ONO-4641 (Ceralifimod) Reduces MRI Lesions and Prevents Disease Progression in an Animal Model of Multiple Sclerosis (P1.219)

OBJECTIVE: Evaluate ONO-4641 (ceralifimod) therapeutic effect using longitudinal magnetic resonance imaging (MRI) in an animal model of multiple sclerosis (MS). BACKGROUND: MRI is a well-established tool for diagnosing, monitoring disease progression, and evaluating therapeutic efficacy in MS. In MS animal models, MRI can provide a comprehensive, 9real-time9 evaluation of therapeutic effects on the central nervous system (CNS) across the disease course, to bridge the gap between preclinical and clinical studies. Experimental autoimmune encephalomyelitis (EAE) in Dark Agouti (DA) rats mimics neurological and pathological changes in MS, making EAE a suitable model to evaluate ONO-4641 effects using longitudinal MRI. METHODS: EAE was induced in female DA rats using full-length myelin oligodendrocyte glycoprotein. Disease severity was monitored daily (qualitative 0- to 5-point clinical score scale), and longitudinal MRI (9.4T magnet) was conducted at five disease stages. Immediately following peak of disease, baseline MRI was performed, animals randomized, and daily oral dosing with vehicle or ONO-4641 (0.3 mg/kg) commenced. T2-weighted, magnetization transfer (MT) and T1-weighted gadolinium-enhanced MRI were conducted to monitor disease progression and evaluate effects of ONO-4641. RESULTS: In vehicle-treated animals, T2-weighted and MT imaging revealed dynamic lesions in the CNS, starting in the spinal cord during the acute phase and progressing to the brain during relapse. T1-weighted gadolinium-enhanced MRI showed blood brain barrier leakage occurring first in the spinal cord, and then in the hindbrain and cerebellum. Spinal cord lesions detected via T2 weighted contrast and MT ratio correlated with neurological disability. Daily ONO-4641 (0.3 mg/kg) treatment, beginning at the acute phase, reduced spinal cord lesion volume and completely prevented the formation of brain lesions. CONCLUSIONS: MRI data provide insights into dynamic pathological (inflammation, demyelination) changes in the DA rat EAE model and demonstrate that ONO-4641 can reduce and prevent such changes. Preclinical MRI readouts may provide predictive values for clinical endpoints. Study Supported by: EMD Serono, Inc., Rockland, MA, USA, a subsidiary of Merck KGaA, Darmstadt, Germany. Disclosure: Dr. Huang has received personal compensation for activities with EMD Serono. Dr. Choi has nothing to disclose. Dr. Gray has received personal compensation for activities with EMD Serono as an employee. Dr. Yu has received personal compensation for activities with EMD Serono. Dr. Jenkins has received personal compensation for activities with Sunovion Pharmaceuticals. Dr. Jenkins holds stock and/or stock options in multiple biotech firms which sponsored research in which Dr. Jenkins was involved as an investigator. Dr. Jenkins has received research support from Biogen Idec and Collagen Medical. Dr. Mandeville has nothing to disclose. Dr. Dai has nothing to disclose. Dr. Boschert has received personal compensation for activities with EMD Serono, Inc. as an employee. Dr. Dellovade has received personal compensation for activities with EMD Serono as an employee. Dr. Graham has received personal compensation in an editorial capacity for EMD Serono as an employee.