Evobrutinib (DB15170): A Comprehensive Analysis of a Covalent BTK Inhibitor from Preclinical Promise to Clinical Discontinuation

Executive Summary

Evobrutinib (DrugBank ID: DB15170) is an investigational, orally administered, small-molecule drug developed by Merck KGaA as a highly selective, covalent inhibitor of Bruton's tyrosine kinase (BTK). The compound was advanced into late-stage clinical development based on a compelling scientific rationale for its use in autoimmune diseases, most notably relapsing multiple sclerosis (MS). The therapeutic hypothesis for Evobrutinib was particularly ambitious, predicated on a dual mechanism of action that targeted both B-lymphocytes of the adaptive immune system and myeloid cells, including microglia of the innate immune system residing within the central nervous system (CNS). This dual modulation, enabled by the drug's demonstrated ability to penetrate the blood-brain barrier, positioned Evobrutinib as a potential next-generation therapy capable of addressing both the inflammatory relapses and the underlying progressive neurodegeneration characteristic of MS.

Initial clinical data from a large Phase II study in relapsing MS were promising, demonstrating that Evobrutinib met its primary endpoint by significantly reducing the number of active, gadolinium-enhancing brain lesions on magnetic resonance imaging (MRI). Long-term follow-up and post-hoc analyses further supported its biological activity, showing sustained low relapse rates and favorable effects on key biomarkers of neuroaxonal damage and chronic inflammation, such as neurofilament light chain (NfL) and slowly expanding lesions (SELs). These encouraging results prompted the initiation of a large-scale Phase III program.