Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study

Selmaj, Krzysztof; Li, David K.B.; Hartung, Hans Peter; Hemmer, Bernhard; Kappos, Ludwig; Freedman, Mark S.; Stüve, Olaf; Rieckmann, Peter; Montalbán, Xavier; Ziemssen, Tjalf; Auberson, Lixin Zhang; Pohlmann, Harald; Mercier, François; Dahlke, Frank; Wallström, Erik

doi:10.1016/s1474-4422(13)70102-9

Cited by 211 publications

(198 citation statements)

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“…Inhibition of lymphocyte egress from secondary lymphoid organs leading to the decrease in total circulating lymphocyte count was considered and proven to be an effective mode of action for the treatment of auto-immune diseases such as MS [16,40,41], psoriasis [42], and ulcerative colitis [43]. Whereas immune cells are depleted by other immunosuppressive drugs currently used for the treatment of auto-immune disorders (e.g., rituximab) [44], following administration of selective and non-selective S1P receptor modulators, immune cells are not killed but sequestered within lymphoid organs.…”

Section: Effect Of S1p 1 Receptor Modulation On Immune Cells: Role Inmentioning

confidence: 99%

Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators

Juif

Kraehenbuehl

Dingemanse

2016

Expert Opinion on Drug Metabolism & Toxicology

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The safety profile of S1P receptor modulators is considered better than other classes of immunomodulators and was further improved by the development of up-titration regimens to mitigate first-dose effects. S1P receptor modulators display similar pharmacodynamic effects but have very different pharmacokinetic profiles. Drugs with a rapid elimination are of interest in case of opportunistic infections or pregnancy, whereas the need of re-initiation of up-titration in case of treatment interruption can present a challenge.

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Section: Effect Of S1p 1 Receptor Modulation On Immune Cells: Role Inmentioning

confidence: 99%

Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators

Juif

Kraehenbuehl

Dingemanse

2016

Expert Opinion on Drug Metabolism & Toxicology

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“…Lymphopenia is thus a predictor of efficacy, but the absolute correlation between degree of lymphopenia in choice of dose is not complete (Kappos et al 2006;Kappos et al 2010;Khatri et al 2011;Devonshire et al 2012;Radue et al 2012). Other agents in clinical development have also shown efficacy in the reduction of gadolinium-enhanced scans in Phase II clinical studies with only 50 % reduction in circulating lymphocytes (Selmaj et al 2013;Reyes et al 2014;You et al 2013;Rey et al 2013;Fernandez et al 2013;Brossard et al 2013;Sobel et al 2013;Piali et al 2011;Bolli et al 2010). Clearly, immunomodulation by S1PR1 signaling has multiple points of engagement in the autoimmune inflammatory cascade and the tissue response to injury.…”

Section: Boundary Conditions For Therapeutic Efficacy: the Challenge mentioning

confidence: 99%

The Organization of the Sphingosine 1-Phosphate Signaling System

Rosen

Sanna

Gonzalez-Cabrera

et al. 2014

Current Topics in Microbiology and Immunology

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The understanding of the role of the sphingosine 1-phosphate signaling system in immunology and host defense has deepened exponentially over the past 12 years since the discovery that lymphocyte egress was reversibly modulated by sphingosine 1-phosphate receptors, and with the development of fingolimod, a prodrug of a nonselective S1P receptor agonist, for therapeutic use in the treatment of relapsing, remitting multiple sclerosis. Innovative genetic and chemical approaches, together with structural biology, now provide a more detailed molecular understanding of a regulated lysophospholipid ligand with a variety of autocrine, paracrine, and systemic effects in physiology and pathology, based upon selective interactions with a high affinity and selective evolutionary cluster of G-protein-coupled receptors.

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“…S1P receptor modulators have been suggested to exert neuroprotective and regenerative actions in the CNS, in addition to anti-inflammatory effects [125]. In an adaptive dose-ranging phase II trial in patients with RRMS, siponimod was shown to reduce brain MRI lesions and relapses by up to 80 % (vs placebo) [126]. A phase III trial of siponimod in patients with SPMS is currently in underway (NCT01665144) [127].…”

Section: Siponimodmentioning

confidence: 99%

Therapeutic Advances and Future Prospects in Progressive Forms of Multiple Sclerosis

2016

Self Cite

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Identifying effective therapies for the treatment of progressive forms of multiple sclerosis (MS) is a highly relevant priority and one of the greatest challenges for the global MS community. Better understanding of the mechanisms involved in progression of the disease, novel trial designs, drug repurposing strategies, and new models of collaboration may assist in identifying effective therapies. In this review, we discuss various therapies under study in phase II or III trials, including antioxidants (idebenone); tyrosine kinase inhibitors ( m a s i t i n i b ) ; s p h i n g o s i n e r e c e p t o r m o d u l a t o r s (siponimod); monoclonal antibodies (anti-leucine-rich repeat and immunoglobulin-like domain containing neurite outgrowth inhibitor receptor-interacting protein-1, natalizumab, ocrelizumab, intrathecal rituximab); hematopoetic stem cell therapy; statins and other possible neuroprotective agents (amiloride, riluzole, fluoxetine, oxcarbazepine); lithium; phosphodiesterase inhibitors (ibudilast); hormone-based therapies (adrenocorticotrophic hormone and erythropoietin); T-cell receptor peptide vaccine (NeuroVax); autologous T-cell immunotherapy (Tcelna); MIS416 (a microparticulate immune response modifier); dopamine antagonists (domperidone); and nutritional supplements, including lipoic acid, biotin, and sunphenon epigallocatechin-3-gallate (green tea extract). Given ongoing and planned clinical trial initiatives, and the largest ever focus of the global research community on progressive MS, future prospects for developing targeted therapeutics aimed at reducing disability in progressive forms of MS appear promising.

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Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study

Cited by 211 publications

References 10 publications

Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators

Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators

The Organization of the Sphingosine 1-Phosphate Signaling System

Therapeutic Advances and Future Prospects in Progressive Forms of Multiple Sclerosis

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