The Food and Drug Administration on March 10 changed the approval for a version of the prescription drug leucovorin to include people with a very rare genetic condition. FDA Commissioner Dr. Marty Makary had previously implied that the drug’s new label would cover a much broader group of people with autism, saying that “hundreds of thousands of kids” would benefit.
The condition targeted in the FDA approval is a genetic version of cerebral folate deficiency, caused by mutations in a folate receptor gene. People with CFD — whether from genetic or other causes — have low levels of folate in their cerebrospinal fluid, which leads to reduced folate in the brain. This affects brain development. Patients with genetic CFD can experience developmental delays, movement disorders and seizures. Some behaviors are similar to those with autism.
However, this form of genetic CFD is estimated to occur in 1 in a million people, according to the FDA. That would translate to around 70 kids in the U.S. — far from “hundreds of thousands of kids.” Leucovorin had already been used for decades to treat genetic CFD via off-label prescribing, a common practice when evidence shows a drug approved for one condition improves another.
Despite this limited approval, Makary had initially implied a more substantial change. “Today the FDA is filing a Federal Register notice to change the label on an exciting treatment called prescription leucovorin so that it can be available to children with autism,” Makary said in a Sept. 22 press conference. “We are going to change the label to make it available,” he went on to say. “Hundreds of thousands of kids, in my opinion, will benefit.”
This was the same press conference in which President Donald Trump and others touted an unproven link between autism and the use of Tylenol, or acetaminophen, during pregnancy.
Makary later referred to a subset of people with autism with antibodies that block their own folate receptors, called autoantibodies. Some researchers have hypothesized that a subset of people with autism have CFD caused by these autoantibodies, but this is not well-established, as we will explain.
The FDA “is approving prescription leucovorin for treatment of autistic children,” Dr. Mehmet Oz, administrator for the Centers for Medicare & Medicaid Services, said at the same event. Health and Human Services Secretary Robert F. Kennedy Jr. said the treatment “may benefit large numbers of children who suffer from autism.” He had previously vowed by September to identify “what has caused the autism epidemic.”
The Federal Register notice Makary referred to described data on the rare genetic form of CFD, however. The notice also stated that data on leucovorin for people who have symptoms with “autistic features” along with antibodies targeting the receptor “is limited” and that “additional studies are needed.”
The then-head of the FDA’s drugs division, Dr. George Tidmarsh, also subsequently clarified that the new indication was the rare genetic one. “We’re not proposing to approve leucovorin for [people with] the diagnosis of autism,” he told the autism publication the Transmitter in an interview for a story published Oct. 2.
When asked this week about the discrepancy between Makary’s earlier comments about broad benefits for kids with autism and the ultimate FDA approval for a rare genetic condition, a spokesperson from the Department of Health and Human Services told us that Makary previously had been talking about an antibody-related form of CFD, and not the rare genetic disorder.
“Dr. Makary was referring to cerebral folate deficiency — which can be caused by antibodies blocking folate receptors — rather than cerebral folate transport deficiency, which is caused by a specific genetic mutation,” the HHS spokesperson wrote in an email.
However, as we’ve said, the idea that a large subset of people with autism have CFD and can benefit from leucovorin has not been well-established.
“There is no substantive evidence that cerebral folate deficiency (CFD) plays a role in the pathogenesis of autism,” two researchers with expertise in folate and cancer treatment wrote in a January perspective in the New England Journal of Medicine. They also said that despite claims that antibodies against folate receptors play a role in autism, most experts consider this conclusion to be “inconclusive.” They added that the presence of the antibodies doesn’t necessarily mean that folate is low in the cerebrospinal fluid, which is the defining feature of CFD.
The new approval was for GSK’s Wellcovorin, a brand-name version of leucovorin that has long been off patent and that is no longer made by the company. Leucovorin remains available in generic versions. It is mainly used for cancer patients alongside certain chemotherapy regimens to reduce toxicity or to improve effectiveness.
Unsupported Claims About Broad Benefits in Autism
While clarifying that Makary’s remarks about broad benefits applied to a different form of CFD, the HHS spokesperson also said that the rare genetic form of CFD “was the focus of the September announcement about this drug.”
But during the Sept. 22 press conference and subsequent media appearances, Makary repeatedly emphasized potentially sweeping benefits of the new leucovorin label.
“For many kids with autism, it will provide some improvement in their symptoms, and for some subset, marked improvement,” Makary said in a Sept. 22 NewsNation interview, urging people to talk to their doctors. “There are 2.5 million kids suffering, and I hope hundreds of thousands of them will see some improvement with this new treatment that we’re going to approve in about two to three weeks,” he went on to say.
“I think the biggest story today was that the FDA is taking action to make leucovorin available to kids with cerebral folate deficiency,” he told ABC News that same day. “That may be 20% to 50% of kids with severe autism, and they have a clinical improvement in studies.” In a Sept. 25 interview on C-Span, he gave an even larger estimate, saying “we are going to approve a drug called leucovorin for the treatment of autism” and that it “may help 50% or 60% of kids with autism.”
There is very limited evidence to support the assertion that wide groups of kids with autism could benefit, as we wrote in September. David S. Mandell, a psychiatry professor at the University of Pennsylvania Perelman School of Medicine and director of the Penn Center for Mental Health, told us then that the evidence on leucovorin “as a treatment for autism is very weak.”
Other researchers told the Transmitter in September that the literature on autism and leucovorin was “meager” and that it would be “extremely premature” for the administration to recommend the treatment for autism.
“These leucovorin studies are small, lack validated biomarkers or outcome measures, and certainly are not generalizable to all children with autism,” Dr. Shafali Jeste, a neurologist at UCLA, told the Transmitter. “The over-simplified conclusions and media hype from these studies take advantage of vulnerable families who are searching for answers and hope.”
At the time, this evidence included a small collection of studies that looked at the impact of leucovorin on communication and other characteristics in children with autism. One of these studies — among the largest, with 80 participants recruited — has since been retracted due to concerns about its data and statistical analysis, according to a notice on the journal website. Another of the studies had been terminated for “investigator non-compliance,” although the authors still published results.
“Larger, well-designed, multisite trials using objective outcome measures are necessary to determine whether leucovorin is safe and effective in autism and in which subgroups it may be most beneficial for,” says an FAQ page from the American Academy of Pediatrics.
Despite these uncertainties and the lack of a broad approval, people appear to have heeded Makary’s advice to talk to their doctors about leucovorin. New outpatient prescriptions of the drug increased by 71% in children ages 5 and older in the first couple of months following the September announcement, according to a study published March 5 in the Lancet.
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