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Tolebrutinib Delays Disability Progression in Nonrelapsing Secondary Progressive MS
Tolebrutinib delayed the time to onset of 6-month confirmed disability progression by 31% compared with placebo in patients with nonrelapsing secondary progressive multiple sclerosis (MS), according to results presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) conference in Copenhagen, Denmark.
The results were from the HERCULES phase 3 study of tolebrutinib, an investigational oral Bruton’s tyrosine kinase inhibitor. Analysis of secondary endpoints in the trial showed the number of patients who experienced confirmed disability improvement was nearly double with tolebrutinib: 10%, compared to 5% with placebo.
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“Secondary progressive MS is characterized by insidious worsening of disability over time, independent of relapses, and represents a critical unmet need because we don’t have effective treatments,” said Robert Fox, MD, vice chair of research at the Cleveland Clinic Neurological Institute, Cleveland, Ohio, and a chair of the HERCULES Global Steering Committee. “The results of HERCULES show clearly that tolebrutinib delayed disability progression in people with nonrelapsing secondary progressive MS — and some people even improved disability — by uniquely targeting the biological processes driving disease progression in the brain.”
Preliminary study analysis identified a slight increase of some adverse events with tolebrutinib. Liver enzyme elevations more than 3 times the upper limit of normal occurred in 4.1% of patients receiving tolebrutinib compared with 1.6% receiving placebo. Some 0.5% of patients in the tolebrutinib group experienced peak alanine aminotransferase increases more than 20 times the upper limit of normal within the first 90 days of treatment.
One patient in the tolebrutinib arm received a liver transplant and died of postoperative complications. A revised study protocol with more frequent monitoring has mitigated such serious liver sequelae, Sanofi stated.
Results from GEMINI 1 and 2 phase 3 studies of tolebrutinib compared with standard-of-care teriflunomide in patients with relapsing MS were also presented at ECTRIMS. Neither study met its primary endpoint of statistically significant improvement in annualized relapse rates with tolebrutinib compared with teriflunomide. However, a pooled analysis of data from both trials showed tolebrutinib delayed the time to onset of 6-month confirmed disability worsening by 29%.
According to Sanofi, annualized relapse rates in the teriflunomide arm were historically low in both GEMINI studies, and pooled analysis showed no difference between teriflunomide and tolebrutinib. Observed rates amounted to approximately 1 relapse every 8 years.
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