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Inflammatory Disorders of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
There are no treatments that reliably reverse or even halt the accumulation of disability in primary or secondary progressive MS. Ocrelizumab can slow the rate of progression in some patients with “active” primary progressive disease; siponimod has very recently been licensed for “active” secondary progressive MS. Trials are underway exploring neuroprotective agents and/or stem cells with this aim.25
Inflammatory myopathies: shedding light on promising agents and combination therapies in clinical trials
Published in Expert Opinion on Investigational Drugs, 2021
Rachel Zeng, Stefanie Glaubitz, Jens Schmidt
Siponimod binds selectively to the sphingosine-1-phosphate receptor 1 on lymphocytes and inhibits the migration of lymphocytes and other immune cells from secondary lymphoid organs to areas of inflammation. A multicenter, double-blind, randomized, placebo-controlled, proof-of-concept study had been set up to evaluate the efficacy and tolerability of siponimod in patients with PM and DM, but was prematurely terminated due to enrollment challenges [ClinicalTrials.gov identifier: NCT01148810]. A following multicenter, randomized, double–blind, placebo-controlled, phase IIa trial enrolled 17 patients with adult dermatomyositis, unfortunately this trial was also prematurely terminated due to the results of an interim analysis, which showed no superior efficacy of the study drug over placebo [ClinicalTrials.gov identifier: NCT02029274]. Siponimod was well tolerated, and no significant side effects were reported. (See Table 1 for an overview of recent clinical trials in DM/PM.)
Siponimod in the treatment of multiple sclerosis
Published in Expert Opinion on Investigational Drugs, 2019
Andrew D Goodman, Nidhiben Anadani, Lee Gerwitz
The results of this study showed a dose–response relation (p = 0.0001) across the five doses of siponimod. The reduction in CUAL’s at 3 months compared with placebo was 35% for siponimod 0.25 mg, 50% for siponimod 0.5 mg, 66% for siponimod 1.25 mg, 72% for siponimod 2 mg, and 82% for siponimod 10 mg. Efficacy was much the same with the 2 mg and 10 mg doses for secondary MRI outcomes, whereas the 0.5 mg dose showed submaximal reductions versus placebo. Taken together, the data suggest that the siponimod 10 mg dose does not offer efficacy advantages compared with the 2 mg dose, and the 0.5 mg dose might not be beneficial in terms of clinical and MRI outcomes. These findings demonstrated that an S1P receptor modulator with selectivity for subtypes 1 and 5 might be effective in RRMS.
Preclinical discovery and development of fingolimod for the treatment of multiple sclerosis
Published in Expert Opinion on Drug Discovery, 2019
Claudia Volpi, Ciriana Orabona, Antonio Macchiarulo, Roberta Bianchi, Paolo Puccetti, Ursula Grohmann
The FDA has approved siponimod for oral treatment of adults with relapsing forms of MS, including clinically isolated syndrome (initial neurological episode), relapsing-remitting disease, and active SPMS. Siponimod is the second S1PR modulator to be approved in the US; fingolimod, which is approved for oral treatment of RRMS in patients ≥10 years old, was the first. Siponimod is under regulatory review in the EU and Japan for SPMS. Overall, although on the surface the development of new inflammatory CNS lesions in MS may appear consistent with a primary recruitment of peripheral immune cells, questions have been raised as to whether lymphocyte and/or monocyte invasion into the brain are really at the root of inflammatory lesion development. Such a concept is discussed in the context of the EXPAND trial, showing that siponimod exerts anti-inflammatory and neuroprotective activities in SPMS patients. The verification or rejection of such a concept is vital for the development of new therapeutic strategies for progressive MS.