Ozanimod (RPC1063) Preserves Central Nervous System (CNS) Tissue in Rodents by Reducing Neuronal Breaks in Vivo and Modulating Astrocyte Activity in Vitro (P5.027)

Objective: To evaluate CNS tissue preservation by ozanimod using animal models of demyelination and direct activity on primary rodent astrocytes. Plasma neurofilament light chain (NfL) was also assessed as a potential biomarker of neurological damage. Background: Ozanimod (RPC1063), an oral, once-daily immunomodulator that selectively targets S1PR1 and S1PR5, has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis (RMS). Ozanimod down-regulates S1PR1 and retains autoreactive lymphocytes in peripheral lymphoid tissues. Furthermore, ozanimod penetrates the blood-brain barrier, potentially modulating S1PR1 and S1PR5 on neural cells, which may confer neuroprotective benefits. Design/Methods: In vivo, C57BL/6 mice were treated with cuprizone to demyelinate axons in the brain and concurrently treated with ozanimod (or an ozanimod surrogate RP-101074) for 6 weeks. Neuroprotection was assessed by axonal pathology in the corpus callosum (SMI-32 staining), functional assessment through kinematic gait analysis and presence of plasma NfL. Direct activity of ozanimod was examined on activated primary rodent astrocytes in vitro. Results: Ozanimod and RP-101074 demonstrated a reduction in swollen and transected axons and improved functional assessment in kinematic gait in the cuprizone-induced demyelination mouse model. Plasma NfL was significantly elevated in cuprizone-treated mice over naive controls and RP-101074 treatment significantly reduced elevated plasma NfL. Ozanimod directly affects primary rodent astrocytes through activation of ERK and AKT signaling pathways and attenuated release of pro-inflammatory cytokines, including IL-1β and TNFα, induced by LPS activation. Conclusions: Ozanimod preserves CNS tissue through direct CNS effects, as treated mice exhibited reduced axonal breaks and improved functional capabilities following cuprizone-induced demyelination. Improved neuronal preservation by ozanimod may be mediated in part by its direct activity on astrocytes, attenuating their inflammatory response to a perturbed environment and maintaining a more optimal milieu for neuronal survival. Furthermore, plasma NfL served as a biomarker indicative of demyelination and was reduced upon ozanimod or RP-101074 treatment. Study Supported by: Celgene Disclosure: Dr. Taylor Meadows has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Celgene. Dr. Taylor Meadows holds stock and/or stock options in Celgene, which sponsored research in which Dr. Taylor Meadows was involved as an investigator. Dr. Taylor Meadows has received research support from Celgene. Dr. Waseem Akhtar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Celgene. Dr. Waseem Akhtar holds stock and/or stock options in Celgene, which sponsored research in which Dr. Waseem Akhtar was involved as an investigator. Dr. Waseem Akhtar has received research support from Celgene. Dr. Brand has received research support from Celgene-Receptos. Dr. Villescaz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Celgene. Dr. Clemons has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Celgene. Dr. Clemons holds stock and/or stock options in Celgene, which sponsored research in which Dr. Clemons was involved as an investigator. Dr. Clemons has received research support from Celgene. Dr. Lopez has nothing to disclose. Dr. Sawa-Ballweber has nothing to disclose. Dr. Dines has nothing to disclose. Dr. Opiteck has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Celgene. Dr. Scott has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Neurocrine Biosciences Inc. Dr. Selkirk has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Celgene. Dr. Selkirk holds stock and/or stock options in Celgene, which sponsored research in which Dr. Selkirk was involved as an investigator.