Contributions
Abstract: P989
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 15 Immunology
Recently, the role of B cells in the pathogenesis of multiple sclerosis (MS) has been clinically validated via the pivotal data and subsequent regulatory approval of Ocrelizumab, which selectively depletes peripheral CD20-expressing B cells. The development of an orally available therapy that could penetrate the central nervous system in order to effectively and safely modulate B-cell function without depleting B-cells could be a significant advance in the treatment of CNS inflammatory diseases like MS. Bruton's tyrosine kinase (BTK) is a key element in the B-cell signaling pathway. Here we demonstrate the preclinical efficacy of PRN2246, a potent and selective oral BTK inhibitor designed to penetrate the blood brain barrier to enable pharmacological inhibition of BTK-dependent disease mechanisms in both the CNS and periphery. PRN2246 combines long duration of action and favourable pharmacokinetic properties to achieve efficacy at low doses. BTK inhibition with PRN2246 impacts multiple immune cell signaling pathways relevant to disease in the periphery and within the CNS. In vitro, PRN2246 inhibits BTK dependent inflammatory immune mechanisms in multiple immune cell types, including B-cells, basophils, neutrophils, monocytes and microglia. PRN2246 demonstrates dose-dependent protection from disease induction in a mouse model of EAE, with BTK occupancy confirmed in both the periphery and CNS. Together, the preclinical data supports the rationale for use of PRN2246 in the treatment of multiple sclerosis, by demonstrating significant effects on disease relevant immune mediated mechanisms on both sides of the blood brain barrier.
Disclosure: All authors are employees of Principia Biopharma
Abstract: P989
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 15 Immunology
Recently, the role of B cells in the pathogenesis of multiple sclerosis (MS) has been clinically validated via the pivotal data and subsequent regulatory approval of Ocrelizumab, which selectively depletes peripheral CD20-expressing B cells. The development of an orally available therapy that could penetrate the central nervous system in order to effectively and safely modulate B-cell function without depleting B-cells could be a significant advance in the treatment of CNS inflammatory diseases like MS. Bruton's tyrosine kinase (BTK) is a key element in the B-cell signaling pathway. Here we demonstrate the preclinical efficacy of PRN2246, a potent and selective oral BTK inhibitor designed to penetrate the blood brain barrier to enable pharmacological inhibition of BTK-dependent disease mechanisms in both the CNS and periphery. PRN2246 combines long duration of action and favourable pharmacokinetic properties to achieve efficacy at low doses. BTK inhibition with PRN2246 impacts multiple immune cell signaling pathways relevant to disease in the periphery and within the CNS. In vitro, PRN2246 inhibits BTK dependent inflammatory immune mechanisms in multiple immune cell types, including B-cells, basophils, neutrophils, monocytes and microglia. PRN2246 demonstrates dose-dependent protection from disease induction in a mouse model of EAE, with BTK occupancy confirmed in both the periphery and CNS. Together, the preclinical data supports the rationale for use of PRN2246 in the treatment of multiple sclerosis, by demonstrating significant effects on disease relevant immune mediated mechanisms on both sides of the blood brain barrier.
Disclosure: All authors are employees of Principia Biopharma