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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.
- systemic lupus erythematosus
- cenerimod
- phase II
- sphingosine-1-phosphate receptor
- S1P1
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Copyright: © Author(s) (or their employer(s)) 2019. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0.
Footnotes
Contributors VH reviewed and interpreted the data. AB and SS were involved in patient recruitment, conduct of the study and acquisition of data. P-EJ analysed and provided interpretation of the PK data. PC provided oversight, review and interpretation of the statistical analyses, and carried out further analyses. All authors were involved in drafting the article and revising it critically for important intellectual content, and all authors approved the final version to be submitted.
Funding This study was sponsored by Actelion Pharmaceuticals. Study sponsorship was transferred to Idorsia Pharmaceuticals in July 2018. These sponsors participated in the design and conduct of the study, collection, management, analysis and interpretation of the data.
Competing interests VH, P-EJ and PC are employees and shareholders of Idorsia.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request.