Nearly six months ago, federal health officials gathered at the White House with President Donald Trump and vowed to “go bold” on autism, outlining plans for an “exciting treatment” for children with the condition – a decades-old drug, leucovorin, newly recast as a potential breakthrough, reports The Washington Post.
“Hundreds of thousands of kids, in my opinion, will benefit,” Food and Drug Administration Commissioner Marty Makary had said at the time.
But on Tuesday, the administration appeared to have scaled back on the vision, with the FDA announcing that while it will expand approval for the medication in question, leucovorin, this will only be for a separate condition afflicting some people with autism, not for autism itself.
The approval targets an ultra-rare disorder known as cerebral folate deficiency, or CFD, caused by a defect in one gene, FOLR1, that can overlap with autism.
The disorder, in which the brain lacks adequate levels of folate despite normal blood levels of the vitamin, is believed to be under-diagnosed, and fewer than 50 cases have been documented in the medical literature.
This is the first treatment for CFD, in which children often develop symptoms such as intellectual disabilities, speech difficulties, seizures and other behaviours sometimes exhibited by those with autism.
FDA officials, speaking on condition of anonymity, acknowledged that, at the outset, they did consider whether they could widen approval for leucovorin to cover a larger share of those on the autism spectrum.
“When we first started considering the ability to expand an indication for leucovorin, we considered whether there was data to support its use in a broader autism spectrum disorder population,” said one senior agency official.
But a systematic review of the literature led the agency to focus elsewhere. The “strongest data”, they said, were concentrated among patients with the genetic form of cerebral folate deficiency, a condition they estimate affects “fewer than one in a million” people.
“That had the best quality data,” the official said. “That was where we saw the largest effect sizes.”
The initial press conference in September where Trump and his aides touted the prospect of expanding the drug’s use triggered immediate criticism. The President separately blamed Tylenol for causing autism, a claim without a proven link – and many in the medical establishment questioned the idea of prescribing leucovorin for a much broader population.
Professional societies and individual physicians alike warned that the evidence base was thin.
A decades-old drug typically used alongside chemotherapy, leucovorin has been tested for autism-related symptoms in only a handful of small clinical trials in the United States and abroad.
Some studies suggested modest gains in speech and behaviour. But the data fell far short of the rigorous, large-scale evidence the FDA generally requires before granting approval for a new use.
The largest of the leucovorin-autism studies was retracted by the European Journal of Paediatrics on 29 January: after the authors acknowledged some errors, the editors wrote that the publication “no longer has confidence in the validity of the results and conclusions reported in this article”.
Still, the administration’s hopeful message has resonated with many families.
Paediatricians and specialists reported being inundated with calls from parents seeking prescriptions.
On social media, anecdotes quickly filled the vacuum left by limited data: some parents described striking improvements, others said the drug had made little difference at all.
Last week, researchers reported in The Lancet that outpatient prescriptions for leucovorin rose 71% among children aged five-17 from roughly three months before Trump’s September announcement to three months afterward – suggesting the administration’s comments may have changed medical decision-making.
The authors expressed concern that the jump in the use of leucovorin “might confer false expectations and unnecessary side effects”.
Some parents have reported difficulty finding the drug. This week, however, FDA officials said leucovorin does not face a shortage. The agency has permitted importation from manufacturers in other countries to bolster supply, they said.
“Demand continues to increase,” one FDA official acknowledged, adding that the agency is in discussions with additional companies about increasing imports and is encouraging existing manufacturers to ramp up production.
Whether physicians will keep prescribing leucovorin off-label for children with autism remains uncertain. Administration officials did not discourage that practice: a senior FDA official noted that the drug “would be available for off-label use if patients would like to try”.
At the same time, the official conceded the limits of the evidence, saying, “Right now, we don’t have sufficient data to say that we could establish efficacy for autism more broadly, but … it will be up to patients to talk to their physicians to see if that might be right for them.”
See more from MedicalBrief archives:
Leucovorin for autism not backed by evidence, say experts
US paediatrician group won’t back leucovorin for autism