands of kids” with autism could benefit, FDA Commissioner Marty Makary, M.D., said during a White House press conference Sept. 22, 2025. The FDA commissioner went on to highlight a study in which, according to him, “two-thirds of kids with autism symptoms had improvement and some marked improvement” after receiving leucovorin.Following U.S. health leaders’ bold claims, however, the American Academy of Pediatrics came out saying it would not recommend the routine use of leucovorin in children with autism, citing “too limited” evidence to support its use in a broad autism population. In its most recent guidance updated Feb. 13, 2026, the physicians’ organization maintained the language that more research of larger trials is needed to determine whether leucovorin is safe and effective in autism and in which subgroups it may be most beneficial.  The Coalition of Autism Scientists also pointed to the lack of scientific evidence linking leucovorin as an effective treatment for autism. Now, in a March 10 statement, Makary said the approval of leucovorin may benefit “some individuals with FOLR1-related cerebral folate transport deficiency who have developmental delays with autistic features.”The FDA did consider whether existing data support a broad label in autism, but, after a “systematic review,” the agency’s reviewers determined that the FOLR1 subpopulation has “the highest quality data,” a senior FDA official told reporters on a press call.  “We narrowed in on that population just because we felt like that was the strongest, both scientific rationale and also the largest treatment effects, that could be used to then overcome some of the limitations in the data sources,” she added.As a small molecule, leucovorin falls in the purview of the FDA’s Center for Drug Evaluation and Research (CDER), which is led by acting director Tracy Beth Høeg, M.D., Ph.D.To approve leucovorin as the first treatment for CFD-FOLR1, the FDA took several highly unusual steps. Unusual moves by the FDAInstead of a clinical trial, the FDA based its decision on published literature, including real-world case reports, as well as leucovorin’s mechanism. According to the updated Wellcovorin label (PDF), the FDA identified 46 patients with CFD-FOLR1 (FOLR1-CFTD) who received leucovorin treatment via various administration routes in past case reports. Among 27 patients who got oral leucovorin only, the FDA label describes “a range of clinical improvements in various neurological symptoms” for 24 (89%) individuals, while the remaining three showed either no change or no progression of symptoms. These improvements include reduction in severity or number of seizures; improvements in motor function, communication, and/or behavior. The patients were about 2 months to 33 years of age at the time of treatment initiation.“[B]oth the observed clinical improvements and the lack of disease progression are unexpected when compared to the progressive natural history of these patients with FOLR1-CFTD,” the label shows.In the historical dataset, CFD-FOLR1 patients who took leucovorin had a clinical response rate of 87%, which was corroborated with normalization in 80% of their laboratory levels of 5-MTHF, a bioavailable form of folate, in the cerebral spinal fluid, another senior FDA official said on the press call.Leucovorin is itself a form of folic acid that can cross the blood-brain barrier, making it plausible to address folate deficiency in the central nervous system, the FDA official said. While unorthodox, the FDA has handed out approvals based on real-world evidence in the past. In 2019, based on data from electronic health records and postmarketing reports of real-world use, the FDA cleared Pfizer’s Ibrance (palbociclib) as part of a regimen for men with HR-positive, HER2-negative breast cancer. In 2021, the FDA approved Astellas’ Prograf (tacrolimus) as part of a combination to prevent organ rejection in patients receiving lung transplants. The approval was based on real-world data from the U.S. Scientific Registry of Transplant Recipients.Randomized controlled clinical trials in general provide the strongest scientific evidence, but it would be very challenging to conduct such a study in an ultrarare condition like CFD-FOLR1, the first FDA official said on the press call. “We were also willing to work with this data because we do know that there is a strong scientific and mechanistic rationale for why leucovorin would be expected to work in this condition,” the official added. “And we felt that we what we heard or saw in the literature was that there were really large and substantial improvements reported with the treatment with leucovorin.”On the call, the other senior officials explained the lack of a clinical trial as fitting with the FDA’s newly announced plausible mechanism pathway, which is meant to enable approvals for individualized therapies, mainly based on gene editing.“This medication directly addresses the deficiency that we’re seeing with this disease, and then the response that we saw to the administration of the medication really diverged from what we see with the natural history of the disease,” the official said, while also noting that conducting a placebo-controlled clinical trial in such an ultrarare disease “would become unethical.”The plausible mechanism pathway as described by the FDA is meant for bespoke therapies that address the underlying cause of disease and use natural history data to demonstrate a clinical benefit. Leucovorin is not personalized to individual patients in any way.The CDER’s sister department at the FDA, the Center for Biologics Evaluation and Research (CBER), has come under fire for its handling of rare disease therapies, even for those that also seem to meet some criteria for the plausible mechanism pathway. UniQure’s gene therapy for Huntington’s disease has been turned away by the CBER despite targeting a defined genetic cause, showing clinical benefit in several patients and using a well-characterized natural history control arm. In explaining the decision to reject uniQure’s proposal of comparing phase 1/2 results to natural history data to support a submission, CBER Director Vinay Prasad, M.D., previously indicated to Fierce that uniQure’s therapy is not tailored for each individual, making it unfit for the plausible mechanism pathway.  In another unusual step to approve leucovorin, the FDA proactively reached out to GSK, which originally developed Wellcovorin for other uses such as certain anemia and reducing toxic side effects of chemotherapy. The British pharma, at the request of the FDA, submitted the case reports data identified by the agency to enable a label update. However, GSK has long discontinued Wellcovorin, and a GSK spokesperson confirmed to Fierce Pharma that the company will not be manufacturing Wellcovorin after the latest approval. Still, there are other generic leucovorin versions available. Because generics must maintain the same label as the originator—unless there are intellectual property restrictions—the FDA’s approval for Wellcovorin in CFD-FOLR1 will apply to all generic leucovorin as well.Despite warnings from the scientific community, leucovorin prescriptions for children aged 5 to 17 years surged by 71% in about 11 weeks following the White House event in September, according to a study published in The Lancet.“Although causal claims cannot be made, the observed associations are consistent with influence of new FDA recommendations on clinical decisions,” the researchers noted.The FDA is allowing importation of leucovorin from other manufacturers outside of the U.S., and the drug is currently not on the agency’s shortage list, one of the senior FDA officials said on the press call. “If demand continues to increase, we are in discussion with other companies to allow for importation and also for existing manufacturers to increase their manufacturing,” she said.