Evobrutinib Is the First and Only BTK Inhibitor Demonstrated to Reduce Key Biomarker of Neuronal Damage and Inflammation in Multiple Sclerosis Patients

German pharmaceutical giant Merck KGaA recently presented data from a placebo-controlled, randomized Phase II trial at the 73rd Annual Meeting of the American Academy of Neurology (AAN) in 2021. The trial demonstrated that treatment with evobrutinib, an oral, highly selective BTK inhibitor, significantly reduced serum neurofilament light chain (NfL) levels in patients with multiple sclerosis (MS), a key biomarker of neuronal damage and inflammation.

Notably, evobrutinib is the first and only Bruton’s tyrosine kinase (BTK) inhibitor demonstrated to reduce key biomarkers of neurodegeneration and inflammation in patients with multiple sclerosis (MS). Elevated levels of neurofilament light chain (NfL) in the blood are associated with neuronal damage and inflammation and may predict future brain atrophy and disease progression.

Professor Jens Kuhle, Director of the Multiple Sclerosis Center at the University Hospital Basel in Switzerland, stated: “Blood neurofilament light chain (NfL) is a biomarker that can monitor disease activity and treatment response, potentially offering a less burdensome and more sensitive alternative to other standard clinical metrics in patients with multiple sclerosis (MS). These data provide key insights into the potential role of evobrutinib in modulating the clinical course of multiple sclerosis, and further indicate that BTK inhibition by evobrutinib reduces tissue damage associated with the disease.”

In this placebo-controlled Phase II trial of evobrutinib in patients with relapsing multiple sclerosis (RMS), a post hoc analysis evaluated 166 patients who had baseline neurofilament light chain (NfL) levels and at least one post-baseline NfL measurement. The data showed that the evobrutinib 75 mg twice-daily (BID) group exhibited the greatest relative reduction in NfL levels at Weeks 12 and 24 compared with the placebo group. Currently, the twice-daily dosing regimen, which provides exposure equivalent to 75 mg BID, is being evaluated in Phase III trials, with patient enrollment scheduled for completion in 2021.

The primary results from this Phase II study were published in the New England Journal of Medicine in 2019. Given that elevated neurofilament light chain (NfL) levels are associated with clinical disability and brain atrophy in multiple sclerosis (MS), these findings, together with prior clinical trial data demonstrating reductions in T1 gadolinium-enhancing (Gd+) lesions and annualized relapse rate (ARR), further support the hypothesis that Bruton’s tyrosine kinase (BTK) inhibition with evobrutinib may simultaneously impact both the inflammatory and progressive aspects of MS within the central nervous system (CNS).

In another oral presentation at the AAN Annual Meeting, levels of BTK and activated (phosphorylated) BTK (pBTK) were measured in B cells isolated from patients with relapsing multiple sclerosis (RMS). The results further support the impact of evobrutinib on central nervous system (CNS) pathology in patients with multiple sclerosis (MS). pBTK was highly expressed in B-cell subsets of RMS patients, including memory B cells expressing T-bet and CXCR3. Evobrutinib reduced the migration of CXCR3+ memory B cells across human CNS endothelial cell monolayers, suggesting that evobrutinib may modulate the activity of pathogenic B cells and influence the progression of MS.

Furthermore, an exploratory analysis scheduled for presentation at the triMS online meeting on May 27 evaluated the relationship between the distribution of evobrutinib in the cerebrospinal fluid (CSF) and its plasma concentration in patients with relapsing multiple sclerosis (RMS). Plasma and CSF samples were collected from a subgroup of patients with multiple sclerosis (MS) receiving 75 mg twice daily (BID) treatment in the Phase II open-label extension (OLE) study. Evobrutinib was detected in the CSF of all patients included in the analysis (n=9). CSF concentrations were largely consistent with plasma free concentrations. This suggests that, in addition to inhibiting Bruton’s tyrosine kinase (BTK) on peripheral cells, evobrutinib may also inhibit BTK-expressing B cells and myeloid cells within the central nervous system (CNS), which could potentially influence disease progression in MS.

Danny Bar Zohar, M.D., Global Head of Business Development for Healthcare at Merck KGaA, stated: “Taken together, current preclinical and clinical data indicate that evobrutinib inhibits multiple sclerosis (MS) mechanisms involved in disease activity and progression. Coupled with its published and presented properties of central nervous system penetration and very high BTK occupancy, these findings further substantiate the significant potential of evobrutinib in the treatment of patients with multiple sclerosis.”

Chemical Structure of Evobrutinib (Image source: medchemexpress.cn)

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system and the most common non-traumatic, disabling neurological disorder among young adults. It is estimated that approximately 2.8 million people worldwide are living with multiple sclerosis. Although symptoms may vary, the most common manifestations of MS include blurred vision, numbness or tingling in the limbs, and issues with strength and coordination. The relapsing-remitting type is the most common form of multiple sclerosis.

Evobrutinib (M2951) is currently under clinical development to explore its potential as a treatment for multiple sclerosis (MS). This drug is an oral, highly selective Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a critical role in the development and function of various immune cells, including B lymphocytes and macrophages.

Evobrutinib is designed to inhibit major B-cell responses, such as proliferation and the release of antibodies and cytokines, without directly affecting T cells. BTK inhibition is believed to suppress autoantibody-producing cells, and preclinical studies have suggested that BTK inhibition may have therapeutic potential in certain autoimmune diseases. Currently, a global Phase III clinical development program is evaluating evobrutinib for the treatment of multiple sclerosis (MS), comprising two pivotal Phase III studies, EVOLUTION RMS 1 and 2. Evobrutinib is currently under clinical development and has not yet been approved in any country.

Original Source: Evobrutinib is the First and Only BTK Inhibitor to Demonstrate Reduction of a Key Biomarker of Neuronal Damage and Inflammation in Patients with MS

Original Title:New Drug for Multiple Sclerosis (MS)! Merck’s Evobrutinib: The First BTK Inhibitor to Reduce Key Biomarkers of Neurodegeneration and Inflammation!

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