Sanofi’s experimental MS therapy tolebrutinib suffers twin setbacks
Approval won't be sought for use in PPMS; FDA delays SPMS decision
- Sanofi will not pursue tolebrutinib approval for PPMS due to negative trial results.
- An FDA decision on tolebrutinib in nonrelapsing SPMS has been delayed again.
- Tolebrutinib trial showed efficacy in nonrelapsing SPMS.
Following negative Phase 3 trial results, Sanofi announced that it will not be pursuing approval of its experimental therapy tolebrutinib for primary progressive multiple sclerosis (PPMS).
Meanwhile, a decision from the U.S. Food and Drug Administration (FDA) on tolebrutinib’s use in nonrelapsing secondary progressive MS (SPMS) is likely to be delayed again, the company said.
Sanofi had applied to the FDA asking for approval of tolebrutinib in two indications: to treat individuals with nonrelapsing SPMS, and to slow disability accumulation independent of relapse activity in adults with MS. The FDA granted the application priority review, and a decision was initially expected in September. However, the FDA pushed back its decision to late December.
Sanofi now expects the FDA’s review of the therapy for nonrelapsing SPMS to extend into the new year, and it anticipates receiving further guidance in early 2026. The other indication wasn’t mentioned in a Sanofi press release.
In response to an FDA request, the company has submitted the protocol for an expanded access program for tolebrutinib in nonrelapsing SPMS. Such programs are designed to allow interested patients the opportunity to access experimental drugs that have not yet been approved for commercial use, thereby enabling patients to receive cutting-edge treatments and providing drug developers with avenues to collect more data on experimental therapies.
Sanofi said it “strongly believes in the risk-benefit profile of tolebrutinib for the treatment of [nonrelapsing] SPMS.”
Tolebrutinib designed to block key enzyme
In MS, inflammation damages healthy cells in the brain and spinal cord. For most people with MS, the disease is marked by relapses, where symptoms suddenly worsen, followed by periods of remission where symptoms ease. These patients can accumulate disability if they recover poorly from relapses, but most will also see their symptoms slowly worsen even in the absence of relapses.
Progressive forms of MS, which include PPMS and SPMS, are marked by disability that gets gradually worse over time, irrespective of relapse activity.
Tolebrutinib is an oral therapy designed to block the activity of Bruton’s tyrosine kinase, an enzyme that contributes to the activation of immune cells thought to play key roles in driving MS disease progression.
A Phase 3 clinical trial called HERCULES (NCT04411641) tested tolebrutinib against a placebo in people with nonrelapsing SPMS, and the trial met its main goal, with results showing that the therapy significantly delayed the onset of six-month confirmed disability progression by 31% compared with a placebo.
Based on those findings, tolebrutinib was approved for nonrelapsing SPMS in the United Arab Emirates earlier this year.
PPMS trial fails to meet main goal
Sanofi’s application to the FDA is based on data from the HERCULES trial, as well as two other Phase 3 trials, GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991). Those two studies tested tolebrutinib against the older MS therapy Aubagio (teriflunomide) in people with relapsing forms of MS.
The studies failed to meet their main goal of showing that tolebrutinib was better than Aubagio at reducing relapse rates. However, secondary endpoints indicated that tolebrutinib significantly reduced the risk of worsening six-month confirmed disability by 29%.
The findings suggested that tolebrutinib may slow the progression that occurs independent of relapses, leading Sanofi to request the approval of tolebrutinib for slowing disability accumulation independent of relapse activity in its application.
Sanofi also conducted a Phase 3 trial called PERSEUS (NCT04458051) testing tolebrutinib against a placebo in PPMS patients. The study’s main goal was to demonstrate that tolebrutinib was more effective than the placebo in delaying the onset of six-month composite confirmed disability progression — a composite measure that assesses changes in disability levels on the Expanded Disability Status Scale, as well as worsening of hand and walking function.
We are disappointed by today’s results; however, we do believe that these results will improve our understanding of the underlying disease biology of multiple sclerosis.
The company has now announced that PERSEUS failed to meet this goal, although detailed results were not shared at this point.
“We are disappointed by today’s results; however, we do believe that these results will improve our understanding of the underlying disease biology of multiple sclerosis,” Houman Ashrafian, PhD, executive vice president, head of research and development at Sanofi, said in another company press release.
Safety data from PERSEUS were consistent with findings from the other trials. Among the noteworthy safety findings, tolebrutinib can cause liver damage, which the company said emphasizes the need for careful monitoring of liver health in patients who take the therapy.
Sanofi is planning to present detailed results from PERSEUS at an upcoming medical meeting.
“We extend our deepest appreciation to the study participants, their families, and healthcare professionals who support our scientific and innovative vision,” Ashrafian said. “Our commitment to the multiple sclerosis community remains unchanged, as do our efforts to pursue novel advancements that address existing unmet needs, and we remain confident in the value tolebrutinib can bring to those living with non-relapsing secondary progressive multiple sclerosis.”
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