The U.S. Food and Drug Administration expanded the approved use of leucovorin to treat cerebral folate deficiency (CFD) linked to a specific genetic variant, according to a March 17 announcement. The move comes as FDA observers note a disconnect between the agency's stated commitment to flexibility in rare disease approvals and recent rejections of similar therapies.
The topic is significant because it highlights ongoing debates about how the FDA evaluates treatments for rare diseases, especially when traditional clinical trial data are limited or unavailable. While some companies have faced setbacks in seeking approval for rare disease drugs, the FDA itself initiated the expansion of leucovorin’s label without randomized controlled trial evidence.
Holly Fernandez Lynch, a bioethics and law professor at the University of Pennsylvania, said in an email to BioSpace: “The apparent discrepancy in evidence standards ‘can’t be rationalized in a coherent sense, other than that leucovorin is a drug that is being shaped to fit RFK’s agenda around autism and it’s outside the reach of Vinay Prasad and [the Center for Biologics Evaluation and Research]. This is exactly the sort of thing that makes the public not trust FDA’s decisions, as this is not based in science, it’s based in politics.’”
Paul Kim, principal at Kendall Square Policy Strategies and former FDA counsel, described the decision as “highly unusual—maybe unprecedented—and I think it’s good and bad.” He added that while mining real-world evidence could benefit other rare diseases, there may be political motivations behind this particular expansion.
At a White House press conference on Sept. 22, 2025, FDA Commissioner Marty Makary announced plans to update leucovorin's label so it could be available for children with autism. “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. “We have a duty to let doctors and the public know. . . . Hundreds of thousands of kids, in my opinion, will benefit.” However, current evidence does not support prescribing leucovorin for autism unless CFD is present.
Policy consultant Steven Grossman suggested that expanding approval for CFD may make it easier for pediatricians under pressure from parents to prescribe leucovorin off-label for autism: “While there may be more going on,” Grossman said, “the whole deal looks very much like a gigantic ‘wink-wink’ from the administration.”
Kim concluded by reflecting on future possibilities: with more research funding and infrastructure, he would "not be surprised to see multiple approvals of very rare disorder therapies like leucovorin," potentially leading to broader access through repurposed or novel treatments.
