{"id":273443,"date":"2025-10-03T02:38:10","date_gmt":"2025-10-03T02:38:10","guid":{"rendered":"https:\/\/www.europesays.com\/us\/273443\/"},"modified":"2025-10-03T02:38:10","modified_gmt":"2025-10-03T02:38:10","slug":"exclusive-the-23-studies-the-fda-based-its-expanded-leucovorin-label-on","status":"publish","type":"post","link":"https:\/\/www.europesays.com\/us\/273443\/","title":{"rendered":"Exclusive: The 23 studies the FDA based its expanded leucovorin label on"},"content":{"rendered":"

When the U.S. Food and Drug Administration (FDA) announced during a White House press conference last week that it would expand the use of leucovorin as \u201ca promising treatment for symptoms of autism,\u201d it cited an analysis<\/a> of 23 publications. The Transmitter has obtained the list of the 23 studies<\/a>\u2014which together examine leucovorin treatment in a total of 46 people who have cerebral folate deficiency (CFD), a rare neurological condition characterized by developmental delays, autism-like traits and seizures.<\/p>\n

Leucovorin came onto the FDA\u2019s radar when Nicole Kleinstreur<\/a>, acting deputy director for program coordination, planning and strategic initiatives at the U.S. National Institutes of Health, met with experts and autistic people to create a list of about a dozen drugs that some doctors prescribe off-label for autism traits, says George Tidmarsh<\/a>, director for the Center for Drug Evaluation and Research at the FDA. \u201cLeucovorin was near the top of the list,\u201d Tidmarsh told The Transmitter in an exclusive interview.<\/p>\n

When Tidmarsh and his colleagues dug into the literature, they identified 23 studies that suggest leucovorin treatment benefits a distinct group of people: those with CFD due to variants in the folate receptor alpha (FOLR1) gene<\/a>. The treatment normalizes levels of folate in their cerebrospinal fluid, decreases the number of seizures and boosts their ability to communicate and interact socially.<\/p>\n

The FDA is \u201cmaking the case for this drug on probably the most convincing clinical use of it in folate receptor-associated cerebral folate transport deficiency,\u201d says I. David Goldman<\/a>, professor emeritus of medicine, oncology and molecular pharmacology at the Albert Einstein College of Medicine. The agency took steps to relabel a branded version of leucovorin called Wellcovorin<\/a> to treat autism traits in people with CFD.<\/p>\n

The FDA\u2019s relabeling of leucovorin is limited to genetic CFD, Tidmarsh says. \u201cWe\u2019re not proposing to approve leucovorin for [people with] the diagnosis of autism,\u201d he says.<\/p>\n

Regardless, \u201cit\u2019s going to create a frenzy around this acquisition of this drug,\u201d says Shafali Jeste<\/a>, chair of pediatrics at the University of California, Los Angeles. There is little evidence to suggest that leucovorin would benefit autistic people, Jeste and several other autism researchers previously told<\/a> The Transmitter.<\/p>\n

The push to address autism itself with leucovorin may stem from a yet-unproven hypothesis that some cases of CFD and autism could be caused by autoantibodies against folate receptors that lead to folate deficiency, says Joseph Buxbaum<\/a>, professor of psychiatry, genetics and genomic sciences, and neuroscience and director of the Seaver Autism Center at the Icahn School of Medicine at Mount Sinai. Some of this research on the autoantibodies has been led by Richard Frye, a child neurologist and researcher at the Rossignol Medical Center, who was\u00a0the subject of a\u00a0profile<\/a> published yesterday by\u00a0The Transmitter.<\/p>\n

This has created \u201cthis gray zone of, \u2018maybe there\u2019s other people with autoantibodies that have a milder case [of folate deficiency]. And that might also be responsive to a treatment like leucovorin,\u2019\u201d Jeste says. \u201cBut that \u2018what if\u2019 has not been tested and studied.\u201d<\/p>\n

In a notice in the Federal Register<\/a>, the FDA said that the new label will make a note of an autoimmune form of CFD and its similarity to autism but will clarify that more data is needed. \u201cWe did not find the data sufficiently compelling for that much larger group of patients,\u201d Tidmarsh says. \u201cWe are being very careful\u2014even though there is some evidence, we are excluding that because we don\u2019t want people to make the mistake to think that this is a cure for all of autism.\u201d<\/p>\n

\n F<\/p>\n

OLR1-associated CFD is an ultra-rare genetic disorder, according to a 2024 review<\/a>. FOLR1 encodes the primary transporter of folate from the choroid plexus into the cerebrospinal fluid, so variants in this gene impair transport and decrease the amount of cerebral folate, which is critical for development. Without enough folate, people with CFD show early developmental delays, particularly in cognition and speech.<\/p>\n

For those with CFD, leucovorin has been the standard treatment of care for the past 20 years, Goldman says. Of the 46 people described in the 23 studies the FDA analyzed, most of whom are toddlers, \u201c85 percent show improvement in the symptoms associated with CFD. Many of those symptoms are autistic symptoms,\u201d Tidmarsh says.<\/p>\n

With this analysis, the FDA \u201cdetermined that the information supports a finding that leucovorin calcium can help individuals suffering from CFD,\u201d particularly to treat \u201csymptoms of autism\u201d in this population, according to the FDA press release.<\/p>\n

Leucovorin<\/a> is currently approved for anemia, colorectal cancer and for counteracting the effect of high-dose chemotherapy. But the list of 23 case studies shows that the drug can also help people with genetic CFD, an example of how the FDA\u2019s recent proposal for finding therapeutics for rare diseases<\/a> would work, Tidmarsh says. \u201cWe are willing to accept real-world data for extremely rare diseases where the mechanism is extremely clear and there\u2019s good, real-world evidence for the efficacy of a drug.\u201d<\/p>\n

The relabeling would legitimize the use of leucovorin for these patients and might help bring awareness to CFD patients, says Helen Tager-Flusberg<\/a>, director of Center for Autism Research Excellence at Boston University, adding that she is, however, concerned it might be extrapolated to autistic people.<\/p>\n

Some studies suggest that CFD and clinical signs of autism may be caused by autoantibodies against the folate receptor<\/a> and consequent folate deficiency, a hypothesis based on weak science, Buxbaum says. The work has been poorly controlled and inconsistent, he adds. \u201cThis reinterpretation of CFD, calling it autoimmune CFD, is not on the [medical] boards. That is a made-up construct.\u201d<\/p>\n

By relabeling, the FDA could be opening the door to broadening the use of leucovorin to larger populations, including those diagnosed with autism, Jeste says. \u201cI think to sort of take small, poorly conducted studies and generalize like this is very problematic,\u201d Jeste says.<\/p>\n

Some statements indicate that leucovorin could be used for anyone with autism. \u201cThe change will authorize treatment for children with ASD, with continued use if children show language, social, or adaptive gains,\u201d reads a 22 September press release by the Department of Health and Human Services. \u201cWhile promising, it is important to note that leucovorin is not a cure for ASD and may only lead to improvements in speech-related deficits for a subset of children with ASD,\u201d the press release<\/a> continues.<\/p>\n

During the 22 September press conference, FDA Commissioner Marty Makary said \u201ca growing body of evidence suggests that some children suffering from autism are folate deficient within the brain\u2014a problem that can be treated with leucovorin.\u201d<\/p>\n

Jeste she says she expects to see an increase in patients and families asking for leucovorin, which is concerning because the drug can have side effects such as gastrointestinal issues and it could create a shortage for people who need it for other conditions. \u201cWhether it\u2019s on the label or not, it will be used \u2018off-label,\u2019\u201d Jeste says. \u201cAnd it\u2019ll be an unfortunate burden for families.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"When the U.S. Food and Drug Administration (FDA) announced during a White House press conference last week that…\n","protected":false},"author":3,"featured_media":273444,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[26],"tags":[815,159,67,132,68],"class_list":{"0":"post-273443","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-genetics","8":"tag-genetics","9":"tag-science","10":"tag-united-states","11":"tag-unitedstates","12":"tag-us"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@us\/115307918421522023","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts\/273443","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/comments?post=273443"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts\/273443\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/media\/273444"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/media?parent=273443"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/categories?post=273443"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/tags?post=273443"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}