First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study
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 SL...
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BMJ Publishing Group
2019-12-01
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| Series: | Lupus Science and Medicine |
| Online Access: | https://lupus.bmj.com/content/6/1/e000354.full |
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| author | Viktoria Hermann Anastas Batalov Svetlana Smakotina Pierre-Eric Juif Peter Cornelisse |
| author_facet | Viktoria Hermann Anastas Batalov Svetlana Smakotina Pierre-Eric Juif Peter Cornelisse |
| author_sort | Viktoria Hermann |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-447b47ef4d1e4dc7870d07a64451ae1e |
| institution | OA Journals |
| issn | 2053-8790 |
| language | English |
| publishDate | 2019-12-01 |
| publisher | BMJ Publishing Group |
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| series | Lupus Science and Medicine |
| spelling | doaj-art-447b47ef4d1e4dc7870d07a64451ae1e2025-08-20T02:35:40ZengBMJ Publishing GroupLupus Science and Medicine2053-87902019-12-016110.1136/lupus-2019-000354First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept studyViktoria Hermann0Anastas Batalov1Svetlana Smakotina2Pierre-Eric Juif3Peter Cornelisse4Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland6Med U. Plovdiv, Plovdiv, BulgariaKemerovo Regional Clinical Hospital, Kemerovo, RussiaNovartis Institutes for BioMedical Research Basel, Basel, Basel-Stadt, SwitzerlandIdorsia Pharmaceuticals Ltd, Allschwil, SwitzerlandObjective 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.https://lupus.bmj.com/content/6/1/e000354.full |
| spellingShingle | Viktoria Hermann Anastas Batalov Svetlana Smakotina Pierre-Eric Juif Peter Cornelisse First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study Lupus Science and Medicine |
| title | First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study |
| title_full | First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study |
| title_fullStr | First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study |
| title_full_unstemmed | First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study |
| title_short | First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study |
| title_sort | first use of cenerimod a selective s1p1 receptor modulator for the treatment of sle a double blind randomised placebo controlled proof of concept study |
| url | https://lupus.bmj.com/content/6/1/e000354.full |
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