Pune, India | September 23, 2025
Sanofi recently announced that the U.S. Food and Drug Administration (FDA) has extended its review period for tolebrutinib. This oral Bruton’s Tyrosine Kinase (BTK) inhibitor is being studied as a treatment for non-relapsing secondary progressive multiple sclerosis (nrSPMS). The FDA delayed its target action date by three months. This followed Sanofi’s submission of additional analyses, which the agency called a major amendment. This decision reflects the thorough regulatory process and Sanofi’s commitment to providing comprehensive data supporting the drug’s approval.
Tolebrutinib targets nrSPMS, a particularly challenging stage of multiple sclerosis. Patients at this stage experience gradual and continuous worsening of symptoms and disability without the relapses typical of earlier forms. The drug works by inhibiting BTK, a key protein involved in immune cell signaling pathways. Its unique ability to cross the blood-brain barrier allows tolebrutinib to directly address neuroinflammation within the central nervous system (CNS). By reducing this “smoldering” inflammation, the drug may slow disability progression—a benefit that many current MS therapies struggle to provide after relapses cease.
Sanofi’s confidence in tolebrutinib is bolstered by the FDA’s Breakthrough Therapy designation for nrSPMS. This status applies to drugs showing substantial potential to treat serious conditions with unmet medical needs. The New Drug Application (NDA) includes extensive clinical data from several key trials. The primary data come from the pivotal Phase III HERCULES study involving nrSPMS patients. The submission also contains results from the GEMINI 1 and GEMINI 2 trials, which evaluated the drug in relapsing MS patients. Additionally, Sanofi is conducting the PERSEUS trial to assess the drug’s impact on primary progressive MS, with results expected later this year.
The HERCULES trial enrolled nrSPMS patients who experienced disability progression over the past year and had no relapses for at least two years. Participants received either daily tolebrutinib or a placebo for nearly four years. The study’s primary goal was to measure confirmed disability progression sustained for six months. Secondary measures included MRI-based markers of brain inflammation and tests of walking ability and upper limb function.
The GEMINI 1 and 2 trials compared tolebrutinib with teriflunomide, an approved therapy, in patients with relapsing MS. These studies aimed to assess the drug’s ability to reduce relapse rates and prevent disease worsening over three years. They also provided insights into how the drug modulates the immune response and protects neurological function.
Sanofi emphasizes tolebrutinib’s brain penetration as a significant advantage. This feature enables the drug to target both peripheral immune cells and CNS-resident innate immune cells, such as microglia. These cells drive persistent inflammation and progressive disability in MS. Most approved therapies primarily target peripheral B and T cells to reduce relapses, with limited impact on progression after relapses stop. Tolebrutinib offers a novel approach that addresses this gap, potentially benefiting patients in the progressive phase of the disease.
The FDA’s decision to extend the review timeline followed Sanofi’s submission of new data and analyses. The agency labeled this a “major amendment,” which required additional evaluation time. Sanofi has expressed its full commitment to collaborating with the FDA and providing any further information needed during the review process.
The medical community and patient advocacy groups agree that nrSPMS presents an urgent unmet need. Patients face a relentless and gradual decline in physical and cognitive function, including difficulty walking, balance issues, fatigue, and bladder or bowel dysfunction. These symptoms significantly reduce quality of life. Current treatments often fail to address progressive forms of MS, underscoring the need for new therapies like tolebrutinib.
Sanofi’s neurology pipeline reflects a strategic focus on developing treatments for neurological diseases with significant unmet needs. The company leverages its expertise in immunology and neurobiology, alongside advanced technologies, to tackle the complex mechanisms of neurodegeneration and neuroinflammation.
The FDA’s review outcome is highly anticipated by patients, clinicians, and the MS community. If approved, tolebrutinib would become the first oral treatment designed specifically to address disability progression in nrSPMS. This could transform the MS treatment landscape. The ongoing PERSEUS trial will also clarify tolebrutinib’s potential role across different progressive MS forms.
While the extended review delays approval, it highlights the FDA’s commitment to ensuring the safety and efficacy of new medicines. Sanofi remains optimistic about tolebrutinib’s potential to improve outcomes for people living with multiple sclerosis. In summary, tolebrutinib offers hope as a novel BTK inhibitor that penetrates the brain to combat CNS inflammation and potentially slow disability progression. Its approval would mark a significant milestone, providing a much-needed option for patients with limited choices.
