학술논문
Central Versus Peripheral Drug Exposure Ratio, a Key Differentiator for Siponimod Over Fingolimod?
Original Research
Original Research
Document Type
Report
Author
Source
Neurology and Therapy. August 2023, Vol. 12 Issue 4, p1187, 17 p.
Subject
Language
English
Abstract
Author(s): Marc Bigaud [sup.1] , Pamela Ramseier [sup.1] , Sarah Tisserand [sup.1] , Meike Lang [sup.1] , Beatrice Urban [sup.1] , Christian Beerli [sup.1] , Göril Karlsson [sup.2] Author Affiliations: [...]
Introduction Siponimod, a potent and selective sphingosine-1-phosphate (S1P.sub.1,5) agonist, is the only therapeutic agent that has shown efficacy against 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 S1P.sub.1,3,45 agonist, failed to show efficacy against disability progression in PPMS. Differentiating siponimod from fingolimod at the level of their central effects is believed to be the key to a better understanding of the underlying characteristics that could make siponimod uniquely efficacious in progressive MS (PMS). Methods Here, we compared the central vs. peripheral dose-dependent drug exposures for siponimod and fingolimod in healthy mice and mice with experimental autoimmune encephalomyelitis (EAE). Results Siponimod treatment achieved dose-dependent efficacy and dose-proportional increases in steady-state drug blood levels, with a central nervous system (CNS)/blood drug-exposure ratio (.sub.CNS/bloodDER) of ~ 6 in both healthy and EAE mice. In contrast, fingolimod treatments achieved dose-proportional increases in fingolimod and fingolimod-phosphate blood levels, with respective .sub.CNS/bloodDER that were markedly increased ([greater than or equal to] threefold) in EAE vs. healthy mice. Conclusion If proven to have translational value, these observations would suggest that .sub.CNS/bloodDER may be a key differentiator for siponimod over fingolimod for clinical efficacy in PMS.
Introduction Siponimod, a potent and selective sphingosine-1-phosphate (S1P.sub.1,5) agonist, is the only therapeutic agent that has shown efficacy against 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 S1P.sub.1,3,45 agonist, failed to show efficacy against disability progression in PPMS. Differentiating siponimod from fingolimod at the level of their central effects is believed to be the key to a better understanding of the underlying characteristics that could make siponimod uniquely efficacious in progressive MS (PMS). Methods Here, we compared the central vs. peripheral dose-dependent drug exposures for siponimod and fingolimod in healthy mice and mice with experimental autoimmune encephalomyelitis (EAE). Results Siponimod treatment achieved dose-dependent efficacy and dose-proportional increases in steady-state drug blood levels, with a central nervous system (CNS)/blood drug-exposure ratio (.sub.CNS/bloodDER) of ~ 6 in both healthy and EAE mice. In contrast, fingolimod treatments achieved dose-proportional increases in fingolimod and fingolimod-phosphate blood levels, with respective .sub.CNS/bloodDER that were markedly increased ([greater than or equal to] threefold) in EAE vs. healthy mice. Conclusion If proven to have translational value, these observations would suggest that .sub.CNS/bloodDER may be a key differentiator for siponimod over fingolimod for clinical efficacy in PMS.