FDA approves leucovorin for cerebral folate deficiency but not autism

The Food and Drug Administration on Tuesday approved a decades-old prescription vitamin called leucovorin as the first treatment for a rare genetic disorder in certain adults and children. 

The move comes months after the Trump administration touted leucovorin as a potential therapy for a broader group of patients with autism spectrum disorder symptoms. The claim sparked skepticism among some in the medical and research community, but fueled excitement among families, spiking prescriptions of the drug in the U.S. 

One FDA official told reporters on Monday that “we don’t have sufficient data to say that we could establish efficacy for autism more broadly,” but said the agency is open to interest from companies in studying leucovorin in the autism population. 

The medication, also referred to as folinic acid, is a synthetic form of vitamin B9 that has been used to treat the toxic side effects of chemotherapy. Just a handful of small trials have suggested that leucovorin could be effective as an off-label treatment for children with autism, and some families have reported that it helped their nonverbal kids develop more language and social skills.

FDA officials, who requested anonymity to discuss the decision, told reporters on Monday that they started with a broad review of leucovorin as an autism treatment before narrowing its approval to a smaller population with cerebral folate deficiency, a rare genetic mutation that prevents folate – a key vitamin – from properly reaching the brain. 

The condition shares overlapping features with autism, typically develops in young children under age 2 and can cause severe developmental delays, seizures, a lack of muscle control and other serious neurological complications. 

The officials said the FDA found that using leucovorin in patients with that condition produced the “highest quality data” to support an expanded approval, which will apply to both generic versions of the drug and GSK’s old branded medication, Wellcovorin. 

“That was the data where we saw the largest effect sizes,” one FDA official said on the call. “So we narrowed in on that population, just because we felt like that was the strongest, both scientific rationale and also the largest treatment effects that could be used to then overcome some of the limitations in the data sources.”

The approval was based on a systematic review of published literature on the area, including patient case reports, but not a randomized controlled clinical trial. The same official acknowledged there can be biases with systematic reviews, but emphasized that the treatment effects were so large that they outweighed those concerns. 

The FDA is encouraging existing manufacturers of leucovorin to increase production to match higher demand for the drug, the officials added. While GSK originally marketed the drug from 1983 until 1997, the company said in September that it has no plans to re-launch and manufacture the product itself.

In a release on Tuesday, Dr. Tracy Beth Hoeg, acting director of the FDA’s Center for Drug Evaluation and Research, said the approval demonstrates the FDA’s commitment to “rapidly identifying effective treatments for ultra rare diseases while maintaining the same evidentiary standards for approval.”