Sanofi’s brain-penetrant BTK inhibitor could reduce disability markers progression for people with MS

Sanofi believes its brain-penetrant BTK inhibitor shows promise for reducing both neuroinflammation and neurodegeneration, markers of disability progression in people living with MS.

The company’s investigational BTK (Bruton’s tyrosine kinase) inhibitor, an oral, brain-penetrant, selective small molecule achieved both the primary and secondary endpoints in a Phase 2b trial evaluating efficacy and safety in participants with relapsing forms of multiple sclerosis. The BTK inhibitor (SAR442168) significantly reduced disease activity associated with multiple sclerosis (MS) as measured by magnetic resonance imaging (MRI).
                

The Phase 2 study was designed to assess the dose-response relationship after 12 weeks of treatment with SAR442168, by measuring the number of new brain lesions on MRI, Sanofi said. The study evaluated four doses ranging from 5mg – 60mg after 12 weeks and used placebo data obtained at four weeks. In the primary objective measuring the number of new Gd-enhancing T1 hyperintense lesions, a multiple comparison procedure with modeling was applied to the dose-response data, revealing the exponential model provided the best fit (p=0.03), the company has explained. The treatment effect of SAR442168 at the 60mg dose was 85% relative reduction of new Gd-enhancing T1 hyperintense lesions. For the secondary objective measuring the number of new or enlarging T2 hyperintense lesions, the linear model was the best fit (p<0.0001), and compared to placebo, treatment with SAR442168 60mg resulted in an 89% relative reduction.

Sanofi said that the BTK inhibitor modulates both adaptive (B-cell activation) and innate (CNS microglial cells) immune cells thought to be linked to neuroinflammation and neurodegeneration in the brain and spinal cord, the clinical significance of which is under investigation. 

The academic principal investigator of the Phase 2b study, Daniel Reich said that the results of this study give hope that SAR442168 may become an important treatment for relapsing MS. Reich, MD, PhD, who is a Senior Investigator at the National Institutes of Health, Chief of the Translational Neuroradiology Section in the National Institute of Neurological Disorders and Stroke, said: “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.”

Sanofi noted that approximately 1.2 million people in the US and Europe have been diagnosed with MS, an unpredictable, chronic disease that attacks the central nervous system. Despite current treatments, many MS patients continue to accumulate disability, and one in four MS patients suffers from progressive forms of the disease with limited or no treatments available.

John Reed, MD, PhD, Sanofi’s Global Head of Research & Development. “The effect on brain lesions seen in our Phase 2b study is encouraging. As we go forward, we will explore whether our brain-penetrant BTK inhibitor offers strong efficacy and exceptional safety for a broad spectrum of MS patients with either relapsing or progressive forms of disease. Our phase 3 program is moving rapidly to initiate four pivotal clinical trials.”