evobrutinib (M2951) / EMD Serono - LARVOL DELTA

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

How Does Fenebrutinib Work? Exploring Kinetic and Mechanistic Features That Influence BTK Potency, Selectivity and Pharmacology (ACTRIMS Forum 2025) - P2, P3 | "Fenebrutinib (FEN) is being developed because it is a potent and highly selective noncovalent reversible BTKi that has shown efficacy in several diseases, including a Ph 2 RMS study (NCT05119569) and is currently in Ph 3 trials in RMS (NCT04586010, NCT04586023) and PPMS (NCT04544449).Objectives: Define the BTK binding mechanisms and selectivities of FEN and irreversible covalent inhibitors remibrutinib (REMI), tolebrutinib (TOL) and evobrutinib (EVO); compare their projected relative rates of BTK inhibition at clinical-dose concentrations reported in human CSF. Using biochemical kinetic competition binding assays, we defined binding mechanisms to BTK and to an off-target BMX, a related cytoplasmic protein tyrosine kinase. Fenebrutinib’s slowly reversible binding mechanism allows for potent, selective BTK inhibition and illustrates how kinetic and mechanistic features of drug-target interactions impact pharmacology. Fenebrutinib’s properties and observed..."

CNS Disorders • Hematological Disorders • Immunology • Multiple Sclerosis

Ionic Liquid Aided [11C]CO Fixation for Synthesis of 11C-carbonyls. (PubMed, ChemistryOpen) - "The use of [11C]CO is limited by its low solubility in organic solvents. Herein, we report a proof-of-concept study evaluating a new method to prepare 11C-labeled amides, ureas and carbamates via reaction of [11C]CO in [P4442][Pen] and applied for fully automated radiosyntheses of Bruton's tyrosine kinase inhibitors, [11C]evobrutinib and [11C]ibrutinib."

Journal

Evolution-RMS Trials: Did Teriflunomide Perform Beyond Expectations? A Predictive Meta-Analytic Testing for Teriflunomide 14mg in Relapsing Multiple Sclerosis (ISPOR-EU 2024) - "OBJECTIVES: In December 2023, two Phase III trials (evolutionRMS1 and evolutionRMS2) comparing evobrutinib and teriflunomide in people with relapsing multiple sclerosis (RMS) were terminated as it was indicated that teriflunomide annualised relapse rates (ARR) were lower than those reported in recent Phase III randomised controlled trials (RCTs). PIs could support better decision-making about clinical trial planning and execution. With wide PIs, as in the case of teriflunomide, there is a higher risk that the new trial may not show statistically significant difference. Future phase III studies planning should consider both RCT and RWS evidence and clinical and HEOR stakeholders should work in collaboration to enhance the strategic planning and execution for a successful trial."

CNS Disorders • Multiple Sclerosis

THERAPEUTIC INHIBITION OF BRUTON'S TYROSINE KINASE (BTK) ACTS ON BOTH IMMUNE CELLS AND HEPATOCYTES TO ATTENUATE IMMUNE CELL ACTIVATION AND STEATOSIS IN A MOUSE MODEL OF ALCOHOL-ASSOCIATED HEPATITIS (AASLD 2024) - "Some mice received daily oral gavages of evobrutinib, a BTK inhibitor (BTKi), or DMSO on days 7-10... Our study demonstrates a central role of alcohol-induced BTK activation in regulating steatosis, inflammation, NLRP3 inflammasome activation and NETs formation in AH by acting on both hepatocytes and immune cells. Our novel findings highlight the therapeutic potential of BTK inhibition as a new potential strategy to treat AH."

Immune cell • Preclinical • Hepatology • Inflammation • ELANE • FASN • NLRP3 • PPARA

Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): two multicentre, randomised, double-blind, active-controlled, phase 3 trials. (PubMed, Lancet Neurol) - P3 | "The efficacy of evobrutinib was not superior to that of teriflunomide. Together, efficacy and liver-related safety findings do not support the use of evobrutinib in people with relapsing multiple sclerosis."

Journal • P3 data • CNS Disorders • Infectious Disease • Multiple Sclerosis • Novel Coronavirus Disease • Pain

Evobrutinib in multiple sclerosis: challenges and unmet goals. (PubMed, Lancet Neurol) - No abstract available

Journal • CNS Disorders • Multiple Sclerosis

FCRL5: A Biomarker Shedding Light on Atypical B Cell in Multiple Sclerosis (ECTRIMS 2024) - "REC-1 cell line expressing FCRL5 was treated with Evobrutinib, followed by FCRL5 membrane expression analysis by flow cytometry as well as measurement of its soluble form in super-natant by ELISA... Our results demonstrate a potential role for atypical B-cells in MS pathogenesis, with FCRL5 as a surrogate marker. FCRL5 may play a diagnostic and prognostic role in the management of MS."

Biomarker • CNS Disorders • Inflammation • Multiple Sclerosis • BTK • CCL2 • CRTAM • CXCL13 • MMP9 • NEFL • TNFSF14

Targeting Inflammation: Evobrutinib's Role in Controlling CNS Autoimmune Disease Through B Cell and Myeloid Cell Modulation (ECTRIMS 2024) - "These findings highlight evobrutinib's dual mechanism of promoting regulatory B cells whilst dampening inflammatory responses in other BTK-expressing cells. These mechanisms collaborate to prevent spontaneous EAE and offer potential therapeutic benefits for disease progression."

IO biomarker • Late-breaking abstract • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • FASLG • PD-L1 • TIGIT

Antibody-mediated recognition of CNS-antigen as therapeutic target (ECTRIMS 2024) - "In addition, we analysed the effects of evobrutinib on human macrophage-like cells focusing on their phagocytic ability and antigen presentation... BTK inhibition dampens the pro-inflammatory activity and antigen presentation of APC while promoting phagocytosis. This leads to a reduced incidence and severity of MOG-IgG-mediated EAE in transgenic TCRMOG mice."

IO biomarker • CNS Disorders • Immunology • Inflammation • Solid Tumor • CD14 • CD40

Bruton Tyrosine Kinase Inhibitors decrease inflammatory-associated immune cell phenotypes in treatment naïve relapsing and progressive multiple sclerosis (ECTRIMS 2024) - "In MS and age/sex-matched HCs, whole PBMCs responded to both tolebrutinib and evobrutinib by decreasing inflammatory cytokine release and normalizing microRNA expression levels. The inability of BTKis to influence expression of co-stimulatory markers on B cells and myeloid cells suggests that the antigen presenting capacity of these cells is not influenced by BTK inhibition."

Immune cell • CNS Disorders • Inflammation • Multiple Sclerosis • CD80 • CD86 • IL6 • MIR155 • MIR223