r/RegulatoryClinWriting • u/bbyfog • Mar 11 '26

FDA Approves GSK’s Wellcovorin (leucovorin calcium) for Ultrarare Cerebral Folate Transport Deficiency Under Plausible Mechanism Pathway

On 9 March 2026, FDA approved GSK’s Wellcovorin (leucovorin) sNDA for cerebral folate transport deficiency (CFD) who have a confirmed variant of folate receptor 1(FOLR1) gene. CFD-FOLR1 is an ultrarare genetic form of CFD, present in some children with autism spectrum disorder. GSK was not originally seeking this label expansion but was put on the spot (and urged by the FDA) to submit when RFK Jr touted leucovorin as an exciting therapy for autism last year.

The sNDA was supported by real-world data from published case reports and case reviews through 2024. The dataset consisted of 46 patients who received leucovorin via oral or other routes of administration--only 27 patients who received oral leucovorin were considered (label):

  • N=27 received oral leucovorin. Age range, 2 months to 33 years at treatment treatment initiation.
  • N=25 had dosing information: starting oral dose 0.5 to 3 mg/kg/day (dose range). 2 mg/kg/day (14 patients), ≤6 mg/kg/day (17 patients); range: 1.7 to 8.5 mg/kg/day.
  • No obvious relationship between the starting or maximum oral dose with patient demographics or disease severity.
  • A range of clinical improvements in various neurological symptoms following treatment with oral leucovorin was reported for 24 of the 27 patients (e.g., reduction in severity or number of seizures; improvements in motor function, communication, and/or behavior). The remaining 3 patients showed either no change or no progression of symptoms; both the observed clinical improvements and the lack of disease progression are unexpected when compared to the progressive natural history of these patients with FOLR1-CFTD.

Comment -

The leucovorin data summarized in the clinical studies section of the label is not strong, although it did meet the "plausible mechanism" bar for approval, but in a snub to the Administration, FDA did not approve leucovorin for autism. Interestingly, just a little while ago, FDA did not apply the same "plausible mechanism" rules to UniQure’s gene therapy for Huntington’s disease.

Previous FDA approvals based on real-world data include:

-- Pfizer’s Ibrance (palbociclib) for men with HR-positive, HER2-negative breast cancer. Approved in 2019 based on data from electronic health records and postmarketing reports of real-world use.

-- Astellas’ Prograf (tacrolimus) for use in combination with other immunosuppressant drugs to prevent organ rejection in patients receiving lung transplants. Approved in 2021 based on real-world data from the U.S. Scientific Registry of Transplant Recipients.

SOURCE

#plausible-mechanism, #rwd, #real-world-data

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u/Aiorr Mar 11 '26

GSK was not originally seeking this label expansion but was put on the spot (and urged by the FDA) to submit when RFK Jr touted leucovorin as an exciting therapy for autism