ONO-4641 (Ceralifimod) Prevents Evoked Potential Deficits in an Animal Model of Multiple Sclerosis (P1.218)

OBJECTIVE: Examine ONO-4641 (ceralifimod) therapeutic efficacy using longitudinal evoked-potential (EP) electrophysiology in a relapsing-remitting multiple sclerosis (MS) model. BACKGROUND: Sphingosine-1-phosphate (S1P) receptor-1 is a clinically validated target for treating relapsing MS (RMS). One mode of action is lymphocyte sequestration within lymph nodes; additional mechanisms in the central nervous system (CNS) have been proposed. ONO-4641, an oral, non-pro-drug, selective S1P receptor-1 and -5 agonist, is in clinical trials for RMS and has demonstrated efficacy in several preclinical models. EP electrophysiology in MS models provides a comprehensive evaluation of therapeutic effects on CNS function across the disease course. METHODS: Dark Agouti rats were surgically implanted with cortical surface electrodes, and baseline visual and somatosensory EPs (VEPs, SEPs) were determined. Experimental autoimmune encephalomyelitis (EAE) was induced with myelin oligodendrocyte glycoprotein, and neurological disability was monitored daily (standardized 0- to 5-point clinical score system). Immediately after acute phase of disease, rats were randomized into groups and daily oral treatment with vehicle or ONO-4641 (0.3 or 1.0mg/kg) initiated. EPs were monitored longitudinally over the disease course. RESULTS: Vehicle-treated EAE rats showed significant latency delays in VEPs and SEPs at the acute phase and throughout the chronic phase of disease, consistent with demyelination in visual and somatosensory pathways. ONO-4641 (0.3 or 1.0mg/kg) significantly reversed deficits observed early in disease (p<0.05 vs vehicle-treated EAE rats). During the chronic phase of disease, ONO-4641 1.0mg/kg prevented the development of VEP and SEP deficits. At study end, ONO-4641 reduced levels of inflammation, demyelination, and neurofilament damage in the spinal cord and optic nerve. Linear regression analysis revealed a significant correlation between myelin loss in the spinal cord and SEP deficits, and in the optic nerve and VEP deficits. CONCLUSIONS: In -vivo electrophysiology data provide insights into functional changes in the CNS throughout EAE and demonstrate that ONO-4641 can reduce, and possibly prevent, such changes. Study supported by: EMD Serono, Inc., Rockland, MA, USA, a subsidiary of Merck KGaA, Darmstadt, Germany. Disclosure: Dr. Crawford has received personal compensation for activities with EMD Serono as an employee. Dr. Yu has received personal compensation for activities with EMD Serono. Dr. Bernard has received personal compensation for activities with Serono, Inc. as an employee. Dr. Graham has received personal compensation in an editorial capacity for EMD Serono as an employee. Dr. Boschert has received personal compensation for activities with EMD Serono as an employee. Dr. Dellovade has received personal compensation for activities with EMD Serono as an employee.