evobrutinib (M2951) / EMD Serono - LARVOL DELTA

Mechanistically resolved prediction of compound hepatotoxicity using primary human liver spheroids-Application to recent real-world cases. (PubMed, Drug Metab Dispos) - "Cholestatic liability was identified using bile acid coexposure with accurate classification of chlorpromazine and bosentan and confirmation of bile salt export pump downregulation. Importantly, the model also recapitulated hepatotoxicity signals observed in recent clinical development, including for Bruton's tyrosine kinase inhibitors (tolebrutinib and evobrutinib), oral glucagon-like peptide-1 receptor agonists (danuglipron vs orforglipron), synergistic toxicity on azelaprag-tirzepatide coexposure and enhanced sensitivity to the IL-17A inhibitor LY3509754 on coculture with nonparenchymal liver cells...The model maintains stable CYP expression and metabolic activity, captures the impact of nonparenchymal cells on hepatic clearance, and detects mitochondrial, cholestatic, and interaction-driven toxicity, including recent real-world clinical cases. These findings support 3-dimensional human liver spheroids as translational new approach methodologies for integrating..."

Journal • Real-world evidence • Hepatology • Liver Failure • Metabolic Disorders • IL17A

Transcriptomic analysis of B cells treated with evobrutinib in a mouse model of neuromyelitis optica spectrum disorders (EAN 2026) - No abstract available

Omic analysis • Preclinical • CNS Disorders • Neuromyelitis Optica Spectrum Disorder • Rare Diseases

Emerging Role of BTK Inhibitors in Multiple Sclerosis: From Immunobiology to Clinical Translation. (PubMed, Brain Sci) - "BTK inhibitors reduce inflammatory disease activity in relapsing MS and have emerging efficacy in progressive MS phenotypes; however, continued monitoring for hepatotoxicity is warranted. Optimization of CNS penetrance and pharmacologic selectivity may influence long-term clinical positioning."

Journal • Review • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis

Early Combined B-Cell Depletion and BTK Inhibition Reduced TLS-like Structures and Relapse in PLP139-151-Induced EAE. (PubMed, Int J Mol Sci) - "These data indicate that established TLS-like structures may represent treatment-resistant compartments, and that both B cells and microglia may be crucial during early formation for sustaining their disease relapse-driving activity. Our study confirms that TLS-like structures may be a key factor driving the compartmentalization of central nervous system inflammation, points to a potentially narrow therapeutic window for intervention, and proposes that early combined B-cell depletion and BTK inhibition may represent a promising strategy worthy of further investigation."

Journal • CNS Disorders • Inflammation • Multiple Sclerosis

Bruton's Tyrosine Kinase Inhibitors in Multiple Sclerosis: Mechanistic Considerations Across Relapsing and Progressive Disease. (PubMed, Molecules) - "Second-generation BTK inhibitors, including evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, and orelabrutinib, have advanced through Phase II-III development in MS. This review integrates molecular pharmacology and the most recent clinical evidence available through 2026 to examine how pharmacologic properties translate into stage-dependent therapeutic positioning. We also consider safety constraints within a disease-stage-specific benefit-risk framework, aiming to clarify the evolving role of BTK inhibition in MS."

Journal • Review • CNS Disorders • Inflammation • Multiple Sclerosis

Uncoupling Relapse Reduction and Disability Progression: Evidence From Tolebrutinib Studies. (PubMed, Neurol Clin Pract) - "Tolebrutinib was the only therapy to show a benefit on CDW without a measurable effect on relapses, highlighting a dissociation between disability worsening and relapse suppression not observed with other DMTs."

Journal • CNS Disorders • Multiple Sclerosis

Safety Comparison of Teriflunomide and Next-generation BTK Inhibitors in Relapsing Multiple Sclerosis: Network Meta-analysis of Randomized Controlled Trials (AAN 2026) - "Results Mortality was lower with tolebrutinib than teriflunomide (OR 0.50, CI 0.05-5.58), while evobrutinib had similar rates (OR 1.01, CI 0.06-16.14). Conclusions BTK inhibitors demonstrated less alopecia events and no increased ALT levels as compared to teriflunomide, whereas evobrutinib has more overall adverse events. These results point to targeted monitoring of patients and highlight the need for more."

Retrospective data • Alopecia • CNS Disorders • Immunology • Infectious Disease • Multiple Sclerosis

Bruton’s Tyrosine Kinase Inhibitors in Multiple Sclerosis: A Meta-analysis With Reconstructed Individual Patient Data (AAN 2026) - "Design/Methods A literature search was conducted through PubMed, Scopus, and WOS to identify RCTs evaluating BTK inhibitors (Tolebrutinib; Evobrutinib) in MS. Event-specific analyses revealed a lower risk of alopecia and gastrointestinal effects compared with teriflunomide (RR=0.49,0.48; respectively), as well as a higher risk of ALT elevation compared with placebo (RR=2.58). Conclusions BTK inhibitors showed potential in reducing MRI lesions and disability progression, improving confirmed disability, and demonstrated acceptable safety profile; however, further studies are needed to confirm these findings."

Retrospective data • Alopecia • CNS Disorders • Immunology • Multiple Sclerosis

BTK-Inhibitor Loaded Polymeric Nanoparticles Alleviate Systemic Lupus Erythematosus by Targeting Elimination of Autoreactive BAFFRhigh B Cells. (PubMed, Int J Mol Sci) - "Here, a liposome-delivery system capable of targeting BAFFRhigh autoreactive B cells by conjugating anti-BAFFR antibody on the surface of the PEG-liposomes and loading BTK-inhibitor ibrutinib (BTEL) was rationally designed. Notably, the BTEL nanoparticles could inhibit the survival and activation of B cells, and systemic administration of BTEL could alleviate the development of the lupus mouse model by decreasing the production of anti-dsDNA autoantibodies, along with reduced secretion of inflammatory cytokines and kidney damage, and without apparent side effects. These findings suggest the potential of BTEL in targeting autoreactive B cells, blocking signaling pathways, and improving the efficacy of BTK inhibitors, providing a promising therapeutic approach for SLE, while also reducing toxicity."

Journal • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • ITGAX

Efficacy and safety of Bruton's tyrosine kinase inhibitors compared to Teriflunomide in relapsing multiple sclerosis: A systematic review and meta-analysis. (PubMed, Mult Scler Relat Disord) - "Compared with teriflunomide, BTK inhibitors were associated with a reduced risk of short-term disability progression, whereas no differences were observed in relapse rates, MRI activity, or safety outcomes."

Journal • Retrospective data • Review • CNS Disorders • Multiple Sclerosis

Bruton Tyrosine Kinase Inhibition Limits Multiple Sclerosis Disease-Driving Inflammation While Promoting Regulatory B Cells. (PubMed, Neurol Neuroimmunol Neuroinflamm) - "These findings highlight the potential of BTK inhibition as a selective and sustainable immunomodulatory strategy for both B cells and myeloid cells in the context of chronic CNS inflammation. Despite their efficacy, broad-spectrum immunosuppressive therapies often fail to provide targeted immune modulation. By contrast, BTK inhibition promotes regulatory B-cell properties while leaving other B-cell functions intact, providing the basis for its broad use-potentially in combination with established anti-inflammatory agents."

Journal • CNS Disorders • Immune Modulation • Immunology • Inflammation • Multiple Sclerosis • Neuromyelitis Optica Spectrum Disorder • Rare Diseases • Solid Tumor

A large-scale human toxicogenomics resource for drug-induced liver injury prediction. (PubMed, Nat Commun) - "It flagged recent phase III clinical failures, including Evobrutinib, TAK-875, and BMS-986142, overlooked by animal studies. Unlike single-endpoint readouts-even from 3D models-transcriptomics offers a multi-dimensional system-level view of hepatocyte responses, capable of detecting diverse DILI mechanisms not captured by conventional assays. Scalable, actionable, and integrated into a broader AI/ML drug discovery platform, this work establishes toxicogenomics as a promising tool for developing safer therapeutics and addressing one of the most pressing challenges in toxicology."

Journal • Hepatology • Liver Failure

Effect of Evobrutinib on Pharmacokinetics of a Combined Oral Contraceptive (clinicaltrials.gov) - P1 | N=20 | Completed | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

New P1 trial

A TQT Study of Effect of M2951 on Cardiac Repolarization (clinicaltrials.gov) - P1 | N=36 | Completed | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

New P1 trial

Relative Bioavailability of Evobrutinib Tablet Batches (clinicaltrials.gov) - P1 | N=28 | Completed | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

New P1 trial

NEW TREATMENTS OF MULTIPLE SCLEROSIS (WCN 2025) - "This teaching course will provide a comprehensive overview of the latest advancements in MS treatment, including B-cell depleting therapies (e.g., ocrelizumab), cladribine, Bruton's tyrosine kinase (BTK) inhibitors, and sphingosine-1-phosphate (S1P) receptor modulators, with a focus on their mechanisms, clinical applications, emerging indications, and safety considerations...BTK inhibitors (e.g., evobrutinib, tolebrutinib), currently in phase III trials, target both peripheral and CNS-resident immune cells, showing promise for progressive MS. S1P receptor modulators (e.g., fingolimod, siponimod) regulate lymphocyte trafficking and are approved for RMS and secondary progressive MS (SPMS)...Additionally, this course will explore smoldering MS pathology, including chronic active lesions and neurodegeneration, and discuss whether emerging therapies, particularly BTK inhibitors, can address progression beyond relapse suppression. Through case discussions and trial data,..."

CNS Disorders

BRUTON'S TYROSINE KINASE REGULATES INFLAMMATION AND FIBROSIS IN PRIMARY BILIARY CHOLANGITIS (AASLD 2025) - "These findings uncover a novel role for BTK in liver fibrosis and support its potential as a therapeutic target in PBC and chronic liver diseases."

Fibrosis • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Liver Failure • Primary Biliary Cholangitis • BTK • COL1A2 • IL1B • TGFB1 • TIMP1 • TNFA • VIM

BRUTON'S TYROSINE KINASE INHIBITION AS A NOVEL MULTIMODAL THERAPY FOR ALCOHOL-ASSOCIATED HEPATITIS (AASLD 2025) - "WT mice received daily oral gavage of evobrutinib (BTK inhibitor; BTKi, 5mg/kg) or DMSO (vehicle control) for 11 days... Alcohol-induced BTK activation occurs in parenchymal and immune cells in the liver and drives steatosis, inflammation, NLRP3 inflammasome activation, and NET formation in AH involving hepatocytes and immune cells. BTK inhibition in multiple cell types may serve as a promising therapeutic strategy for AH."

Hepatology • Inflammation • Liver Failure • ELANE • FASN • IL1B • NLRP3 • PPARA • TNFA

Multiple sclerosis updates and the safety and efficacy of Bruton tyrosine kinase inhibitors in it: A systematic review. (PubMed, Dis Mon) - "With good safety and efficacy profiles in treating relapsing multiple sclerosis, both of the BTKis (Evobrutinib and Tolebrutinib) show promise. Both have promise as oral treatments of the future, but Tolebrutinib might have better effects on the central nervous system. To confirm long-term results and determine their role in progressive MS, more phase III trials are necessary."

Journal • CNS Disorders • Immunology • Infectious Disease • Inflammation • Multiple Sclerosis

Efficacy and safety of evobrutinib in relapsing multiple sclerosis: A meta-Analysis of randomized trials (EAN 2025) - No abstract available

Retrospective data • CNS Disorders • Multiple Sclerosis

The contribution of BTK signaling in myeloid cells to neuroinflammation. (PubMed, Front Immunol) - "We evaluated i) the impact of the BTK inhibitor (BTKi) evobrutinib on monocyte markers for activation, costimulation, adhesion and phagocytosis in peripheral blood mononuclear cell (PBMC) cultures from healthy and MS subjects; ii) the therapeutic effects and the action of evobrutinib on myeloid cell phenotype in the experimental autoimmune encephalomyelitis (EAE) model of MS; iii) the contribution of BTK in short-lived vs. long-lived myeloid cells to EAE expression via experiments with double transgenic mice allowing inducible inactivation of BTK in CX3CR1 expressing cells...However, conditional BTK deletion in short-lived or long-lived CX3CR1-positive cells did not reduce EAE severity. This functional evidence questions the real contribution of BTK expressing myeloid cells to experimental MS."

Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • CD163 • CX3CR1 • ITGA4

Next generation Bruton's tyrosine kinase inhibitors - characterization of in vitro potency and selectivity. (PubMed, Eur J Pharmacol) - "BTKi ranked in their selectivity as follows (most selective to least): remibrutinib, fenebrutinib, evobrutinib, orelabrutinib, rilzabrutinib and tolebrutinib. These data suggest that next generation BTKi show important differences in their in vitro target binding and selectivity when compared under the same conditions."

Journal • Preclinical • Allergy • Immunology

Evobrutinib mitigates neuroinflammation after ischemic stroke by targeting M1 microglial polarization via the TLR4/Myd88/NF-κB pathway. (PubMed, Mol Med) - "Evobrutinib inhibits the expression and activation of BTK in microglia, reducing M1 microglia-mediated neuroinflammation and alleviating ischemic injury following stroke. This effect is mechanistically linked to the inhibition of TLR4/Myd88/NF-κB-mediated M1 polarization of microglia."

Journal • Cardiovascular • Inflammation • Ischemic stroke • MYD88 • TLR4

Positive effect of evobrutinib in CNS remyelination models and lack of synergy with clemastine-A dose response study. (PubMed, Mult Scler J Exp Transl Clin) - "In both experimental models tested no significative improvement on remyelination of co-treatment with evobrutinib plus clemastine was observed. While evobrutinib increased 1.59 fold the number of microglia/macrophages, in the presence of clemastine the number of innate immune cells was decreased by 0.39 fold, therefore counteracting the beneficial effect of microglia/macrophages on remyelination."

Journal • CNS Disorders • Multiple Sclerosis • Solid Tumor

Design and application of a fluorescent probe for imaging of endogenous Bruton's tyrosine kinase with preserved enzymatic activity. (PubMed, RSC Chem Biol) - "Evobrutinib, a second-generation BTK inhibitor with high selectivity, was chosen as the scaffold...The dynamic signalling pathway of BTK in its native environment was investigated by confocal microscopy with Evo-2. This methodology is a valuable asset in the chemical biology toolbox for studying protein dynamics and interactions in real time without interfering with the protein activity."

Journal • Oncology • BTK