Tolebrutinib Receives FDA CRL for Nonrelapsing Secondary Progressive Multiple Sclerosis

The FDA issued a complete response letter (CRL) for tolebrutinib (Sanofi) in December 2025. This Bruton tyrosine kinase inhibitor would have been indicated to treat adults with nonrelapsing secondary progressive multiple sclerosis (nrSPMS), according to a news release from Sanofi.¹

The FDA's decision followed a prior update from Sanofi, in which they announced that the FDA's review period was expected to stretch beyond the previously communicated Prescription Drug User Fee Act date of December 28, 2025. In this communication, the FDA noted that further guidance was expected by the end of the first quarter of 2026. Sanofi had submitted an expanded access protocol for tolebrutinib in nrSPMS in response to an FDA request.

“Today’s FDA decision is a significant and meaningful change in direction from the feedback the agency previously provided to Sanofi. We are very disappointed by the FDA's action," Houman Ashrafian, executive vice president and head of research and development at Sanofi, said in the news release. "We remain committed to working with the FDA to find a path forward for tolebrutinib and ultimately serve the MS community."

The efficacy and safety of tolebrutinib were previously established in the phase 3 HERCULES trial, in which the agent met the primary end point of improvement in time to onset of confirmed disability progression compared with placebo. HERCULES was the first and only trial to successfully demonstrate reductions in disability accumulation in nrSPMS and formed the basis of the approval.²

Additionally, findings from the phase 3 GEMINI 1 and 2 studies demonstrated that tolebrutinib successfully met a key secondary end point of pooled confirmed disability worsening, for which tolebrutinib significantly reduced the time to onset. These data, along with insights from further clinical and preclinical studies, supported the FDA's review of tolebrutinib and the potential for the drug to meaningfully target the innate inflammatory processes in nrSPMS.²

Based on the positive trial results, tolebrutinib was previously granted breakthrough therapy designation by the FDA in December 2024, accelerating its path towards possible approval. However, discussions among FDA officials led to the CRL being issued for tolebrutinib, despite the strong belief in the agent's risk-benefit profile among Sanofi officials.^3,4

In an interview with Pharmacy Times® at the American Academy of Neurology's 2025 Annual Meeting and Exposition. Robert Fox, MD, FAAN, staff neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic and tolebrutinib investigator, discussed some of the key safety considerations that pharmacists should recognize when considering tolebrutinib for treatment of nrSPMS. These considerations remain salient despite tolebrutinib's CRL.⁵

In the HERCULES trial, Fox and investigators observed a slight uptick in the rate of respiratory infections. Furthermore, there was an increased rate of liver enzyme elevation. Notably, these instances occurred within the 3 months of treatment; Fox recommends intensive, weekly liver monitoring for patients undergoing therapy with tolebrutinib in the event that the agent is approved in the future.⁵

REFERENCES

1. Press Release: Sanofi provides update on tolebrutinib regulatory submission in non-relapsing secondary progressive multiple sclerosis. News Release. Sanofi. Released December 24, 2025. Accessed January 5, 2025. https://www.sanofi.com/en/media-room/press-releases/2025/2025-12-24-06-00-00-3210238

2. Halpern L. Tolebrutinib Shows Reduction in Disability Accumulation in Non-Relapsing Secondary Progressive Multiple Sclerosis. Pharmacy Times. Published September 4, 2024. Accessed September 16, 2025. https://www.pharmacytimes.com/view/tolebrutinib-shows-reduction-in-disability-accumulation-in-non-relapsing-secondary-progressive-multiple-sclerosis

3. Halpern L. FDA Grants Breakthrough Therapy Designation to Tolebrutinib for Non-Relapsing Secondary Progressive Multiple Sclerosis. Pharmacy Times. Published December 16, 2024. Accessed September 16, 2025. https://www.pharmacytimes.com/view/fda-grants-breakthrough-therapy-designation-to-tolebrutinib-for-non-relapsing-secondary-progressive-multiple-sclerosis

4. Press Release: Sanofi provides update on tolebrutinib regulatory submission in non-relapsing secondary progressive multiple sclerosis. News Release. Sanofi. Released December 15, 2025. Accessed January 5, 2025.

5. Halpern L, Fox R. AAN 2025: Tolebrutinib Shows Promise in Slowing Disability Progression for Secondary Progressive Multiple Sclerosis. Pharmacy Times. Published April 8, 2025. Accessed September 16, 2025. https://www.pharmacytimes.com/view/aan-2025-tolebrutinib-shows-promise-in-slowing-disability-progression-for-secondary-progressive-multiple-sclerosis