Leucovorin (Wellcovorin), a drug used to treat cerebral folate deficiency, will be used off-label for autism without evidence, doctors warned.
"There is no substantive evidence that cerebral folate deficiency plays a role in the pathogenesis of autism," wrote Bruce Chabner, MD, of the Mass General Brigham Cancer Institute in Boston, and David Goldman, MD.
Leucovorin, also known as folinic acid, is a type of folate used with cancer drugs like methotrexate to counteract their toxic effects. It can cross into the brain even when folate transport is impaired.
Interest in treating autism with leucovorin is based mainly on the presence of autoantibodies to the FOLR1 protein in autistic persons and the implication that these antibodies impair folate transport into cerebrospinal fluid (CSF), Goldman and Chabner noted.
However, evidence supporting this mechanism is lacking, they wrote in a perspective article in the New England Journal of Medicine.
The article was prompted by an announcement from FDA Commissioner Marty Makary, MD, MPH, on Sept. 22, 2025, that stressed the importance of investigating leucovorin for autism in general, Chabner said.
"The approval statement for leucovorin calcium tablets, issued 2 days later, however, didn't apply to autism -- only to a rare hereditary disorder, FOLR1-related cerebral folate transport deficiency, for which leucovorin has been shown to be an effective treatment," Goldman and Chabner wrote.
"The approval was for a very narrow indication. There really isn't any good evidence for the role of leucovorin in most cases of autism," Chabner told MedPage Today.
Autism has many etiologies, Chabner noted. "A very small group of people with folate transport mutations display some autistic symptoms in the early phases of their illness. If they're untreated, they go on to develop global neurologic problems," he said.
But that's not the same as autism, Chabner pointed out. "The promotion of leucovorin by HHS Secretary Robert F. Kennedy Jr. and "this preliminary announcement 2 days before the approval are likely to induce people to use leucovorin for an unapproved use," he said.
"Leucovorin is potentially in short supply for its approved uses," he added. "It's always been a problem, and if a million people start using it for autism, not only are they using it for something that's unproven, but they're compromising its use for its proven uses, which is to support chemotherapy."
Helen Tager-Flusberg, PhD, of Boston University and the founder of the Coalition of Autism Scientists, a group of more than 250 autism researchers, called the opinion piece important in laying out key concerns about prescribing leucovorin to children with autism. "Unfortunately," she said, "the warnings expressed by the authors are already too late, as clinicians around the country have been bombarded by requests for prescriptions by parents."
The perspective article "perfectly summarizes the concerns of the medical and scientific community about leucovorin for autism: we lack data on efficacy, safety, or long-term consequences of the drug," said Shafali Jeste, MD, of the David Geffen School of Medicine at UCLA.
"Without robust clinical trials and long-term safety data, we must remain cautious about its use," Jeste told MedPage Today. "I have spoken with many parents whose children were prescribed the medication and now are experiencing side effects or lack of efficacy, and they now face uncertainty about next steps."
Cerebral folate deficiency is caused by a low level of 5-methyltetrahydrofolate (5-MTHF) in CSF due to a disruption in the function of the folate receptor alpha. It is diagnosed by assessing 5-MTHF levels in CSF through a lumbar puncture.
In the small number of autism patients with FOLR1 autoantibodies in whom CSF folate has been measured, levels were within the normal range, Goldman and Chabner said.
This contrasts with "the extremely low CSF folate levels documented in untreated children" with one of two inherited cerebral folate transport deficiency disorders -- either FOLR1-cerebral folate transport deficiency due to a mutation in the folate receptor alpha gene, or hereditary folate malabsorption due to proton-coupled folate transporter (PCFT) gene mutations, they wrote.
The proposition that FOLR1 autoantibodies indicate low CSF folate levels "rests entirely on 16 patients" reported in a 2013 study, Goldman stated. "And on this basis, it is proposed that a diagnosis of cerebral folate deficiency can be made without measuring CSF folate levels," he told MedPage Today.
The Coalition of Autism Scientists reviewed leucovorin studies and concluded there was lack of scientific evidence establishing the drug as a safe and effective autism treatment. The coalition called for a well-designed, large scale clinical trial of leucovorin "with all of the rigor needed (biomarkers, proper endpoints) and most importantly a pre-registered analysis plan."
The American Academy of Pediatrics (AAP) issued interim guidance in October stating it does not recommend the routine use of leucovorin for autistic children.
Children with autism deserve the same level of evidence to support interventions for them as anyone else, noted Kristin Sohl, MD, of the AAP Council on Children with Disabilities Executive Committee. "Unfortunately, the data isn't strong enough to make a strong recommendation one way or the other for a treatment like leucovorin and to know whether that's going to improve outcomes for most, or even many, autistic kids," Sohl told MedPage Today.
Disclosures
Goldman had no disclosures.
Chabner reported relationships with AbbVie, Agilent, Alnylam, Blueprint, BridgeBio, Chugai, CRISPR Technologies, EMD Serono, Immunogen, Jazz, Kura Oncology, Marengo, PharmaMar, Relay Therapeutics, Revolution Medicines, Sanofi, Seagen, Springworks, Syndax, and Takeda Oncology.
No comments:
Post a Comment
Note: Only a member of this blog may post a comment.