Tolebrutinib, an investigational, oral, brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor under review for the treatment of non-relapsing secondary progressive multiple sclerosis (nrSPMS), will have its review period pushed back to later this year, according to Sanofi, the drug manufacturers. The agency noted that additional information constituted a major amendment to the new drug application (NDA), leading to a new PDUFA decision date of December 28, 2025.1
Sanofi’s application for tolebrutinib included data from the global phase 3 HERCULES study (NCT04411641) in nrSPMS, as well as the phase 3 GEMINI 1 and 2 trials (NCT04410978; NCT04410991) of patients with relapsing MS. If approved, tolebrutinib will become the only marketed BTK available for the treatment of MS, as well as the first marketed BTK specific to patients with nrSPMS. Of note, the agent is still being tested in patients with primary progressive MS, through the PERSEUS study (NCT04458051), which will have data read out later this year.
According to Sanofi, the company is confident in the treating potential of tolebrutinib and will continue to work closely with the FDA during the review period. Tolebrutinib, a BTK inhibitor meant to address smoldering neuroinflammation, a key driver of disability progression in MS, is the furthest along among BTK inhibitors in the clinical pipeline.
Unlike earlier-generation BTK inhibitors developed for oncology, tolebrutinib was optimized for neurological diseases, with properties allowing it to cross the blood-brain barriers. By irreversibly binding to BTK, it blocks downstream signaling of the B-cell receptor and Fc receptors on myeloid lineage cells, thereby reducing pathogenic immune activity linked to demyelination and neuroinflammation in MS.
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HERCULES, the main supportive study for tolebrutinib in nrSPMS, was a double-blind, randomized trial that comprised 1131 patients with an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5, no clinical relapses for the previous 24 months, and documented evidence of disability accumulation over that time. In the trial, patients were randomly assigned 2:1 to either daily tolebrutinib or matching placebo for up to 48 months.
Data from HERCULES showed that tolebrutinib treatment led to delayed time to onset of 6-month confirmed disability progression (CDP), the primary end point, by 31% relative to placebo (HR, 0.69; 95% CI, 0.55-0.88; P = .0026). In addition, data revealed a nearly 2-fold increase in confirmed disability improvement, a secondary outcome, for those on the investigational BTK inhibitor (HR, 1.88; 95% CI, 1.10-3.21; P = .021).2
A post-hoc analysis of HERCULES revealed that tolebrutinib might be more effective in patients with higher paramagnetic rim lesion (PRL) counts. While this data was not included in the submission, the results showed a 54% reduced risk in 6-month CDW among those with at least 4 baseline PRLs, the highest quartile group observed. A similar risk mitigation was observed in GEMINI, with reductions of 46% and 49% among those with 1-3 PRLs and those with at least 4 PRLs, respectively.3