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Central versus peripheral drug exposure ratio, a key differentiator for siponimod over fingolimod ?

Bigaud, Marc, Ramseier, Pamela, Tisserand, Sarah, Lang, Meike, Urban, Beatrice, Beerli, Christian and Karlsson, Goeril (2023) Central versus peripheral drug exposure ratio, a key differentiator for siponimod over fingolimod ? Neurology and Therapy. ISSN 2193-6536; 2193-8253


Siponimod, a potent and selective sphingosine-1-phosphate (S1P1,5) agonist, is the only therapeutic agent that has shown efficacy on disability progression, decline in cognitive processing speed, total brain volume loss, gray matter atrophy, and signs of demyelination in patients with secondary progressive multiple sclerosis (SPMS). Although the pathophysiology of progression in SPMS and primary progressive MS (PPMS) is thought to be similar, fingolimod, the prototype S1P1,3,45 agonist, failed to show efficacy on disability progression in PPMS. Differentiating the mechanisms of siponimod’s effects on progression from those of fingolimod is believed to be key to better understand the key characteristics that could make siponimod uniquely efficacious in progressive MS (PMS).
Here, we compared the dose-dependent central vs peripheral drug exposure of siponimod and fingolimod in healthy mice and mice with experimental autoimmune encephalomyelitis (EAE). Siponimod treatment achieved dose-dependent efficacy and dose-proportional increases in steady state drug blood levels, with a similar central nervous system (CNS)/blood drug-exposure ratio (CNS/BloodDER) in both healthy and EAE mice. In contrast, fingolimod treatment achieved dose-proportional increases in fingolimod/fingolimod-P drug blood levels with a CNS/BloodDER that was markedly increased in EAE vs healthy mice. These results, taken together with recent preclinical observations implying a bell-shaped dose-effect relationship for S1P receptor-dependent central effects, suggest that at human-equivalent therapeutic doses an increase in CNS/BloodDER with loss of central efficacy for fingolimod/fingolimod-P but not for siponimod. Therefore, CNS/bloodDER is a potential new differentiator for siponimod over fingolimod, that warrants further investigation and clinical validation.

Item Type: Article
Keywords: Siponimod Fingolimod PK/PD
Date Deposited: 31 May 2023 00:45
Last Modified: 31 May 2023 00:45