Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial

Vaclavkova, Andrea; Chimenti, Sergio; Arenberger, Petr; Holló, Péter; Sator, Paul‐Gunther; Burcklen, Michel; Stefani, Mylène; D’Ambrosio, Daniele

doi:10.1016/s0140-6736(14)60803-5

Cited by 129 publications

(132 citation statements)

References 30 publications

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“…In terms of safety and tolerability, a similar incidence and nature of adverse events was observed in Study 1 and Study 2. No new findings were observed, in comparison with previous studies [7][8][9][10][11][12][13]. The incidence of adverse events and the percentage of subjects displaying adverse events were dose dependent.…”

Section: Discussioncontrasting

confidence: 64%

“…Ponesimod (ACT-128800) is a potent, orally active, selective, reversible S1P 1 receptor modulator [6] currently in clinical development for the treatment of autoimmune diseases and has successfully reached its study end points in recent phase II trials in patients with chronic plaque psoriasis [7] or relapsing-remitting multiple sclerosis [8]. Single-and multiple-dose administration of ponesimod results in a dose-dependent decrease in circulating lymphocytes in healthy subjects and is associated with heart rate reduction, a delay in atrioventricular conduction, and pulmonary effects [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Biocomparison of THREE formulations of the S1P1 receptor modulator ponesimod in healthy subjects

Juif

Hoch

D’Ambrosio

et al. 2015

Clinical Therapeutics

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Section: Discussioncontrasting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Biocomparison of THREE formulations of the S1P1 receptor modulator ponesimod in healthy subjects

Juif

Hoch

D’Ambrosio

et al. 2015

Clinical Therapeutics

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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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“…Thus, S1P 1 receptor modulators as ponesimod may be a valuable therapeutic approach for various autoimmune diseases such as rheumatoid arthritis, type I diabetes, MS and psoriasis. In the last two mentioned diseases, the modulation of lymphocytes in peripheral blood by ponesimod was shown to have positive effects in Phase II trials [6,7].At single doses ranging from 1 to 75 mg and multiple doses of up to 100 mg once daily, in healthy individuals, ponesimod's pharmacokinetic (PK) profile was characterized by a rapid absorption, with time to maximum concentration (t max ) of 2-4 hr, a terminal half-life (t 1/2 ) of approximately 30 hr and an accumulation factor of 2-2.5 with generally low variability [8]. These PK properties were also confirmed in a thorough QT study in which 40 and 100 mg multiple doses of ponesimod were administered to healthy individuals [9].…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Effect of Hepatic or Renal Impairment on the Pharmacokinetics, Safety, and Tolerability of Ponesimod, a Selective S1P₁ Receptor Modulator

Guérard

Zwingelstein

Hoch

et al. 2015

Basic Clin Pharma Tox

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Ponesimod, a selective S1P 1 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. Individuals with severe hepatic or renal impairment were to be matched (sex and body mass index) with healthy individuals. All individuals received a single dose of 10 mg ponesimod. For ponesimod, the ratio of geometric means of AUC 0-∞ for individuals with severe hepatic impairment versus healthy individuals was 3.07 (90% CI: 2.19, 4.32). For severely renally impaired individuals versus healthy individuals, this ratio was 1.14 (0.82, 1.58). C max and t max values of ponesimod were comparable across all groups in both studies. Exposure to metabolites was increased in individuals with moderate or severe hepatic impairment as compared to healthy individuals. During the course of these studies, there were no clinically relevant abnormalities related to vital signs, 12-lead electrocardiograms and clinical laboratory values. Sixteen adverse events (AEs) were reported, 12 of them of mild intensity. No AEs were considered to be treatment related. Overall, ponesimod was well tolerated. In individuals with renal function impairment, dose adjustment is not warranted, whereas the dose should be reduced in individuals with moderate and severe hepatic impairment.Multiple sclerosis (MS) is a global health concern, affecting approximately 2.5 million people worldwide. More than 200 people are newly diagnosed with MS every week in the United States [1][2][3]. MS is a chronic, autoimmune and neurodegenerative disease of the central nervous system (CNS) associated with irreversible progression of disability, physical and cognitive impairment, as well as fatigue, pain, depression and bladder dysfunction. Circulation of lymphocytes between blood, lymphatic system and non-lymphoid tissues is involved in the immune response inducing autoimmune diseases such as MS and psoriasis. Lymphocytes trafficking is tightly regulated, and it has been shown that the lysophospholipid sphingosine 1-phosphate (S1P) plays a central role in this mechanism. The pleiotropic effects of S1P are mediated by its cognate cell surface G-protein-coupled receptors (GPCRs), expressed on a wide range of cellular cell types and with five described subtypes, S1P 1-5 [4,5].Ponesimod, an iminothiazolidinone derivative, is a selective, reversible and potent orally available S1P 1 receptor modulator. Activation of S1P 1 GPCRs blocks the egress of lymphocytes from lymphoid organs and, as a consequence, reduces the number of circulating effector T cells driving the immune response. Thus, S1P 1...

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Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial

Cited by 129 publications

References 30 publications

Biocomparison of THREE formulations of the S1P1 receptor modulator ponesimod in healthy subjects

Biocomparison of THREE formulations of the S1P1 receptor modulator ponesimod in healthy subjects

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

Effect of Hepatic or Renal Impairment on the Pharmacokinetics, Safety, and Tolerability of Ponesimod, a Selective S1P₁ Receptor Modulator

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Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial

Cited by 129 publications

References 30 publications

Biocomparison of THREE formulations of the S1P1 receptor modulator ponesimod in healthy subjects

Biocomparison of THREE formulations of the S1P1 receptor modulator ponesimod in healthy subjects

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

Effect of Hepatic or Renal Impairment on the Pharmacokinetics, Safety, and Tolerability of Ponesimod, a Selective S1P1 Receptor Modulator

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Product

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Effect of Hepatic or Renal Impairment on the Pharmacokinetics, Safety, and Tolerability of Ponesimod, a Selective S1P₁ Receptor Modulator