Daniel Reich, MD, PhDDaniel Reich, MD, PhD
An investigational oral agent that inhibits Bruton’s tyrosine kinase significantly reduced multiple sclerosis (MS) disease activity on MRI in a phase 2b clinical trial. SAR442168, a brain-penetrant, selective small molecule met both the primary and secondary end points in patients with relapsing forms of MS.

The data announced by Sanofi were accepted to be presented at the canceled American Academy of Neurology 2020 Annual Meeting.

“The results of this study give hope that SAR442168 may become an important treatment for relapsing MS,” said Daniel Reich, MD, PhD, senior investigator at the National Institutes of Health, chief of the Translational Neuroradiology Section in the National Institute of Neurological Disorders and Stroke, and the academic principal investigator of the phase 2b study. “In the context of compelling, emerging data about the role of the brain’s innate immune system in smoldering MS lesions, there is also good reason to believe that SAR442168 — due to its molecular mechanism of action and ability to cross the blood-brain barrier — may have additional effects that we need to study more deeply. In my view, it’s important to move forward with broad and innovative testing of this BTK inhibitor in phase 3 studies in MS.”

The 12-week, randomized, double-blind, placebo-controlled crossover trial (NCT03889639) assessed the dose-response relationship of 4 doses of the study drug, ranging from 5 mg to 60 mg, versus placebo in patients with active relapsing forms of MS. Patients enrolled (N=130) were age 18 to 55 with an Expanded Disability Status Scale score of 0 to 5.5, and also met criteria for active MS, including having ≥1 relapse within the prior year, ≥2 relapses within the prior 2 years, or ≥1 active gadolinium-enhancing brain lesion on MRI in the past 6 months prior to screening.

Ultimately, participants were randomly assigned to the 4 dose groups or placebo: 5 mg (n=33), 15 mg (n=32), 30 mg (n=33), 60 mg (n=32), and placebo (n=66). One group received the study drug for 12 weeks then crossed over to placebo for 4 weeks, while the other group first received placebo for 4 weeks before crossing over to the study drug for 12 weeks.

After 12 weeks of treatment, an exponential model used to analyze the data showed a 85% relative reduction in new gadolinium-enhancing lesions in the 60-mg group with a mean number of new lesions of 0.13 (P = .03) compared with 0.76 in the 30-mg group, 0.77 in the 15-mg group, 1.39 in the 5-mg group, and 1.03 with placebo.

The findings for the secondary end point were also significant, with patients in the 60-mg group demonstrating an 89% relative reduction in new or enlarging T2 hyperintense lesions (P <.0001) at 12 weeks, with a mean number of lesions of 0.23 compared with 1.30 in the 30-mg group, 1.32 in the 15-mg group, 1.90 in the 5-mg group, and 2.12 in the placebo group.

Overall, 129 patients completed the study successfully, with no adverse events that led to study or treatment discontinuation. Fifty percent of patients in the 60-mg group reported experienced any AE, with 22% deemed treatment-related. The most frequently reported AEs were headache, upper respiratory tract infection, and nasopharyngitis; 1 serious AE was reported. Notably, 2 patients, 1 in the 30-mg group and 1 in the 60-mg group, had elevated alanine aminotransferase levels more than 3 times the upper limit of normal, which were recorded at a single post-baseline time point before returning to normal, and both patients remained on treatment.

Additional study end points, including those related to the modulation of B-cells and microglial cells, are currently being explored for clinical significance.

Based on the results, Sanofi plans to initiate 4 phase 3 pivotal trials.

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REFERENCE
Sanofi brain-penetrant BTK inhibitor significantly reduced disease activity in Phase 2 trial in relapsing multiple sclerosis [news release]. Paris, France: Sanofi. April 23, 2020. sanofi.com/en/media-room/press-releases/2020/2020-04-23-07-00-00. Accessed April 23, 2020.