The fast track may have turned into a dead end for tolebrutinib, Sanofi’s Bruton tyrosine kinase (BTK) inhibitor for multiple sclerosis (MS) treatment. The US Food and Drug Administration (FDA) has denied approval of the experimental treatment in its current form, saying “a favorable benefit-fisk profile could not be established for any patient population.”
In a Complete Response Letter (CRL), released with redactions on January 6, 2026, the agency said it was concerned that a “serious risk of severe drug-induced liver injury (DILI), which was identified during the conduct of [Sanofi’s] clinical trials, [could not] be adequately mitigated by the proposed risk evaluation and mitigation strategy.” DILI is a known side effect of BTK inhibitors, but the FDA noted that the risk of fatal DILI cases associated with tolebrutinib seemed to be “among the highest in the class.”
Just 9 days before the FDA issued that CRL, Sanofi had sent out a news release announcing that the company had, at the FDA’s request, submitted an expanded access protocol. Although Sanofi had expected the FDA’s review to extend beyond its target action date of December 28, 2025, it also expected to receive further FDA guidance by the end of the first quarter of 2026. I doubt it expected a CRL.
In a late-December news release, the company called the CRL very disappointing and “a significant and meaningful change in direction from the feedback the agency previously provided.”
Hopes had been high for tolebrutinib
Back in January 2025, very encouraging news about tolebrutinib emerged. The drug had just been designated an FDA Breakthrough Therapy for the treatment of adults with non-relapsing secondary progressive MS (nrSPMS), putting it on the fast track to approval. At the time I wondered if tolebrutinib would be the next big disease-modifying therapy for MS.
The Breakthrough Therapy designation followed positive results from the HERCULES trial in September 2024. The study reported the experimental treatment delayed the time to onset of 6-month confirmed MS disability progression (6MCDP) by 31% compared with placebo. In addition, 10% of trial participants saw their disability improve—double the percentage of those who received the placebo.
BTK inhibitors penetrate the blood-brain barrier and have the potential to treat both relapsing and progressive forms of MS by blocking inflammation. According to an April 2023 Nature Reviews Neurology review of 5 potential BTK inhibitors, the drugs can suppress B cell activation, lymphocyte infiltration of the central nervous system, inflammation of brain and spinal cord membranes, proinflammatory activation of the microglia, and demyelination.
Other BTK Inhibitors
Two other BTK inhibitors are in trials in the US, fenebrutinib and orelabrutinib.
Fenebrutinib has completed Phase 3 trials for treating relapsing MS (RMS) and primary progressive MS (PPMS), both with positive results. A second study for RMS is ongoing, with a readout expected in the first half of 2026.
Orelabrutinib is being studied in a Phase 3 trial to treat PPMS. Another phase 3 trial, for SPMS, is expected to begin in the first quarter of 2026.
The authors of an April 2024 review article in Therapeutic Advances in Neurological Disorders remained hopeful. “So far, the benefit-risk profile of second-generation BTK inhibitors in the treatment of MS is encouraging,” the authors wrote. “The introduction of BTK inhibition was perceived as a major breakthrough in oncology; it is hoped that these drugs will bring a similar incremental value to the therapeutic tools available in fighting MS.”
But that article was written over 18 months ago.
Now, What’s Next?
The road to FDA approval for BTK inhibitors has been bumpy.
In early December Sanofi’s PERSEUS Phase 3 study failed to meet its primary endpoint of delaying time to onset of disability progression compared to a placebo, Sanofi then announced it was withdrawing its application to use tolebrutinib to treat primary progressive MS (PPMS).
In addition to tolebrutinib’s problems, in late 2023 the makers of evobrutinib halted development after a pair of Phase 3 trials failed to show benefit over the comparator drug, teriflunomide.
To this day, the FDA has failed to approve any disease-modifying therapy specifically aimed at people who, like me, live with nrSPMS and there are few that target PPMS. Let’s hope this latest FDA decision doesn’t mean an end to the BTK inhibitor research road.
“We remain committed to working with the FDA to find a path forward for tolebrutinib and ultimately serve the MS community,” Houman Ashrafian, PhD, executive vice president and head of research and development at Sanofi, said in a news release in late December.
I hope so.
