FDA grants priority review to application for tolebrutinib for MS
Approval decision on Sanofi oral therapy for 2 indications due by Sept. 28
Note: This story was updated April 4, 2025, to clarify the specific disability measures and that tolebrutinib is believed to target smoldering neuroinflammation.
The U.S. Food and Drug Administration (FDA) has granted priority review to an application from Sanofi seeking the approval of its BTK inhibitor tolebrutinib to treat multiple sclerosis (MS).
As its name suggests, priority review means that the FDA will speed its regulatory evaluation of the oral therapy, completing it in six months instead of the usual 10. A final decision is now expected by Sept. 28, according to a company press release.
Sanofi is specifically asking the agency to approve tolebrutinib for two indications: to treat nonrelapsing secondary progressive MS (SPMS), and to slow disability accumulation independent of relapse activity in adults with MS.
“If approved, tolebrutinib would be the first and only brain-penetrant BTK inhibitor to both treat nonrelapsing secondary progressive multiple sclerosis (MS) and slow disability accumulation independent of relapse activity,” the release stated.
Tolebrutinib is also being considered for approval in Europe, per the release.
Tolebrutinib aims to target smoldering, or chronic, neuroinflammation
MS is marked by inflammation in the brain and spinal cord that causes damage to the myelin sheath, a fatty substance surrounding nerve fibers that’s important for nerve cell communication.
The vast majority of people with MS initially develop a disease form called relapsing-remitting MS, or RRMS. It’s marked by relapses in which symptoms suddenly worsen, interspersed with periods of remission when symptoms ease.
Over time, people with RRMS can eventually transition to another disease type called SPMS, which is defined by symptoms that get gradually worse over time independent of relapse activity. Some people with SPMS continue to experience relapses, and many of the same treatments available for RRMS can also be used in these patients. But little to no options exist for people with nonrelapsing SPMS.
Tolebrutinib is an oral therapy designed to block the activity of the Bruton tyrosine kinase (BTK) enzyme, which plays a key role in the activation of certain inflammatory immune cell types. The therapy can cross the blood-brain barrier, a semipermeable cellular membrane that regulates which substances can pass from the blood to the brain.
While most available disease-modifying therapies for MS target immune processes involved in relapses, tolebrutinib is believed to target the smoldering, or chronic, inflammation that contributes to disability progression in the absence of relapses.
According to Erik Wallström, MD, PhD, Sanofi’s global head of neurology development, “people living with non-relapsing secondary progressive multiple sclerosis or who experience disability independent of relapse activity suffer from disability that worsens over time due to persistent inflammation in the brain, known as smoldering neuroinflammation, which is the primary driver of disability.”
“The totality of data across our clinical program validates our scientific understanding of smoldering neuroinflammation as a distinct inflammatory process in MS,” Wallström said.
Approval application based on HERCULES, GEMINI data
Sanofi’s applications seeking tolebrutinib’s approval were based on data from three Phase 3 clinical trials: HERCULES (NCT04411641), GEMINI 1 (NCT04410978), and GEMINI 2 (NCT04410991). HERCULES involved people with nonrelapsing SPMS, while both GEMINI trials enrolled participants with relapsing forms of MS.
Results from HERCULES showed that tolebrutinib significantly delayed six-month confirmed disability progression by 31% compared with a placebo. This was evidenced by an increase in Expanded Disability Status Scale scores sustained for at least six months.
The demonstrated ability of tolebrutinib to delay disability by targeting underlying drivers of the disease represents a potential paradigm shift in treating [MS] patients.
In the GEMINI trials, tolebrutinib did not outperform Aubagio (tolebrutinub) — an approved MS treatment — in reducing relapse rates in people with relapsing forms of MS, thus failing to meet the studies’ main goal. However, the risk of six-month confirmed disability worsening was 29% lower with tolebrutinib.
“The demonstrated ability of tolebrutinib to delay disability by targeting underlying drivers of the disease represents a potential paradigm shift in treating these patients,” Wallström said.
The FDA last year granted breakthrough designation to tolebrutinib as a potential treatment for nonrelapsing SPMS based on data from the HERCULES trial.
While the HERCULES and the GEMINI trials are now complete, a fourth Phase 3 study, called PERSEUS (NCT04458051), is ongoing. That trial is evaluating tolebrutinib in people with primary progressive MS. Results from that study are expected later this year.
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