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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...
2016: Journal of Neuroinflammation
Kasra Shakeri-Nejad, Vassilios Aslanis, Uday 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...
July 22, 2016: 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
Shibadas Biswal, Florine Polus, Parsar Pal, Uday Kiran Veldandi, Thomas C Marbury, Robert Perry, Eric Legangneux
OBJECTIVE: To evaluate the cardiac and pulmonary effects of siponimod (BAF312) and propranolol co-administration in healthy subjects. METHODS: Healthy subjects (n=76) were randomized in a doubleblind manner to receive propranolol at siponimod steady state (group A), siponimod at propranolol steady state (group B), placebo (group C) and propranolol (group D). Pharmacodynamic evaluations included maximum change from baseline in time-matched hourly average heart rate (Emax HR) and mean arterial blood pressure (Emax MABP) over 24 hours postdose, change from baseline in PR intervals, cardiac rhythm, and forced expiratory volume in 1 second (FEV1)...
October 2015: International Journal of Clinical Pharmacology and Therapeutics
Adnan M Subei, Jeffrey A Cohen
Sphingosine 1-phosphate (S1P) receptor modulators possess a unique mechanism of action as disease-modifying therapy for multiple sclerosis (MS). Subtype 1 S1P receptors are expressed on the surfaces of lymphocytes and are important in regulating egression from lymph nodes. The S1P receptor modulators indirectly antagonize the receptor's function and sequester lymphocytes in lymph nodes. Fingolimod was the first S1P agent approved in the USA in 2010 for relapsing MS after two phase III trials (FREEDOMS and TRANSFORMS) demonstrated potent efficacy, and good safety and tolerability...
July 2015: CNS Drugs
Malihe Safavi, Shekoufeh Nikfar, Mohammad Abdollahi
Multiple sclerosis (MS) is a heterogeneous, chronic, debilitating immune-mediated disease of the central nervous system (CNS). There are four types of MS according to their relapsing or progressive pattern that include relapsing-remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS), and progressive relapsing (PRMS). There is no definite cure for MS, thus medications typically focus on slowing the progression of the disease, managing symptoms and improving the quality of life. There is no specific medication for the management of PPMS and thus these patients are often neglected...
2015: Inflammation & Allergy Drug Targets
Emmanuelle Briard, Bettina Rudolph, Sandrine Desrayaud, Joel A Krauser, Yves P Auberson
BAF312 (siponimod) is a sphingosine-1-phosphate (S1P) receptor modulator in clinical development for the treatment of multiple sclerosis, with faster organ/tissue distribution and elimination kinetics than its precursor FTY720 (fingolimod). Our aim was to develop a tracer to better quantify the penetration of BAF312 in the human brain, with the potential to be labeled for positron emission tomography (PET) or single-photon emission computed tomography (SPECT). Although the PET radioisotopes (11)C and (18)F could have been introduced in BAF312 without modifying its structure, they do not have decay kinetics compatible with the time required for observing the drug's organ distribution in patients...
June 2015: ChemMedChem
O Stuve, H P Hartung, M Freedman, D Li, B Hemmer, L Kappos, P Rieckmann, X Montalban, T Ziemssen, K Selmaj
BACKGROUND/OBJECTIVES: In the adaptive dose-ranging, 6- or 3-month BOLD study in patients with relapsing-remitting multiple sclerosis, once-daily siponimod (BAF312) showed dose-dependent reduction of combined unique active lesion number and annualized relapse rate (ARR); near-maximal effects were observed at 2mg. Here, we report the efficacy findings of first 12 months of the extension (representing >18 or 15 months of total treatment). DESIGN/METHODS: Patients either continued on siponimod doses assigned in the core phase or were re-randomized from placebo to siponimod 10, 2, 1...
November 2014: Multiple Sclerosis and related Disorders
L Kappos, A Bar-Or, B Cree, R Fox, G Giovannoni, R Gold, P Vermersch, E Lam, H Pohlmann, E Wallström
BACKGROUND/OBJECTIVE: Siponimod (BAF312), a next generation selective sphingosine 1-phosphate (S1P)-1 and -5 receptor modulator administered once-daily orally reduces lymphocyte infiltration into the CNS and may have direct CNS effects. Experimental studies indicate that siponimod readily crosses the blood-brain-barrier and may modulate neurobiological processes via S1P1 and S1P5 receptors on astrocytes and oligodendrocytes. In relapsing MS, S1P receptor modulation reduces accumulation of neurological impairment and slows progression of brain atrophy...
November 2014: Multiple Sclerosis and related Disorders
Daniel Ontaneda, Robert J Fox
PURPOSE OF REVIEW: The purpose of this study is to highlight the pathological features and clinical aspects of progressive multiple sclerosis (PMS) and also the results of clinical trial experience to date and review ongoing clinical trials and prospective new treatment options. This study will explain the challenges of clinical trial design in PMS. RECENT FINDINGS: Multiple sclerosis (MS) has been identified as a chronic immune mediated disease, and the progressive phase of the disease appears to have significant neurodegenerative mechanisms...
June 2015: Current Opinion in Neurology
Yukihiro Yagi, Yuji Nakamura, Ken Kitahara, Takuma Harada, Kazuhiko Kato, Tomohisa Ninomiya, Xin Cao, Hiroshi Ohara, Hiroko Izumi-Nakaseko, Kokichi Suzuki, Kentaro Ando, Atsushi Sugiyama
Fingolimod, a sphingosine 1-phosphate (S1P) receptor subtype 1, 3, 4 and 5 modulator, has been used for the treatment of patients with relapsing forms of multiple sclerosis, but atrioventricular conduction block and/or QT-interval prolongation have been reported in some patients after the first dose. In this study, we directly compared the electropharmacological profiles of fingolimod with those of siponimod, a modulator of sphingosine 1-phosphate receptor subtype 1 and 5, using in vivo guinea-pig model and in vitro human ether-a-go-go-related gene (hERG) assay to better understand the onset mechanisms of the clinically observed adverse events...
November 15, 2014: Toxicology and Applied Pharmacology
Shibadas Biswal, Uday Kiran Veldandi, Caroline Derne, GangaRaju Golla, Naguib Muhsen, Eric Legangneux
OBJECTIVE: To evaluate the effects of siponimod (BAF312) on the pharmacokinetics (PK) and pharmacodynamics (PD) of a monophasic oral contraceptive (OC). MATERIALS AND METHODS: This was a phase 1, single-center, open-label, multipledose, single-sequence study in healthy females. Eligible subjects (n = 23) were exposed sequentially to two treatment periods: period 1 (OC alone) and period 2 (OC + siponimod) in two consecutive menstrual periods. PK parameters were assessed on day 21 of both treatment periods...
November 2014: International Journal of Clinical Pharmacology and Therapeutics
Shifeng Pan, Nathanael S Gray, Wenqi Gao, Yuan Mi, Yi Fan, Xing Wang, Tove Tuntland, Jianwei Che, Sophie Lefebvre, Yu Chen, Alan Chu, Klaus Hinterding, Anne Gardin, Peter End, Peter Heining, Christian Bruns, Nigel G Cooke, Barbara Nuesslein-Hildesheim
A novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure-activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid (32, BAF312, Siponimod), which has recently completed phase 2 clinical trials in patients with relapsing-remitting multiple sclerosis.
March 14, 2013: ACS Medicinal Chemistry Letters
Bruce A C Cree
Rapid advances are occurring in multiple sclerosis disease modifying therapies. Recent therapeutic advances include modifications to improve tolerability of existing products (e.g. interferon beta and glatiramer acetate), development of novel anti-neuroinflammatory medications (e.g. fingolimod, teriflunomide and dimethyl fumarate, daclizumab, alemtuzumab, ocrelizumab) and investigation of treatments in progressive MS (e.g. natalizumab, mastinib, natalizumab, siponimod). The impact of vitamin D supplementation on the disease course in relapsing MS patients is also being studied in several clinical trials...
April 2014: Neurohospitalist
H Markus Weiss, Ewa Gatlik
For very highly bound drugs (fu < 2%), the determination of the unbound fraction in plasma (fu) and a reliable estimation of protein-binding differences across species, populations, or concentrations is challenging. The difficulty is not mostly assay sensitivity but rather experimental bias. In equilibrium gel filtration (EGF)--opposite to the commonly used methods--the amount bound at a set-free concentration is determined. Therefore, signals and differences are bigger for more highly protein-bound drugs...
February 2014: Journal of Pharmaceutical Sciences
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