Sanofi brain-penetrant BTK inhibitor shows reduced activity in Phase 2 relapsing MS trial

Paris: Sanofi'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. 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 modelling was applied to the dose-response data, revealing the exponential model provided the best fit (p=0.03).

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.

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 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 smouldering MS lesions, there is also a 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 a broad and innovative testing of this BTK inhibitor in phase 3 studies in MS."

In the US and Europe, approximately 1.2 million people 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.

"We believe that our brain-penetrant BTK inhibitor shows promise for reducing both neuroinflammation and neurodegeneration, markers of disability progression in people living with MS," said 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 the disease. Our phase 3 program is moving rapidly to initiate four pivotal clinical trials."

In the Phase 2b trial, no new safety signals were identified, with only a single serious adverse event (MS relapse) reported, in a patient treated with SAR442168, over 12 weeks. The most frequent adverse events (AEs) were headache (3 to 13%), upper respiratory tract infection (3 to 6%) and nasopharyngitis (3 to 9%).

The BTK inhibitor SAR442168 is currently under clinical development, and its safety and efficacy have not been confirmed by any regulatory authority.

Read also: Sanofi to present Phase 2 detailed results of its brain-penetrant BTK inhibitor in relapsing multiple sclerosis