Remibrutinib Inhibits Neuroinflammation Driven by B Cells and Myeloid Cells in Preclinical Models of Multiple Sclerosis (P2-3.013)

Abstract

<h3>Objective:</h3> To assess the mechanism of action and efficacy of remibrutinib in experimental autoimmune encephalomyelitis (EAE) mouse models of multiple sclerosis (MS). <h3>Background:</h3> Bruton’s tyrosine kinase (BTK) is a key node in B-cell receptor and fragment crystallizable receptor signaling. BTK inhibitors (BTKis) are an emerging oral option for patients with MS. Remibrutinib (LOU064) is a potent and highly selective covalent BTKi with promising preclinical and clinical profiles for the treatment of MS. <h3>Design/Methods:</h3> Two C57BL/6 mouse EAE models (induced by immunization with human or rat myelin oligodendrocyte glycoprotein [HuMOG and RatMOG EAE, respectively]) were used. Target engagement was assessed in tissue and clinical disease activity was determined. Serum antibody levels, biomarkers, and central nervous system tissue transcriptome were analyzed. <h3>Results:</h3> Remibrutinib inhibited B-cell–dependent HuMOG EAE at daily oral doses of 3 and 30 mg/kg and strongly reduced neurological symptoms. The ex vivo MOG-specific T-cell recall response was inhibited, but the polyclonal T-cell response was not, indicating selective B-cell inhibition. Remibrutinib did not decrease total immunoglobulin G antibody levels. Remibrutinib demonstrated strong BTK occupancy in the peripheral immune organs and brain at the efficacious dose of 30 mg/kg. Remibrutinib also inhibited RatMOG EAE, indicating that myeloid cell and microglia inhibition contributes to its efficacy in MS; this is supported by anti-inflammatory effects detected via single-cell RNA sequencing of the mouse brain and spinal cord. Remibrutinib also significantly reduced neurofilament light chain levels in serum. <h3>Conclusions:</h3> Remibrutinib exhibited dose-dependent efficacy in B-cell–driven EAE models. Potential for efficacy and anti-inflammatory effects on myeloid cells and microglia was observed. Remibrutinib may represent a novel treatment option for patients with MS. <b>Disclosure:</b> Bernd C. Kieseier, MD has nothing to disclose. Mr. Cenni has received personal compensation for serving as an employee of Novartis. Dr. Nuesslein-Hildesheim has received personal compensation for serving as an employee of Novartis Pharma AG. Dr. Nuesslein-Hildesheim has stock in Novartis Pharma AG. Dr. Ferrero has received personal compensation for serving as an employee of Novartis. Catherine Huck has received personal compensation for serving as an employee of Novartis. Mr. Eichlisberger has nothing to disclose. Dr. Ziehn has received personal compensation for serving as an employee of Novartis AG.