FDA denies tolebrutinib approval for nonrelapsing progressive MS
Sanofi is working with FDA to find path forward for experimental MS therapy
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- The FDA declined to approve tolebrutinib for nonrelapsing secondary progressive multiple sclerosis (SPMS), with reasons not immediately given.
- Sanofi says it will work to find a path forward with the FDA for the experimental MS therapy.
- Tolebrutinib is also up for approval in Europe, with a decision expected within months.
After months of delay, the U.S. Food and Drug Administration (FDA) has rejected Sanofi‘s application seeking approval of tolebrutinib for the treatment of adults with nonrelapsing secondary progressive multiple sclerosis (MS).
While Sanofi announced earlier this month that the decision was likely to be delayed again and that further guidance from the FDA was expected in early 2026, the agency has now issued a complete response letter indicating the new drug application will not be approved in its present form.
The reasons behind the decision were not disclosed at this time. However, the rejection is a “significant and meaningful change in direction from the feedback the agency previously provided to Sanofi,” said Houman Ashrafian, executive vice president and head of research and development at Sanofi, in a company press release.
Tolebrutinib showed promise as 1st of its kind
Most people with MS initially develop relapsing-remitting MS (RRMS), which is marked by relapses in which symptoms suddenly worsen, followed by periods of remission when symptoms ease.
Over time, people with RRMS may progress to secondary progressive MS (SPMS), which is marked by symptoms that gradually worsen over time, independent of relapse activity. Some people with SPMS continue to experience relapses, and treatments used for RRMS may be effective in these patients. However, for people with SPMS who don’t experience relapses, treatment options are extremely limited.
Tolebrutinib is a once-daily oral therapy aimed at modulating the activity of immune cells such as B-cells and microglia. By inhibiting the BTK protein in these cells, the therapy is thought to reduce both the acute inflammation that drives relapses and new lesions, as well as the chronic inflammatory processes within the brain and spinal cord that contribute to progressive neurodegeneration and long-term disability in MS.
According to Sanofi, this feature distinguishes tolebrutinib from other disease-modifying MS therapies, which are designed to target acute MS inflammation. Sanofi says tolebrutinib may be the first therapy to target smoldering (chronic) neuroinflammation, a key driver of disability accumulation in MS.
Tolebrutinib’s path to this point, and what’s next
“We are very disappointed by the FDA’s action. Disability progression remains a large unmet medical need in MS, and tolebrutinib was previously awarded breakthrough therapy designation by the FDA in recognition of its potential to address this critical gap,” Ashrafian said.
Sanofi had sought approval for the therapy specifically for nonrelapsing SPMS and to slow disability accumulation independent of relapse activity in adults with MS. Tolebrutinib was approved in the United Arab Emirates for those indications in July, marking its first worldwide approval.
The FDA’s decision was originally expected to be announced in September, but the agency pushed back its decision to the end of the year. While Sanofi was expecting the decision to be delayed again based on recent discussions with the FDA, a rejection has now been issued.
The therapy is also being considered for approval in Europe, with a decision expected in the coming months.
Sanofi’s regulatory applications were based on data from three Phase 3 clinical trials: HERCULES (NCT04411641), which tested tolebrutinib in nonrelapsing SPMS, and the GEMINI 1 and 2 trials (NCT04410978 and NCT04410991), which investigated it in people with relapsing forms of MS.
The HERCULES trial demonstrated that the therapy significantly reduced the risk of six-month confirmed disability progression by 31% compared with a placebo. Six-month confirmed disability progression refers to an increase in Expanded Disability Status Scale (EDSS) scores that persists for at least six months.
The therapy also increased the odds of six-month confirmed disability improvement by 88% and reduced the rate of new or enlarging lesions on MRI scans by 38%.
The GEMINI studies tested tolebrutinib against an older approved treatment called Aubagio (teriflunomide). Tolebrutinib did not outperform Aubagio at reducing relapse rates, meaning the studies failed to meet their main goal. However, the risk of six-month confirmed disability worsening was significantly lower with tolebrutinib, by 29%, suggesting that the therapy can slow disability accumulation independent of relapses.
A fourth Phase 3 clinical trial called PERSEUS (NCT04458051) tested tolebrutinib against a placebo in people with primary progressive MS (PPMS). The goal of the trial was to demonstrate that the therapy would reduce the risk of a composite measure of six-month confirmed disability progression, but Sanofi announced a few weeks ago that it had missed its goal. The company said it is no longer planning to pursue approval of tolebrutinib for PPMS.
“We remain committed to working with the FDA to find a path forward for tolebrutinib and ultimately serve the MS community,” Ashrafian said. “We believe that the FDA should also take the advice of scientific experts, clinicians, and patients in this matter to ensure all perspectives are considered.”
