FDA approves leucovorin for rare genetic condition, but not for autism

(CNN) — The prescription drug leucovorin is getting a label update, but it’s not what that the US Food and Drug Administration suggested during a White House briefing in September, when officials touted the drug as a potential treatment for thousands of children with autism. On Tuesday, the FDA approved the high-dose B vitamin — a treatment long used to counteract the side effects of chemotherapy — for cerebral folate deficiency in the receptor 1 gene, a genetic condition that’s estimated to affect only about 1 in 1 million people. Fewer than 50 cases have ever been identified worldwide. FDA Commissioner Dr. Marty Makary called Tuesday’s approval “a significant milestone” for patients with the condition. But in September, Makary and US Health and Human Services Secretary Robert F. Kennedy Jr. indicated that the drug would be available to help many more children. Standing alongside President Donald Trump at a White House briefing, Kennedy said they had “identified an exciting therapy that may benefit large numbers of children who suffer from autism.” The update on leucovorin may hit some families of children with autism especially hard. At the September briefing — when Trump made unsupported claims about the painkiller Tylenol as a cause of autism and cautioned parents about getting too many vaccines for their kids — the president said changing the label on leucovorin “gives hope to the many parents with autistic children that it may be possible to improve their lives.” In the months since, leucovorin prescriptions surged, making the drug hard to find.

Drug approved for rare condition, not autism

With cerebral folate deficiency in the receptor 1 gene, a defect causes proteins that guide folate into the brain to malfunction. The result is normal levels of folate in the blood but not in the brain and nervous system, where it’s important for thinking, speech and movement. In an op/ed published in Politico and reposted on the White House website last fall, Makary said his agency would “approve prescription leucovorin as a treatment for children with cerebral folate deficiency and autistic symptoms.” Makary said in the televised briefing that between 20% and 50% of children with autism might make antibodies that block the proteins that help ferry folate into their brains – meaning some of the more severe symptoms of autism might be caused by an autoimmune condition. Although he 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 for roughly 60%. The Trump administration was making a bold move to expand the use of the drug, “opening the door to the first FDA-recognized treatment for autism,” Makary and other HHS leaders wrote. Senior FDA officials said in a briefing Monday that while the data was strong enough to approve use of leucovorin for the 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. “Right now, we don’t have sufficient data to say that we can establish efficacy for autism more broadly,” a senior agency official said. “They really wanted a review of the data to support potential approval for some forms of autism. And in this case, the review was performed as was asked for, and the data that we had supported the approval for this specific indication,” meaning the rare genetic formof the folate deficiency, anothersenior FDA official said. The 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 done’

In the weeks after the September White House briefing, new prescriptions for leucovorin doubled, according to a study published this month in the Lancet medical journal. Parents had trouble getting the drug, with some describing complicated searches for providers and pharmacies that could help. In some cases, people turned to unregulated over-the-counter folate supplements when they couldn’t get the prescription version. Study author Dr. Jeremy Faust, an emergency medicine physician at Brigham and Women’s Hospital, told CNN last week that the evidence for leucovorin to treat autism is thin and didn’t warrant a shift in practice, but he wasn’t surprised to see prescriptions spike. “I think that the White House lectern is a very powerful place, and people do listen to our leaders, even though RFK says things like ‘don’t take medical advice from me,’ ” Faust said. News of the FDA’s shift on leucovorin was a blow to some parents, including Meagan Johnson, a mom in Pflugerville, Texas, who recently struggled to find the medication for her 3-year-old son Jack. “I’m upset and more than just mad, I’m hurt,” Johnson said on Tuesday. “I’m frustrated with the administration. I’m tired of them coming out and prematurely saying things without the information to back it.” “I feel like I just fought really hard,” to get the drug for her son. Now, she said she wonders if his doctor — or any doctor — will continue to prescribe it. She also worries that insurance may stop covering it. She believes it’s helping. Jack has been on the medication for two weeks and he has started saying the names of his classmates, something he hadn’t done before and using words instead of just babbling. “To me, it’s working. It’s working for Jack, and I wasn’t expecting to see it this quickly,” she said. Dr. I. David Goldman, a retired professor of medicine and medical pharmacology at the Albert Einstein College of Medicine who’s written papers on this ultrarare form of folate deficiency, said there’s no overlap between the rare genetic form of folate deficiency in the brain and autism. He said doctors have been using leucovorin to treat the rare folate deficiency since 2009, when the condition was first identified. It’s good to set the record straight on where the evidence stands on this treatment, he said. “But, you know, the damage is done, because parents with autistic kids are desperate,” Goldman said. Asked on Monday whether the FDA planned to further probe whether leucovorin might help some children with autism by doing its own studies, the senior officials said that while there might be other federal efforts underway to support such research, none was being done at the agency. “The FDA does not run clinical trials, and although we do have some funding mechanisms, we typically don’t fund large clinical trials for drugs and autism,” one official said. Beyond its narrow scope, Tuesday’s approval was also unusual because it was based on a systematic literature review, “including published case reports with patient-level information, as well as mechanistic data.” Typically, the FDA requires randomized, placebo-controlled clinical trials to show that drugs are safe and effective before they can be approved or their use is expanded. But the senior officials said 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 gene defect and cerebral folate deficiency saw large improvements when taking leucovorin. “These children were becoming seizure-free, or, if given early enough, they became completely clinically asymptomatic,” one senior FDA official said. “That would actually make doing a randomized controlled trial difficult, because of this such a dramatic response to the treatment, just because it would become unethical to, after we’ve already seen such a dramatic response, to then randomize people to placebo,” the official said. It’s a response that’s often used to explain why it may be unethical to conduct randomized controlled trials of new versions of vaccines that are already in use.

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