Evobrutinib Demonstrates Significant Reduction in Inflammatory Biomarkers and Chronic CNS Lesions in Phase 2 Trial for Multiple Sclerosis

Recently, Merck KGaA announced post-hoc analysis data from a Phase 2 clinical trial evaluating the brain-penetrant BTK inhibitor evobrutinib in patients with multiple sclerosis (MS). The trial results demonstrated that evobrutinib can mitigate central nervous system (CNS) brain damage associated with chronic inflammation. The press release highlighted that evobrutinib is the first BTK inhibitor to significantly reduce slow expanding lesions (SELs). SELs serve as early indicators of disease progression in chronic, active, demyelinating multiple sclerosis.

Multiple sclerosis is an autoimmune disease of the central nervous system caused by the immune system attacking myelin. Myelin is a lipid-rich substance that insulates and protects nerve fibers in the brain and spinal cord. The inflammation and tissue damage resulting from the disease disrupt the normal functioning of the brain, optic nerves, and spinal cord. Onset typically occurs between the ages of 20 and 40, making it the leading cause of disability in young and middle-aged adults, second only to trauma. Approximately 2.5 million people worldwide are affected. Currently, there is no curative therapy.

Evobrutinib is a highly selective, oral BTK inhibitor capable of crossing the blood-brain barrier. BTK plays a crucial role in the development and function of various immune cells, including B lymphocytes and macrophages. Therefore, BTK inhibition is expected to suppress autoantibody-producing cells. Preclinical studies have demonstrated that BTK inhibition may have therapeutic potential for certain autoimmune diseases. Evobrutinib is designed to inhibit B-cell proliferation and the release of antibodies/cytokines without directly affecting T-cell function.

This post hoc analysis evaluated the effect of 48 weeks of evobrutinib treatment on SEL volume in patients. The trial results demonstrated that, compared with placebo, evobrutinib reduced SEL volume in a dose-dependent manner, with the 75 mg twice-daily regimen exhibiting the greatest effect (p=0.047). Furthermore, in a subgroup analysis, the impact of evobrutinib on SEL volume was particularly pronounced in patients with more advanced disease.

Slowly expanding lesions (SELs) are a potential consequence of cumulative neuronal injury, particularly axonal loss. Previously reported results demonstrate that evobrutinib also significantly reduces gadolinium-enhancing (Gd+) lesions associated with acute inflammation. This indicates that evobrutinib can attenuate both acute and chronic neuroinflammation, which collectively contribute to the worsening of patient symptoms. Furthermore, in the evobrutinib group, blood neurofilament light chain (NfL) levels associated with disease progression were significantly reduced as early as Week 12 and remained reduced at the final analysis time point at Week 24.

The integrated safety analysis summarizes three Phase 2 clinical trials of evobrutinib treatment in patients with systemic lupus erythematosus, rheumatoid arthritis, and relapsing multiple sclerosis.

References:

[1] New Data Presented at ECTRIMS Show Evobrutinib is First BTK Inhibitor to Demonstrate a Significant Reduction in Slowly Expanding Lesions (SEL) in Patients with RMS. Retrieved October 15, 2021, from https://www.businesswire.com/news/home/20211014005717/en/New-Data-Presented-at-ECTRIMS-Show-Evobrutinib-is-First-BTK-Inhibitor-to-Demonstrate-a-Significant-Reduction-in-Slowly-Expanding-Lesions-SEL-in-Patients-with-RMS

(The original text has been abridged.)

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