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Simon Faissner, Ralf Gold
Multiple sclerosis treatment faces tremendous changes owing to the approval of new medications, some of which are available as oral formulations. Until now, the four orally available medications, fingolimod, dimethylfumarate (BG-12), teriflunomide, and cladribine have received market authorization, whereas laquinimod is still under development. Fingolimod is a sphingosine-1-phosphate inhibitor, which is typically used as escalation therapy and leads to up to 60% reduction of the annualized relapse rate, but might also have neuroprotective properties...
March 2, 2018: Cold Spring Harbor Perspectives in Medicine
Salvatore Cuzzocrea, Timothy Doyle, Michela Campolo, Irene Paterniti, Emanuela Esposito, Susan Farr, Daniela Salvemini
Traumatic brain injury (TBI) provokes secondary pathological mechanisms, including ischemic and inflammatory processes. The new research in sphingosine 1-phosphate (S1P) receptor modulators has opened the door for an effective mechanism of reducing central nervous system (CNS) inflammatory lesion activity. Thus, the aim of this study was to characterize the immunomodulatory effect of the functional S1PR1 antagonist siponimod in Phase III clinical trials for autoimmune disorders and of the competitive S1PR1 antagonist TASP0277308 in preclinical development in an in vivo model of TBI in mice...
January 8, 2018: Journal of Neurotrauma
Yi Jin, Hubert Borell, Anne Gardin, Mike Ufer, Felix Huth, Gian Camenisch
PURPOSE: The purpose of the study is to investigate the enzyme(s) responsible for siponimod metabolism and to predict the inhibitory effects of fluconazole as well as the impact of cytochrome P450 (CYP) 2C9 genetic polymorphism on siponimod pharmacokinetics (PK) and metabolism. METHODS: In vitro metabolism studies were conducted using human liver microsomes (HLM), and enzyme phenotyping was assessed using a correlation analysis method. SimCYP, a physiologically based PK model, was developed and used to predict the effects of fluconazole and CYP2C9 genetic polymorphism on siponimod metabolism...
December 22, 2017: European Journal of Clinical Pharmacology
Andreas Pelz, Hanne Schaffert, Radharani Diallo, Falk Hiepe, Andreas Meisel, Siegfried Kohler
Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and fatigue in the presence of circulating antibodies against components of the neuromuscular junction. Most patients have a good prognosis, but some are refractory to standard-of-care immunosuppressive treatment and suffer from recurrent myasthenic crises. Functional sphingosine-1-phosphate (S1P) antagonists like fingolimod and siponimod (BAF312) are successfully used for the treatment of multiple sclerosis, and fingolimod was shown to prevent the development of myasthenic symptoms in experimental autoimmune myasthenia gravis (EAMG), the standard model of MG...
December 4, 2017: European Journal of Immunology
Alberto Gajofatto
Siponimod (BAF312) is a synthetic molecule belonging to the sphingosine-1-phosphate (S1P) modulator family, which has putative neuroprotective properties and well-characterized immunomodulating effects mediated by sequestration of B and T cells in secondary lymphoid organs. Compared to fingolimod (ie, precursor of the S1P modulators commercially available for the treatment of relapsing-remitting [RR] multiple sclerosis [MS]), siponimod exhibits selective affinity for types 1 and 5 S1P receptor, leading to a lower risk of adverse events that are mainly induced by S1P3 receptor activation, such as bradycardia and vasoconstriction...
2017: Drug Design, Development and Therapy
Tomasz Litwin, Łukasz Smoliński, Anna Członkowka
Among patients with multiple sclerosis, discontinuing highly effective disease-modifying treatments can potentially lead to severe disease recurrence, especially cessation of natalizumab and fingolimod. Similar to fingolimod, siponimod is a sphingosine-1-phosphate receptor modulator that inhibits the egress of a lymphocyte subpopulation from lymph nodes. In the present case report, we describe a patient with MS who experienced substantial disease exacerbation after withdrawal from siponimod.
October 13, 2017: Neurologia i Neurochirurgia Polska
Ranjeet Prasad Dash, Nuggehally R Srinivas, Rana Rais
Sphingosine 1-phosphate (S1P1 ) modulators provide an emerging therapeutic approach for various autoimmune disorders such as multiple sclerosis and psoriasis. Fingolimod is the first approved orally active, selective and potent drug of this class. Other drugs belonging to this class include siponimod, ponesimod, ceralifimod, amiselimod, CS-0777 and GSK2018682. However, owing to the high protein binding, polarity and zwitter-ionic nature of the phosphate metabolite of parent drugs, it becomes challenging to optimize the extraction method for this class of compounds...
January 2018: Biomedical Chromatography: BMC
Mike Ufer, Kasra Shakeri-Nejad, Anne Gardin, Zhenzhong Su, Ines Paule, Thomas C Marbury, Eric Legangneux
OBJECTIVE: To evaluate effects of siponimod on response to T-cell-dependent (influenza) and T-cell-independent (pneumococcal polysaccharide vaccine [PPV-23]) vaccinations in healthy participants. METHODS: In this double-blind, placebo-controlled, parallel-group study, each participant underwent a 7-week treatment period and received intramuscular injections of influenza and PPV-23 vaccines (day 21). Participants were randomized to 4 treatment groups (N = 30 each) and received placebo or siponimod 2 mg once daily in concomitant, interrupted, or preceding fashion...
November 2017: Neurology® Neuroimmunology & Neuroinflammation
Burhan Z Chaudhry, Jeffrey A Cohen, Devon S Conway
Sphingosine 1-phosphate receptor (S1PR) modulators possess a unique mechanism of action in the treatment of multiple sclerosis (MS). Subtype 1 of the S1PR is expressed on the surface of lymphocytes and is important in regulating egression from lymph nodes. The S1PR modulators indirectly antagonize the receptor's function leading to sequestration of lymphocytes in the lymph nodes. Fingolimod was the first S1PR modulator to receive regulatory approval for relapsing-remitting MS after 2 phase III trials demonstrated potent efficacy, safety, and tolerability...
October 2017: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Abdelkrim Mannioui, Quentin Vauzanges, Jean Baptiste Fini, Esther Henriet, Somya Sekizar, Loris Azoyan, Jean Léon Thomas, David Du Pasquier, Carine Giovannangeli, Barbara Demeneix, Catherine Lubetzki, Bernard Zalc
BACKGROUND: In multiple sclerosis, development of screening tools for remyelination-promoting molecules is timely. OBJECTIVE: A Xenopus transgenic line allowing conditional ablation of myelinating oligodendrocytes has been adapted for in vivo screening of remyelination-favoring molecules. METHODS: In this transgenic, the green fluorescent protein reporter is fused to E. coli nitroreductase and expressed specifically in myelinating oligodendrocytes...
July 1, 2017: Multiple Sclerosis: Clinical and Laboratory Research
Gavin Giovannoni, Gary Cutter, Maria Pia Sormani, Shibeshih Belachew, Robert Hyde, Harold Koendgen, Volker Knappertz, Davorka Tomic, David Leppert, Robert Herndon, Claudia A M Wheeler-Kingshott, Olga Ciccarelli, David Selwood, Elisabetta Verdun di Cantogno, Ali-Frederic Ben-Amor, Paul Matthews, Daniele Carassiti, David Baker, Klaus Schmierer
Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms...
February 2017: Multiple Sclerosis and related Disorders
Nelleke Snelder, Bart A Ploeger, Olivier Luttringer, Dean F Rigel, Randy L Webb, David Feldman, Fumin Fu, Michael Beil, Liang Jin, Donald R Stanski, Meindert Danhof
Sphingosine 1-phosphate (S1P) receptor agonists are associated with cardiovascular effects in humans. This study aims to develop a systems pharmacology model to identify the site of action (i.e., primary hemodynamic response variable) of S1P receptor agonists, and to predict, in a quantitative manner, the cardiovascular effects of novel S1P receptor agonists in vivo. The cardiovascular effects of once-daily fingolimod (0, 0.1, 0.3, 1, 3, and 10 mg/kg) and siponimod (3 and 15 mg/kg) were continuously recorded in spontaneously hypertensive rats and Wistar-Kyoto rats...
February 2017: Journal of Pharmacology and Experimental Therapeutics
Antonietta Gentile, Alessandra Musella, Silvia Bullitta, Diego Fresegna, Francesca De Vito, Roberta Fantozzi, Eleonora Piras, Francesca Gargano, Giovanna Borsellino, Luca Battistini, Anna Schubart, Georgia Mandolesi, Diego Centonze
BACKGROUND: Data from multiple sclerosis (MS) and the MS rodent model, experimental autoimmune encephalomyelitis (EAE), highlighted an inflammation-dependent synaptopathy at the basis of the neurodegenerative damage causing irreversible disability in these disorders. This synaptopathy is characterized by an imbalance between glutamatergic and GABAergic transmission and has been proposed to be a potential therapeutic target. Siponimod (BAF312), a selective sphingosine 1-phosphate1,5 receptor modulator, is currently under investigation in a clinical trial in secondary progressive MS patients...
August 26, 2016: Journal of Neuroinflammation
Kasra Shakeri-Nejad, Vassilios Aslanis, Uday Kiran Veldandi, Anne Gardin, Andreas Zaehringer, Angela Dodman, Zhenzhong Su, Eric Legangneux
OBJECTIVE: To assess the pharmacokinetics (PK), safety, and tolerability of siponimod and major metabolites in subjects with mild, moderate, and severe hepatic impairment (HI) compared with demographically-matched healthy subjects (HS). METHODS: This open-label, parallel-group study enrolled 40 subjects (each HI group, n = 8; HS group, n = 16). A staged design was employed starting with the enrollment of subjects with mild HI, followed by those with moderate and severe HI...
January 2017: International Journal of Clinical Pharmacology and Therapeutics
Ludwig Kappos, David K B Li, Olaf Stüve, Hans-Peter Hartung, Mark S Freedman, Bernhard Hemmer, Peter Rieckmann, Xavier Montalban, Tjalf Ziemssen, Brian Hunter, Sophie Arnould, Erik Wallström, Krzysztof Selmaj
IMPORTANCE: This dose-blinded extension of the phase 2 BOLD (BAF312 on MRI Lesion Given Once Daily) Study in relapsing-remitting multiple sclerosis provides evidence on disease activity and safety of a range of siponimod doses for up to 24 months. OBJECTIVE: To assess the safety and efficacy of siponimod for up to 24 months during the dose-blinded extension of the BOLD Study. DESIGN, SETTING, AND PARTICIPANTS: At extension baseline in a randomized clinical trial, patients taking siponimod continued at the originally assigned dose and patients taking placebo were rerandomized to the 5 siponimod doses...
September 1, 2016: JAMA Neurology
Edward R Hammond
No abstract text is available yet for this article.
September 1, 2016: JAMA Neurology
Eric Legangneux, Kasra Shakeri-Nejad, Vassilios Aslanis, Alexandros Sagkriotis, Nicole Pezous, Bruno Brendani, Rhett Behrje, Maria Gutierrez
PURPOSE: The goal of this study was to investigate the effect of siponimod treatment re-initiation on the initial negative chronotropic effects and cardiac rhythm after variable drug discontinuation periods. METHODS: This partially double-blind, randomized, placebo-controlled study was conducted in healthy subjects. Siponimod doses (0.5-4.0 mg) and placebo were evaluated in combination with drug discontinuation periods ranging from 48 to 192 hours. Twelve-lead Holter ECGs were performed from 1...
March 2016: Clinical Therapeutics
Rehana Hussain, Shirley O'Leary, Fides M Pacheco, Tresa E Zacharias, Paul Litvak, Peter Sguigna, Ellen Marder, Kevin Kia, Karanjit Kooner, Olaf Stüve
Sphingosine 1-phosphate (S1P) is a signaling molecule that binds to five G protein-coupled receptors (Proc Natl Acad Sci USA 108:751-756, 2011). Modulation of these receptors has been associated with pleiotropic biological effects in the immune, cardiovascular, and central nervous systems (CNS). The functional S1P receptor antagonist fingolimod was the first member of this class of pharmacotherapeutics to be approved for treatment of relapsing multiple sclerosis (MS). Siponimod is currently in clinical trial in patients with secondary progressive (SP) MS, a clinical trial for which there is an unmet need for disease-modifying agents...
March 2016: Journal of Neurology
Catherine O'Sullivan, Anna Schubart, Anis K Mir, Kumlesh K Dev
BACKGROUND: BAF312 (Siponimod) is a dual agonist at the sphingosine-1 phosphate receptors, S1PR1 and S1PR5. This drug is currently undergoing clinical trials for the treatment of secondary progressive multiple sclerosis (MS). Here, we investigated the effects of BAF312 on isolated astrocyte and microglia cultures as well as in slice culture models of demyelination. METHODS: Mouse and human astrocytes were treated with S1PR modulators and changes in the levels of pERK, pAkt, and calcium signalling as well as S1PR1 internalization and cytokine levels was investigated using Western blotting, immunochemistry, ELISA and confocal microscopy...
February 8, 2016: Journal of Neuroinflammation
Lea Radick, Stanton R Mehr
Several new medications are being investigated in late-phase studies for the treatment of patients with relapsing or progressive multiple sclerosis (MS). These agents represent a variety of mechanisms of action and provide not only lower relapse rates but also improvement in disabilities. The majority of investigational trials involve selective sphingosine-1-phosphate receptor 1 immunomodulators, such as laquinimod, ozanimod, ponesimod, and siponimod, in an effort to build on the success of fingolimod. Ocrelizumab is a CD20-positive B-cell-targeting monoclonal antibody with a promising new mechanism of action...
November 2015: American Health & Drug Benefits
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