Written By: Pharmacally Medical News Desk
The U.S. Food and Drug Administration has issued a complete response letter (CRL) for the new drug application of tolebrutinib, Sanofi’s investigational therapy for adults with non-relapsing secondary progressive multiple sclerosis (nrSPMS). The decision means the FDA is not prepared to approve the application in its current form and is requesting additional information before continuing the review.
What the FDA Decision Means
A CRL does not represent a final rejection, but it formally pauses the approval process. In this case, the FDA indicated that it could not complete its review by the previously communicated revised target action date of December 28, 2025. Instead, further regulatory guidance is now expected by the end of the first quarter of 2026.
According to Sanofi, the agency’s position reflects a change from earlier feedback. While the FDA has not released a public, line-by-line explanation, the CRL signals that outstanding issues remain that prevent approval at this stage. CRL signals that outstanding issues remain that prevent approval at this stage. These typically relate to the need for additional clinical, safety, or regulatory clarification before a benefit-risk conclusion can be finalized.
Background Leading Up to the CRL
On December 15, 2025, Sanofi disclosed that discussions with the FDA suggested the review would extend beyond December. As part of those discussions, the FDA requested that Sanofi submit an expanded access protocol for tolebrutinib in nrSPMS, which the company has since provided. These interactions occurred shortly before the CRL was formally issued.
Sanofi’s Response
Sanofi expressed strong disappointment with the decision, noting that disability progression remains a major unmet need in multiple sclerosis. tolebrutinib had previously received FDA breakthrough therapy designation, reflecting its potential to address progression independent of relapse activity.
Houman Ashrafian, Executive Vice President and Head of R&D at Sanofi, said the company views the CRL as a meaningful shift from earlier regulatory feedback and emphasized its intention to continue working with the FDA, alongside clinicians and patients, to identify a path forward for the MS community.
Regulatory Status Outside the US
Despite the setback in the United States, tolebrutinib’s regulatory journey continues elsewhere. The drug received provisional approval in the United Arab Emirates in July 2025 for adults with nrSPMS, including an indication to slow disability accumulation independent of relapses. Regulatory reviews are also ongoing in the European Union and other regions worldwide.
About Tolebrutinib
Tolebrutinib is an investigational, oral, brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor designed to target smoldering neuroinflammation, a key driver of disability progression in multiple sclerosis. By focusing on inflammatory processes within the central nervous system, the drug aims to address mechanisms that contribute to neurodegeneration and long-term disability, particularly in progressive forms of MS.
Looking Ahead
Sanofi has reiterated its commitment to neurology and immunoscience, with multiple phase 3 programs ongoing across neuroinflammatory and neurodegenerative diseases. For tolebrutinib, the next steps will depend on further FDA guidance in early 2026 and how the company addresses the issues outlined in the CRL.
Reference
Press Release: Sanofi provides update on tolebrutinib regulatory submission in non-relapsing secondary progressive multiple sclerosis, 24 December 2025, https://www.sanofi.com/en/media-room/press-releases/2025/2025-12-24-06-00-00-3210238
Press Release: Sanofi provides update on tolebrutinib regulatory submission in non-relapsing secondary progressive multiple sclerosis, 15 December 2025, https://www.sanofi.com/en/media-room/press-releases/2025/2025-12-15-06-00-00-3205091
Press Release: Sanofi provides update on tolebrutinib in primary progressive multiple sclerosis, 15 December 2025, https://www.sanofi.com/en/media-room/press-releases/2025/2025-12-15-06-05-00-3205094