Tolebrutinib may hold promise for progressive MS, too
by Judy George, Senior Staff Writer, MedPage Today September 3, 2021
Tolebrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, reduced new, active brain lesions in people with relapsing multiple sclerosis (MS), a phase IIb dose-finding trial showed.
After 12 weeks of daily oral tolebrutinib treatment, MRI showed dose-dependent reductions in the number of new gadolinium-enhancing lesions, reported Daniel Reich, MD, of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, and co-authors.
Mean lesions per patient at week 12 were 1.03 for placebo, 1.39 for the 5 mg dose, 0.77 for the 15 mg dose, 0.76 for the 30 mg dose, and 0.13 for the 60 mg dose (P=0.03), the researchers wrote in the study online in Lancet Neurology.
“This trial report shows for the first time the safety and activity of this new therapy in relapsing MS,” co-author Robert Fox, MD, of the Cleveland Clinic, told MedPage Today.
“It shows that a BTK inhibitor that penetrates the brain can reduce MS disease activity on MRI and have a favorable safety and tolerability profile,” Fox continued. “Since this drug can penetrate the central nervous system, it may have an impact on some of the mechanisms that drive progressive MS.”
“As a result, the tolebrutinib phase III trial program is including patients with primary progressive MS and secondary progressive MS. These forms of MS currently have very limited treatment options and are in great need of effective therapies,” he said.
Given the heterogeneity of MS and the fact that many patients have refractory or progressive disease, new treatments are needed, despite the explosive growth in MS drugs in the past few decades, noted Jorge Correale, MD, of the Institute for Neurological Research in Buenos Aires, Argentina, in an accompanying editorial.
“Bruton’s tyrosine kinase is a cytoplasmic tyrosine kinase expressed by B cells and myeloid cells,” Correale wrote. “Both B cells and myeloid cells (particularly microglia) are important drivers of multiple sclerosis, suggesting that inhibitors of Bruton’s tyrosine kinase, such as the irreversible inhibitors evobrutinib, tolebrutinib, and orelabrutinib, and the reversible inhibitors fenebrutinib and BIIB091, might provide therapeutic benefits for patients.”
Bruton’s tyrosine kinase inhibitors may be less likely than monoclonal antibodies to trigger antibody responses, allergic reactions, or neutralization of their therapeutic actions, Correale noted. “Additionally, these inhibitors, as small molecules, might be able to access the [central nervous system] and inhibit microglial activation.”
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