First use of cenerimod, a selective S1P1receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study
Open Access
- 17 May 2019
- journal article
- research article
- Published by BMJ in Lupus Science & Medicine®
- Vol. 6 (1), e000354
- https://doi.org/10.1136/lupus-2019-000354
Abstract
Objective To investigate the pharmacodynamics, pharmacokinetics and safety of cenerimod—a potent, oral, selective sphingosine 1-phosphate 1 receptor modulator—in patients with SLE. Methods This multicentre, double-blind, placebo-controlled study was conducted in two parts. In part A, patients with SLE were randomised 1:1:1:1 to receive oral cenerimod 0.5, 1 or 2 mg, or placebo once daily for 12 weeks. Following an interim safety review of part A, additional patients were randomised 3:1 for part B and received cenerimod 4 mg or placebo once daily for 12 weeks. Endpoints included changes in total lymphocyte count, SLE Disease Activity Index-2000 (SLEDAI-2K) score (modified (mSLEDAI-2K) to exclude leucopenia), biomarker anti-double-stranded DNA (anti-dsDNA) antibodies, pharmacokinetic assessments and treatment-emergent adverse events (TEAEs). Results Part A included 49 patients (1:1:1:1 receiving cenerimod 0.5, 1 or 2 mg, or placebo) and part B included 18 patients (13 cenerimod; 5 placebo). Cenerimod caused a statistically significant dose-dependent reduction in total lymphocyte count from baseline to end of treatment (EOT). Compared with placebo at EOT, cenerimod 4 mg had an estimated treatment effect on change from baseline in mSLEDAI-2K score of −2.420 (p=0.0306), and on anti-dsDNA antibodies of −64.55 U/mL (p=0.0082), suggesting clinical and biological improvement in these exploratory efficacy analyses. Trough plasma concentrations were dose proportional and reached steady-state conditions after 4 weeks of once daily dosing. All groups reported similar, non-dose-related frequencies of TEAEs (cenerimod 0.5 mg: 41.7%; 1 mg: 41.7%; 2 mg: 46.2%; 4 mg: 38.5% and placebo: 58.8%). A small, dose-related, non-clinically relevant decrease in heart rate was only observed in the first 6 hours after initiation. Conclusions With an acceptable safety profile, the efficacy findings suggest that cenerimod has the potential to treat patients with SLE. Further investigation in larger patient populations with longer treatment duration is warranted.Keywords
Funding Information
- Idorsia Pharmaceuticals Ltd
This publication has 26 references indexed in Scilit:
- Targeting the S1P receptor signaling pathways as a promising approach for treatment of autoimmune and inflammatory diseasesPharmacological Research, 2019
- Cenerimod, a novel selective S1P1 receptor modulator with unique signaling propertiesPharmacology Research & Perspectives, 2017
- Modeling Tolerance Development for the Effect on Heart Rate of the Selective S1P1 Receptor Modulator PonesimodClinical Pharmacology & Therapeutics, 2017
- Unmet Needs in the Pathogenesis and Treatment of Systemic Lupus ErythematosusClinical Reviews in Allergy & Immunology, 2017
- The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studiesRheumatology, 2017
- Cardiac effects of amiselimod compared with fingolimod and placebo: results of a randomised, parallel‐group, phase I study in healthy subjectsBritish Journal of Clinical Pharmacology, 2016
- Sphingosine-1-Phosphate and Its Receptors: Structure, Signaling, and InfluenceAnnual Review of Biochemistry, 2013
- Development of a conceptual model of health-related quality of life for systemic lupus erythematosus from the patient's perspectiveLupus, 2012
- Understanding the Epidemiology and Progression of Systemic Lupus ErythematosusSeminars in Arthritis and Rheumatism, 2010
- T Cells and B Cells in Lupus NephritisSeminars in Nephrology, 2007