Remibrutinib Inhibits Neuroinflammation Driven by B Cells and Myeloid Cells in Preclinical Models of Multiple Sclerosis
Bernd Kieseier1, Bruno Cenni2, Barbara Nuesslein-Hildesheim2, Enrico Ferrero2, Catherine Huck2, Denis Eichlisberger2, Marina Ziehn1
1Novartis Pharma AG, 2Novartis Institutes for Biomedical Research
Objective:
To assess the mechanism of action and efficacy of remibrutinib in experimental autoimmune encephalomyelitis (EAE) mouse models of multiple sclerosis (MS).
Background:
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.
Design/Methods:
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.
Results:
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.
Conclusions:
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.