ACTRIMS 2026: Tolebrutinib misses main goal in PPMS Phase 3 PERSEUS trial
Therapy was linked to fewer new brain lesions and less brain volume loss on MRI
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- Tolebrutinib failed to reduce disability progression in primary progressive multiple sclerosis (PPMS) in a Phase 3 trial.
- However, the drug showed benefits on MRI scans, reducing new brain lesions and slowing brain volume loss.
- Tolebrutinib's safety profile was consistent with prior studies, with higher rates of liver-related side effects observed.
The investigational BTK inhibitor tolebrutinib did not lower the risk of confirmed disability progression compared with placebo in people with primary progressive multiple sclerosis (PPMS), failing to meet the main goal and several key secondary goals of the Phase 3 PERSEUS trial.
It did, however, show signs of benefit on MRI scans, including fewer new brain lesions and slower brain volume loss.
Prior trials showed disability benefit in other MS types
In previous trials involving people with relapsing MS and nonrelapsing secondary progressive MS (SPMS), tolebrutinib was shown to lower the risk of disability accumulation.
But in December, developer Sanofi announced that PERSEUS (NCT04458051) had failed to meet its main goal, and the company would not seek U.S. approval of tolebrutinib for this form of multiple sclerosis (MS).
Robert Fox, MD, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, shared detailed study findings at last week’s Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2026, held in San Diego and virtually.
“Disability accumulation observed in the … PPMS population appears to be less impacted by the BTK inhibitor tolebrutinib than seen in other tolebrutinib MS trials,” Fox said in his oral presentation titled, “Efficacy and Safety of Tolebrutinib Versus Placebo in Primary Progressive Multiple Sclerosis: Results From the Phase 3 PERSEUS Trial.”
Tolebrutinib is a daily oral therapy that blocks the BTK enzyme, which helps drive inflammatory activity in certain immune cells that contribute to nervous system damage in MS.
The therapy is thought to address both the acute inflammation associated with relapsing forms of MS and the chronic inflammatory processes that contribute to neurodegeneration and disability progression in progressive forms of the disease.
PERSEUS tested tolebrutinib in primary progressive MS
PERSEUS was the fourth of a series of Phase 3 trials designed to test tolebrutinib across different types of MS. Based on data from the first three trials — GEMINI 1 (NCT04410978), GEMINI 2 (NCT04410991), and HERCULES (NCT04411641) — Sanofi had sought U.S. approval for the therapy specifically for nonrelapsing SPMS and to slow disability accumulation independent of relapse activity in adults with MS.
U.S. regulators declined to approve the drug for those indications, but tolebrutinib was approved in the United Arab Emirates for those indications in July and is also under regulatory review in the European Union.
The PERSEUS trial enrolled 767 adults with PPMS, some of whom had previously received Ocrevus (ocrelizumab). Ocrevus and its under-the-skin formulation, Ocrevus Zunovo, are the only therapies approved for PPMS in the U.S.
Participants received either oral tolebrutinib (60 mg) or a placebo once daily for up to five years. The main goal was to evaluate the therapy’s effects on a composite measure of six-month confirmed disability progression (cCDP).
This measure specifically includes the Expanded Disability Status Scale (EDSS), which measures functional disability; the timed 25-foot walk test (T25FW), which measures walking function; and the nine-hole peg test (9HPT), which evaluates hand and finger dexterity.
If participants showed confirmed worsening on EDSS, or at least a 20% worsening on the T25FW or 9HPT that lasted for at least six months, they were then considered to have met the cCDP endpoint. People who experienced confirmed six-month EDSS worsening had the option to receive open-label tolebrutinib.
The results showed “there was no difference between the treatment arms,” according to Fox, meaning that tolebrutinib failed to lower the risk of six-month cCDP compared with placebo.
The treatment also failed to lower the risk of three-month cCDP and had no effect on six-month confirmed disability improvement or decreases in disability.
Some signals suggested possible disability benefit
Looking only at six-month EDSS results, there was a “little bit of a suggestion” that tolebrutinib may have slowed disability progression. However, Fox emphasized that the results were not statistically significant.
The scientist noted that the observed 14% lower risk of EDSS progression with tolebrutinib was “directionally consistent” with findings in other MS types.
Tolebrutinib also significantly reduced the formation of new and enlarging brain lesions on MRI scans by 46%, which Fox said was “no surprise” given the known effects of tolebrutinib on this aspect of disease.
At the last study visit, tolebrutinib was associated with significantly less brain volume loss than placebo.
The safety profile of tolebrutinib was consistent with previous clinical studies. As expected with a BTK inhibitor, tolebrutinib was associated with higher rates of liver safety events than placebo.
The scientist noted that, compared with previous Ocrevus trials for PPMS, participants in this study had fewer active inflammatory brain lesions at study start and were more often exposed to prior MS therapies.
“How those differences may have impacted the treatment response will require some additional analyses,” Fox said.
The Multiple Sclerosis News Today team is providing virtual coverage of the ACTRIMS Forum 2026 from Feb. 5-7. Go here to see the latest stories from the conference.
