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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
Magdalena Birker-Robaczewska, Martin Bolli, Markus Rey, Ruben de Kanter, Christopher Kohl, Cyrille Lescop, Maxime Boucher, Sylvie Poirey, Beat Steiner, Oliver Nayler
S1P1 (sphingosine-1-phosphate receptor 1) agonists prevent lymphocyte egress from secondary lymphoid organs and cause a reduction in the number of circulating blood lymphocytes. We hypothesized that S1P1 receptor modulators with pathway-selective signaling properties could help to further elucidate the molecular mechanisms involved in lymphocyte trapping. A proprietary S1P1 receptor modulator library was screened for compounds with clear potency differences in β -arrestin recruitment and G protein alpha i subunit (G α i ) protein-mediated signaling...
February 2018: Molecular Pharmacology
Andreas Krause, Daniele D'Ambrosio, Jasper Dingemanse
BACKGROUND: Ponesimod is currently the only S1P receptor modulator studied in psoriasis. In a dose-finding study, the active doses showed similar efficacy. OBJECTIVE: Prediction of efficacy at lower doses to aid clinical phase 3 planning with respect to dose selection, duration of treatment, and patient inclusion criteria based on pharma-co-kinetic/pharmacodynamic (PK/PD) modeling and simulation. METHODS: The dose-finding study treated 326 patients (67 on placebo, 126 on 20mg, and 133 on 40mg) over 16 weeks...
February 2018: Journal of Dermatological Science
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
Dominik Lott, Thorsten Lehr, Jasper Dingemanse, Andreas Krause
Ponesimod is a selective sphingosine-1-phosphate-1 (S1P1 ) receptor modulator currently under investigation for the treatment of multiple sclerosis. S1P receptor modulators reduce heart rate following treatment initiation. This effect disappears with repeated dosing, enabling development of innovative uptitration regimens to optimize patient safety. There are currently no published pharmacokinetic/pharmacodynamic models describing the heart rate reduction of S1P receptor modulators in humans. The model developed here provides quantification of this effect for ponesimod...
September 15, 2017: Clinical Pharmacology and Therapeutics
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
D Redelstein, M Fleck
The treatment of psoriatic arthritis (PsA) necessitates different and highly effective treatment strategies due to the diverse clinical manifestations. Drugs that exhibit efficacy for most of the musculoskeletal (e.g. arthritis, dactylitis, enthesitis and spondyloarthritis) and extra-articular manifestations (e.g. skin and nail lesions) are therefore of special interest. This review presents a selection of drugs for the treatment of PsA, which might be available within the (near) future. Based on an improved understanding of the pathopysiology of psoriasis as well as PsA, novel therapeutic approaches are under development...
August 2017: Zeitschrift Für Rheumatologie
Ranjeet Prasad Dash, Rana Rais, Nuggehally R Srinivas
1. Ponesimod, a selective sphingosine 1-phosphate (S1P1 ) receptor modulator, is undergoing clinical development for the treatment of autoimmune diseases (multiple sclerosis/psoriasis). 2. Published literature data describing pharmacokinetic disposition of ponesimod were collected, reviewed and tabulated. 3. Across various clinical phase-I studies, ponesimod displayed consistent pharmacokinetics - relatively faster absorption peak time (approximately 2.5 h), elimination half-life of approximately 30 h and modest accumulation (2- to 2...
May 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Jashin J Wu, Shivani P Reddy
Oral ponesimod is a new therapy for the treatment of moderate-to-severe plaque psoriasis. Vaclavkova et al conducted a phase 2 trial that demonstrated moderate efficacy of ponesimod in the treatment of psoriasis. Here we discuss various biologic agents with alternative mechanisms of action, that have demonstrated superior efficacy in psoriasis, and call into question the risks versus benefits of ponesimod therapy.
September 15, 2016: Dermatology Online Journal
Stipo Jurcevic, Pierre-Eric Juif, Colleen Hamid, Roseanna Greenlaw, Daniele D'Ambrosio, Jasper Dingemanse
This study investigated the effects of ponesimod, a selective S1P1 receptor modulator, on T lymphocyte subsets in 16 healthy subjects. Lymphocyte subset proportions and absolute numbers were determined at baseline and on Day 10, after once-daily administration of ponesimod (10 mg, 20 mg, and 40 mg each consecutively for 3 days) or placebo (ratio 3:1). The overall change from baseline in lymphocyte count was -1,292±340×10(6) cells/L and 275±486×10(6) cells/L in ponesimod- and placebo-treated subjects, respectively...
2017: Drug Design, Development and Therapy
Dominik Lott, Andreas Krause, Christian A Seemayer, Daniel S Strasser, Jasper Dingemanse, Thorsten Lehr
PURPOSE: This analysis aimed at describing the effect of the selective sphingosine-1-phosphate receptor 1 modulator ponesimod on lymphocyte subsets in peripheral blood. As the involvement of different lymphocyte subsets varies among different autoimmune diseases, characterizing the effect of ponesimod on these may be beneficial in better understanding treatment effects. METHODS: Three phase 1 clinical studies in healthy human subjects were pooled. Non-linear mixed-effects modeling techniques were used to study the effect of ponesimod on lymphocyte subsets such as B cells, T helper cells, T cytotoxic cells, and natural killer cells in a qualitative and quantitative manner...
March 2017: Pharmaceutical Research
Dominik Lott, Thorsten Lehr, Jasper Dingemanse, Andreas Krause
BACKGROUND: Ponesimod is a selective, orally active sphingosine-1-phosphate receptor 1 modulator currently undergoing clinical evaluation for the treatment of multiple sclerosis (MS) in phase III clinical trials. Ponesimod dose-dependently reduces peripheral blood lymphocyte counts by blocking the egress of lymphocytes from lymphoid organs. METHODS: A population pharmacokinetic (PK) analysis was performed based on pooled data from 13 clinical studies. Interindividual variability (IIV) and the impact of key demographic variables and other covariates on ponesimod exposure were assessed quantitatively...
April 2017: Clinical Pharmacokinetics
Pierre-Eric Juif, Matthias Hoch, Andrea Vaclavkova, Andreas Krause, Jim Bush, Jasper Dingemanse
Ponesimod, a potent selective sphingosine-1-phosphate receptor 1 modulator, leads to a reduction in circulating total lymphocyte count and transient decreases in heart rate (HR). Based on a modeling and simulation approach, this study was conducted to investigate whether a gradual up-titration regimen may mitigate these cardiodynamic effects. In this double-blind, placebo-controlled, randomized, 2-way crossover study, 32 healthy participants (15 males) received placebo on day 1 followed by multiple-dose administration of either ponesimod or placebo (ratio 3:1)...
March 2017: Journal of Clinical Pharmacology
Dominik Lott, Andreas Krause, Jasper Dingemanse, Thorsten Lehr
Ponesimod, a selective, orally active S1P1 receptor modulator, reduces total blood lymphocyte counts by blocking the egress of lymphocytes from lymphoid organs. It is currently in clinical development for the treatment of relapsing-remitting multiple sclerosis. Ponesimod has two primary metabolites, M12 and M13, that circulate in human plasma. The work presented in this paper predicts and quantifies the accumulation of ponesimod and both metabolites in healthy and organ-impaired subjects. Based on clinical data including studies in renally and hepatically impaired subjects, a population pharmacokinetic (PK) model was developed to characterize the PK of ponesimod and its primary metabolites and to qualify and quantify the influence of organ impairment on the concentration-time profiles of these compounds...
June 30, 2016: European Journal of Pharmaceutical Sciences
Zenas Z N Yiu, Richard B Warren
Several classes of new oral therapy are in use or in development for the treatment of psoriasis. Despite the high efficacy of biologics, new oral therapies remain important as patients generally prefer this mode of administration and they offer an alternative risk-benefit profile. In this review, we discuss the novel modes of action of these drugs, including modulation of cellular pathways involving diverse targets such as Janus kinase, phosphodiesterase 4, sphingosine 1-phosphate, A3 adenosine receptor and rho-associated kinase 2...
June 2016: American Journal of Clinical Dermatology
Margaux Boehler, Pierre-Eric Juif, Matthias Hoch, Jasper Dingemanse
BACKGROUND AND OBJECTIVES: The pharmacokinetic profile of ponesimod, a sphingosine-1-phosphate receptor 1 modulator, is characterized by a rapid absorption [time to maximum concentration (t max) of 2-4 h] and a terminal half-life (t ½) of 32 h after single-dose administration. The aim of this study was to assess additional pharmacokinetic parameters [absolute bioavailability, total clearance (CL), and volume of distribution (V ss)] in healthy male subjects. METHODS: After ensuring in a pilot phase the full pharmacokinetic profile, safety, and tolerability of a 5-mg intravenous infusion of ponesimod over 3 h (treatment A), the study proceeded to the randomized, two-way crossover, single-dose (treatment A; treatment B: 10 mg oral) main phase...
February 2017: European Journal of Drug Metabolism and Pharmacokinetics
Sonia Borodzicz, Lidia Rudnicka, Dagmara Mirowska-Guzel, Agnieszka Cudnoch-Jedrzejewska
Sphingolipids, a group of lipids containing the sphingoid base, have both structural and biological functions in human epidermis. Ceramides, as a part of extracellular lipids in the stratum corneum, are important elements of the skin barrier and are involved in the prevention of transepidermal water loss. In addition, ceramides regulate such processes as proliferation, differentiation and apoptosis of keratinocytes. Another important sphingolipid, sphingosine-1-phosphate (S1P), inhibits proliferation and induces differentiation of keratinocytes...
January 19, 2016: Lipids in Health and Disease
Daniele D'Ambrosio, Mark S Freedman, Joerg Prinz
The first oral treatment for relapsing multiple sclerosis, the nonselective sphingosine-1-phosphate receptor (S1PR) modulator fingolimod, led to identification of a pivotal role of sphingosine-1-phosphate and one of its five known receptors, S1P1R, in regulation of lymphocyte trafficking in multiple sclerosis. Modulation of S1P3R, initially thought to cause some of fingolimod's side effects, prompted the search for novel compounds with high selectivity for S1P1R. Ponesimod is an orally active, selective S1P1R modulator that causes dose-dependent sequestration of lymphocytes in lymphoid organs...
January 2016: Therapeutic Advances in Chronic Disease
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
Nicolas Guérard, Christian Zwingelstein, Matthias Hoch, Jasper Dingemanse
Ponesimod, a selective S1P1 receptor modulator, is a potential therapeutic agent for autoimmune disorders. The impact of hepatic or renal impairment on the pharmacokinetics, safety and tolerability of ponesimod and its inactive metabolites, ACT-204426 and ACT-338375, was evaluated. Two separate single-centre, open-label studies with 32 (hepatic study) and 24 (renal study) male and female individuals were conducted. Hepatic impairment was based on the Child-Pugh classification, and renal impairment was determined by creatinine clearance using the Cockcroft-Gault equation...
May 2016: Basic & Clinical Pharmacology & Toxicology
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