FDA retracts support for leucovorin for autism

The prescription drug leucovorin is receiving a label update, but it's not what the U.S. Food and Drug Administration (FDA) suggested during a briefing at the White House in September, when officials touted the drug as a potential treatment for thousands of children with autism. This Tuesday, the FDA approved high-dose vitamin B, a treatment long used to counteract the side effects of chemotherapy, for cerebral folate deficiency in the receptor 1 gene, a genetic condition estimated to affect approximately 1 in every million people. Fewer than 50 cases have been identified worldwide. Dr. Marty Makary, FDA commissioner, called Tuesday's approval a "significant milestone" for patients with this condition. But in September, Makary and U.S. Secretary of Health and Human Services Robert F. Kennedy Jr. indicated that the medication would be available to help many more children. Alongside President Donald Trump at a briefing in the White House, Kennedy stated that they had identified a promising therapy that could benefit a large number of children with autism. The update on leucovorin could especially affect some families with autistic children. In the September briefing, when Trump made unfounded claims about the pain reliever Tylenol as a cause of autism and warned parents about vaccinating their children too much, the president stated that changing the leucovorin label "gives hope to the numerous parents with autistic children that it is possible to improve their lives".

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In the months since then, leucovorin prescriptions increased, making the drug difficult to obtain.

Approved medication for rare disease, not for autism
With folate receptor 1 gene cerebral folate deficiency, a defect causes a malfunction of the proteins that guide folate to the brain. As a result, normal levels of folate are maintained in the blood, but not in the brain or nervous system, where it is essential for thinking, speech, and movement.

In an opinion article published in Politico and republished on the White House website last fall, Makary said his agency would "approve prescribed leucovorin as a treatment for children with cerebral folate deficiency and autistic symptoms." Makary said in the televised press conference that between 20% and 50% of children with autism could produce antibodies that block the proteins that help transport folate to their brains, which means that some of the most severe symptoms of autism could be caused by an autoimmune disease. Although it was noted that leucovorin was not a cure for autism, Makary highlighted small studies showing that among children with folate deficiency and autism, it could improve speech in approximately 60%. The Trump administration was making a bold decision to expand the use of the drug, “opening the door to the first FDA-recognized treatment for autism,” wrote Makary and other HHS leaders. Senior FDA officials said in a briefing on Monday that while the data was solid enough to approve the use of leucovorin for rare genetic cases of folate deficiency in the brain, they could not find enough evidence that it would help children with autism or other causes of cerebral folate deficiency. "At this time we do not have enough data to say that we can establish efficacy for autism more broadly," said a senior agency official. They really wanted a review of the data to support the potential approval for some forms of autism. And in this case, the review was done as requested, and the data we had supported the approval for this specific indication, i.e., the rare genetic form of folate deficiency, said another senior FDA official. Officials also noted that the largest randomized, double-blind, placebo-controlled trial to test the drug in children with autism was recently retracted after errors were identified in the data reported in the study. "The damage is already done"
In the weeks following the September press conference at the White House, new leucovorin prescriptions doubled, according to a study published this month in the medical journal Lancet. The parents had difficulty obtaining the medication; some described the complexity of finding providers and pharmacies that could help them. In some cases, they resorted to unregulated, over-the-counter folate supplements when they could not obtain the prescription version. The study's author, Dr. Jeremy Faust, an emergency physician at Brigham and Women's Hospital, told CNN last week that the evidence that leucovorin treats autism is scant and does not warrant a change in practice, but he was not surprised to see an increase in prescriptions. "I think the White House lectern is a very powerful place and people listen to our leaders, even though RFK says things like 'don't take my medical advice,'" Faust said. Dr. I. David Goldman, a retired professor of medicine and medical pharmacology at the Albert Einstein College of Medicine, author of articles on this ultra-rare form of folate deficiency, stated that there is no overlap between the rare genetic form of folate deficiency in the brain and autism. He added that doctors have been using leucovorin to treat this rare folate deficiency since 2009, when the condition was first identified. It's good to be clear about where the evidence for this treatment lies, he said. "But, you know, the damage is already done, because parents with autistic children are desperate," Goldman said. When asked on Monday if the FDA planned to further investigate whether leucovorin could help some children with autism by conducting its own studies, senior officials said that while there might be other federal efforts underway to support such research, none were being conducted at the agency. "The FDA does not conduct clinical trials and, although we have some funding mechanisms, we do not typically fund large-scale clinical trials on drugs and autism," said an official. Beyond its limited scope, Tuesday's approval was also unusual because it was based on a systematic review of the literature, "including cases published with patient-level information, as well as mechanistic data." Normally, the FDA requires randomized, placebo-controlled clinical trials to demonstrate that drugs are safe and effective before they can be approved or their use expanded. But senior officials said on Monday that because this folate deficiency is so rare, it would be difficult to test leucovorin in randomized placebo-controlled trials with people who have it. In case studies, children with the genetic defect and cerebral folate deficiency experienced significant improvements when taking leucovorin. "These children were ceasing to have seizures or, if they were given the vaccine in time, they became completely asymptomatic from a clinical point of view," said a senior FDA official.

“That would really make it difficult to conduct a randomized controlled trial, because of this very dramatic response to the treatment, simply because it would be unethical, after we’ve already seen such a dramatic response, to randomly assign people to the placebo,” the official said.

It's a response often used to explain why it may be unethical to conduct randomized controlled trials of new versions of vaccines already in use.