Tolebrutinib reduces disability progression in nonrelapsing secondary progressive multiple sclerosis

1. In this randomized controlled trial of patients with nonrelapsing secondary progressive multiple sclerosis (SPMS), oral tolebrutinib reduced the risk of disability progression sustained for at least six months, compared to placebo.

2. Tolebrutinib was associated with an increased risk of respiratory tract infections, relapse of MS, and elevated alanine aminotransferase (ALT) levels, which resulted in one liver transplantation.

Evidence Rating Level: 1 (Excellent)

Study Rundown: MS is a chronic progressive neuroinflammatory disease with a high disability and mortality burden. Current disease-modifying therapies target focal inflammation, thereby reducing lesion formation and the risk of acute relapse. Nevertheless, MS is associated with gradually progressive neurologic impairment, or disability accrual, caused by chronic neuroinflammation independent of relapse activity, for which disease-modifying therapies are minimally effective. Tolebrutinib is an oral Bruton’s tyrosine kinase (BTK) inhibitor targeting these specific pathways. This clinical trial investigated tolebrutinib in patients with nonrelapsing SPMS. Compared to placebo, tolebrutinib resulted in a lower percentage of disability progression sustained for at least six months. Tolebrutinib was associated with a higher incidence of adverse events, including COVID-19, MS relapse, and pneumonia, as well as ALT elevation and one death related to liver transplantation postoperative complications. In the patient who received liver transplantation due to tolebrutinib-related liver failure, this occurred before the implementation of weekly monitoring, which showed that most observed ALT elevations resolved without complications. Nonetheless, these results demonstrated that tolebrutinib lowered the risk of disability progression in patients with nonrelapsing SPMS.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: This was an event-driven trial assessing the safety and efficacy of tolebrutinib in patients with nonrelapsing SPMS. Patients were included who were between 18 and 60 years old, were diagnosed with SPMS, had no superimposed relapses in the preceding 24 months, and had no documented evidence of disability progression in the previous 12 months. In total, 1,131 patients were randomized 2:1 to receive daily oral tolebrutinib 60mg or a placebo. The primary outcome was confirmed disability progression, using the Expanded Disability Status Scale (EDSS) score. A smaller percentage of participants in the tolebrutinib group had confirmed disability progression sustained for at least six months (22.6%) compared to the placebo group (30.7%) (hazard ratio [HR], 0.69; 95% Confidence Interval [CI], 0.55-0.88; p=0.003). Disability progression sustained for more than three months was 27.6% in the tolebrutinib group and 34.2% in the placebo group (HR, 0.76; 95% CI, 0.61-0.94; p=0.01). Annualized rate of new or enlarging lesions on T2-weighted MRI was 1.84 in the tolebrutinib group, compared to 2.95 in the placebo group (relative rate, 0.62; 95% CI, 0.43-0.90; p=0.01). Serious adverse events occurred in 15.0% of patients in the tolebrutinib group and 10.4% in the placebo group. Two deaths occurred in the tolebrutinib group: one due to postoperative complications after a liver transplantation (assessed as related to tolebrutinib) and one physician-assisted suicide (unrelated). One death occurred in the placebo group due to cerebral edema and hemorrhage from a fall. A protocol amendment increased the frequency of liver monitoring implemented after the one participant who underwent liver transplantation following tolebrutinib-related liver failure. After weekly liver monitoring was implemented, all cases of elevated liver-enzyme levels resolved without sequelae. Overall, in patients with nonrelapsing SPMS, treatment with tolebrutinib resulted in a lower risk of disability progression sustained for at least six months compared to placebo.

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