Therapeutic Potential of Ponesimod Alone and in Combination with Dimethyl Fumarate in Experimental Models of Multiple Sclerosis

Innovations in Clinical Neuroscience

Claude CA Bernard¹  Marianne M. Martinic²  Luca Piali³  Beat Steiner⁴  Laetitia Pouzol⁵ 

[1] Dr. Bernard is with Monash University, Faculty of Medicine, Nursing Health Sciences in Melbourne, Australia.;Dr. Martinic is with Idorsia Pharmaceuticals Ltd. in Allschwil, Switzerland.;Dr. Piali was with Actelion Pharmaceuticals Ltd. in Allschwil, Switzerland, at the time of this research, and is presently with Hoffmann la Roche in Basel, Switzerland.;Dr. Steiner was with Actelion Pharmaceuticals Ltd. in Allschwil, Switzerland, at the time of this research.;Drs. Pouzol and Clozel were with Actelion Pharmaceuticals Ltd. in Allschwil, Switzerland, at the time of this research, and are presently with Idorsia Pharmaceuticals Ltd. in Allschwil, Switzerland.

关键词: Experimental autoimmune encephalomyelitis (EAE);    multiple sclerosis (MS);    dimethyl fumarate (DMF);    sphingosine-1-phosphate;    combination therapy;    disease activity;   

DOI  :  

学科分类：精神健康和精神病学

来源: Matrix Medical Communications, LLC

【 摘 要 】

Background: Despite the recent approval of new oral therapies for the treatment of multiple sclerosis (MS), a significant percentage of patients are still not free from disease activity. In view of the complex pathogenesis and the relapsing and progressive nature of MS, combination therapy, a classical approach to treat many chronic diseases, could improve disease control over monotherapy. Ponesimod, a selective and rapidly reversible sphingosine-1-phosphate receptor Type 1 (S1P1) modulator, currently in Phase III clinical trial stage in relapsing MS (RMS), and dimethyl fumarate (DMF) would potentially be an ideal combination due to their differing mechanisms of action and oral administration. Objective: The goal of the study was to evaluate the therapeutic effect of ponesimod monotherapy and investigate the potential additive, or synergistic, activity of ponesimod-DMF combination therapy in experimental autoimmune encephalomyelitis (EAE) animal models of MS. Methods: Efficacy was evaluated in the myelin oligodendrocyte glycoprotein (MOG)-induced EAE model in C57BL/6 mice (ponesimod monotherapy) and in the myelin basic protein (MBP)-induced EAE model in Lewis rats (monotherapies and combination therapy). The principal readout was the clinical score assessing paralysis. Additional readouts, such as histopathology, survival, and disease prevalence, were generated in parallel when applicable. Results: Ponesimod monotherapy in the mouse EAE model showed significant efficacy in both preventative and therapeutic settings. In the rat EAE model, ponesimod demonstrated significant dose-dependent efficacy on clinical scores, while DMF showed only modest activity. Combination therapy synergistically reduced the severity and prevalence of disease. Only the combination treatment of ponesimod and DMF fully suppressed clinical disease activity by the end of the study. Conclusion: The results support the potential therapeutic benefits of combining ponesimod with DMF to improve disease activity control in patients with MS. Additionally, the results suggest that combining ponesimod with other oral agents that have different mechanisms of action might also be therapeutically beneficial to patients with MS.

【 授权许可】

Unknown