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Tolebrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, reduced new, active brain lesions in people with relapsing multiple sclerosis (MS), a 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 .

"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 .

"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."

The trial used a crossover design to minimize exposure to placebo. The primary outcome was the number of new gadolinium-enhancing brain lesions after 12 weeks of treatment; a key secondary outpoint was new or enlarging T2 lesions. Participants underwent MRI at the start of the study, then every 4 weeks over 16 weeks.

Participants had been diagnosed with relapsing MS -- either relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive (SPMS) -- and had at least one relapse within the previous year, or at least two relapses within the previous 2 years, or at least one active gadolinium-enhancing brain lesion in the 6 months before screening. People who had primary progressive MS or SPMS without relapse were excluded.

A total of 130 RRMS and active SPMS patients were randomized to tolebrutinib treatment. Participants received one of four tolebrutinib doses (5, 15, 30, or 60 mg) orally once daily for 12 weeks and 4 weeks of placebo before or after the tolebrutinib treatment period. The total study duration was 24 weeks, including a screening period of 4 weeks, a treatment period of 16 weeks, and a follow-up period of up to 4 weeks.

The secondary endpoint of new or enlarging T2 lesions was significant for all six dose-response models. In exploratory analyses, the researchers evaluated the effects of tolebrutinib on slowly evolving lesions and paramagnetic rim lesions as markers of chronic neuroinflammation. The volume of slowly evolving lesions was lower with 60 mg tolebrutinib than with lower doses or with placebo, raising the possibility that tolebrutinib may help MS patients with progressive disease.

One serious adverse event occurred, a relapse of MS in a patient in the 60 mg group. The most common non-serious adverse event during tolebrutinib treatment was headache, which ranged from 3% of the 5 mg group to 13% of the 60 mg group. No discontinuations related to safety or deaths related to treatment occurred.

Phase III trials of tolebrutinib in patients with both relapsing and progressive forms of MS are underway. In addition, "phase III studies in patients with multiple sclerosis of several other Bruton's tyrosine kinase inhibitors have been initiated," Reich and colleagues noted. "Tolebrutinib and these other agents have distinct pharmacological profiles, differing in potency, selectivity, and CNS distribution."

"Based on CNS exposure and in-vitro potency, tolebrutinib stands out as having the potential to achieve pharmacologically relevant exposures within the CNS," the team added. "How that potential translates to clinical benefits will be evaluated in the ongoing phase III development program."

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