Sanofi brain-penetrant BTK inhibitor SAR 442168 significantly reduced disease activity in Phase IIb trial in relapsing multiple sclerosis.-

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 IIb trial evaluating efficacy and safety in participants with relapsing forms of multiple sclerosis . The BTK inhibitor (SAR 442168) significantly reduced disease activity associated with multiple sclerosis (MS) as measured by magnetic resonance imaging (MRI).

The Phase II study was designed to assess the dose-response relationship after 12 weeks of treatment with SAR 442168, 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 modeling was applied to the dose-response data, revealing the exponential model provided the best fit (p=0.03). The treatment effect of SAR 442168 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 SAR 442168 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.

In the Phase IIb trial, no new safety signals were identified, with only a single serious adverse event (MS relapse) reported, in a patient treated with SAR 442168, 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%.

About the Phase IIb Trial: The Phase IIb trial was a randomized, double-blind, placebo-controlled, cross-over, 12- week dose-ranging trial evaluating SAR 442168 in patients with recurring MS. In one group, patients (n=64) received one of four doses of SAR 442168 for the first 12 weeks, then crossed over to placebo for four weeks. The other group of patients (n=66) received 4 weeks of placebo before crossing over to SAR 442168, providing data that were used to estimate a dose-response curve while minimizing exposure to placebo. In the study, SAR 442168 demonstrated a dose-response relationship in reducing the number of new gadolinium-enhancing T1-hyperintense brain lesions after 12 weeks of treatment. The prespecified model that provided the best-fit to the dose-response relationship will be used for selection of the Phase III dose. 123 of 129 participants who completed the trial have enrolled into a long-term safety follow-up study to assess safety and tolerability of SAR 442168.