Listen to the article
FDA Adjusts Leucovorin Approval for Rare Genetic Condition, Not Broad Autism Treatment
The Food and Drug Administration on March 10 modified the approval for a version of the prescription drug leucovorin to include people with an extremely rare genetic condition, contradicting earlier claims by FDA Commissioner Dr. Marty Makary that the change would benefit “hundreds of thousands of kids” with autism.
The newly approved indication specifically targets a genetic version of cerebral folate deficiency (CFD), caused by mutations in a folate receptor gene. People with this condition have low folate levels in their cerebrospinal fluid, which affects brain development, leading to developmental delays, movement disorders and seizures. Some patients exhibit behaviors similar to those associated with autism.
According to the FDA, genetic CFD affects approximately one in a million people—translating to around 70 children in the United States, far below the “hundreds of thousands” Makary had suggested. Furthermore, leucovorin had already been commonly prescribed off-label for genetic CFD for decades, a standard practice when evidence shows a drug approved for one condition can help another.
During a September 22 press conference alongside President Donald Trump, Makary had characterized the change much more broadly: “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. We are going to change the label to make it available. Hundreds of thousands of kids, in my opinion, will benefit.”
This same press conference featured unsubstantiated claims linking autism to Tylenol (acetaminophen) use during pregnancy. Dr. Mehmet Oz, administrator for the Centers for Medicare & Medicaid Services, stated the FDA “is approving prescription leucovorin for treatment of autistic children,” while Health and Human Services Secretary Robert F. Kennedy Jr. suggested it “may benefit large numbers of children who suffer from autism.”
However, the Federal Register notice actually described data on the rare genetic form of CFD. It specifically noted that data on leucovorin for people with “autistic features” and antibodies targeting the folate receptor “is limited” and that “additional studies are needed.”
Dr. George Tidmarsh, then-head of the FDA’s drugs division, later clarified that the new indication was exclusively for the rare genetic condition: “We’re not proposing to approve leucovorin for [people with] the diagnosis of autism,” he told the autism publication the Transmitter in October.
When questioned about the discrepancy between Makary’s earlier statements and the final FDA approval, an HHS spokesperson explained that Makary had been referring to antibody-related CFD rather than the genetic disorder. However, the scientific consensus does not support claims that CFD plays a significant role in autism or that large numbers of people with autism would benefit from leucovorin treatment.
In a January perspective in the New England Journal of Medicine, two researchers with expertise in folate and cancer treatment wrote: “There is no substantive evidence that cerebral folate deficiency plays a role in the pathogenesis of autism.” They added that despite claims about antibodies against folate receptors in autism, most experts consider this conclusion “inconclusive.”
The new approval was granted for GSK’s Wellcovorin, a brand-name version of leucovorin that has long been off patent and is no longer manufactured by the company. Generic versions remain available. The drug is primarily used to reduce toxicity or improve effectiveness in certain chemotherapy regimens.
Despite clarifying that the focus was on the rare genetic form, Makary continued making sweeping claims about leucovorin’s benefits for autism after the September announcement. In media appearances, he suggested that “20% to 50% of kids with severe autism” or even “50% or 60% of kids with autism” might benefit.
Experts strongly disagree. David S. Mandell, a psychiatry professor at the University of Pennsylvania Perelman School of Medicine, described the evidence for leucovorin as an autism treatment as “very weak.” Other researchers characterized the literature as “meager” and called administration recommendations for autism treatment “extremely premature.”
One of the larger studies on leucovorin in autism has since been retracted due to concerns about its data and statistical analysis. The American Academy of Pediatrics has emphasized that “larger, well-designed, multisite trials using objective outcome measures are necessary” to determine safety and effectiveness.
Despite these uncertainties, Makary’s statements appear to have significantly influenced prescribing patterns. New outpatient prescriptions of leucovorin increased by 71% in children ages 5 and older in the months following the September announcement, according to a recent study published in the Lancet.
Fact Checker
Verify the accuracy of this article using The Disinformation Commission analysis and real-time sources.
13 Comments
It’s a shame the FDA couldn’t find stronger justification for a broader autism indication, but I understand their hesitation given the complex nature of autism. Hopefully continued research will uncover more effective treatments in the future.
Agreed. The causes and manifestations of autism are still not fully understood. The FDA likely wants to avoid prematurely approving a treatment without clear evidence of its efficacy and safety for the broader autism population.
This case highlights the challenges the FDA faces in balancing patient needs, scientific evidence, and potential risks. While the earlier commissioner’s comments raised expectations, the agency appears to have taken a measured approach based on the data. Approving treatments for rare genetic conditions is still valuable, even with small patient numbers.
This is an interesting case study in the challenges of drug approvals, especially for complex conditions like autism. While the earlier commissioner’s comments raised hopes, the FDA appears to have taken a prudent, data-driven approach. Approving treatments for rare genetic conditions like CFD is still valuable, even with small patient numbers. Continued research will be key to unlocking more effective therapies.
The FDA’s focus on the specific patient population for the leucovorin indication is understandable, given the complex nature of autism. Approving a treatment without robust clinical evidence could do more harm than good, even if it raises hopes initially. Continued research will hopefully uncover more effective therapies in the future.
While the FDA’s decision may disappoint some, it’s good to see them taking a rigorous, science-based approach. Approving treatments for rare genetic conditions like CFD is also important, even if the patient numbers are low. Balancing these priorities is tricky but necessary.
The FDA’s decision to limit the leucovorin approval to the rare genetic condition of CFD, rather than a broad autism indication, demonstrates their commitment to an evidence-based approach. Approving treatments for complex, heterogeneous conditions like autism without strong data could have unintended consequences. Hopefully further research will unlock more effective therapies in the future.
While the FDA’s decision may disappoint some, it’s good to see them taking a rigorous, evidence-based approach. Approving treatments for rare genetic conditions like CFD is important, even if the patient numbers are small. Balancing these priorities is not always easy, but necessary to ensure patient safety and efficacy.
This is an interesting case study in the FDA’s approval process. While the earlier commissioner’s comments raised hopes for a broader autism treatment, the agency appears to have taken a more cautious, data-driven approach. Approving treatments for rare genetic conditions is still valuable, even with small patient numbers.
Interesting development. While the FDA’s decision may disappoint some, it seems they are taking a cautious and evidence-based approach to approving new indications. Rare genetic conditions like CFD deserve attention, even if the patient population is small.
You make a fair point. The FDA has to weigh the potential benefits against the strength of the evidence. Approving a drug for a broader population without robust data could do more harm than good.
The FDA’s focus on the evidence and specific patient population for the leucovorin indication seems prudent. It’s understandable they would want to avoid overstating the potential benefits, especially for a complex condition like autism. Continued research will hopefully uncover more effective therapies down the line.
The FDA’s decision to limit the leucovorin approval to the rare genetic condition of CFD, rather than a broad autism indication, is likely rooted in their need for robust clinical evidence. Approving a treatment for a complex, heterogeneous condition like autism without strong data could do more harm than good. Hopefully further research will unlock more effective therapies.