First use of cenerimod, a selective S1P₁receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study

Abstract

ObjectiveTo investigate the pharmacodynamics, pharmacokinetics and safety of cenerimod—a potent, oral, selective sphingosine 1-phosphate 1 receptor modulator—in patients with SLE.MethodsThis 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).ResultsPart 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.ConclusionsWith 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.

WITHDRAWN: No Increase in Rate and Severity of Flares During Pregnancy and Post-Partum Period in Pregnant Patients with Systemic Lupus Erythematosus. A Sex, Age and Disease Duration Matched Controlled Study

“…Secondly, this study used the mSLEDAI-2K instrument (not including anti-dsDNA and complements) to determine disease activity, thus it might not re ect the "standard" disease activity measurement as the original development [26]. However, the mSLEDAI-2K instrument has not only shown very good correlation with the original SLEDAI-2K [17], but also its effective use in clinical studies and clinical trials [27][28][29][30]. Thirdly, the severity of SLE also was modi ed as it did not use the original SLEDAI score [19], and the are and degree of are was captured using the mSFI, which did not included the PGA as in the original description [20].…”

A label‐free impedance assay in endothelial cells differentiates the activation and desensitization properties of clinical S1P1 agonists

“…However, lymphocytes clearly play an important role in these diseases as shown by the success of B cell depletion and IL17/IL23 pathway inhibition in systemic lupus erythematosus and psoriasis, respectively [35,36]. Recently, a S1P 1 modulator, cenerimod, demonstrated promising signals in a lupus trial at lymphocyte-reducing doses [7], raising the question about relative contributions of lymphocyte-reducing and endothelial-protective mechanisms to the effects observed. Our approach to quantifying activation-to-desensitization ratios allows a new dimension to understanding, rationalizing, and potentially predicting relative differences in efficacy and suitability of various molecules targeting this pathway in the clinic.…”

“…Compounds targeting this receptor have been primarily developed as receptor-desensitizing agents with associated peripheral blood lymphopenia, and this has been exploited in the approval of 3 drugs for multiple sclerosis, fingolimod (a nonselective S1P 1/3/4/5 agonist), and more recently siponimod and ozanimod (S1P 1/5 agonists) [3,4,5]. S1P 1 -desensitizing molecules in clinical development include ponesimod (in phase 3 trials for MS) as well as molecules that have shown efficacy in other autoimmune diseases including inflammatory bowel disease, lupus, and psoriasis [6,7,8]. S1P 1 activation has endothelial barrier-stabilizing effects through the formation of adherens and tight junctions [9,10].…”

String of successful trials in SLE: have we cracked the code?

“…This fall, we are seeing another unlikely and largely unexpected but hoped for grouping of events: a series of successful phase III trials in SLE. These successes follow on a longer period during which successes in smaller, phase II trials were emerging with a range of drugs, including ustekinumab,1 baricitinib,2 cenerimod3 and others. But now, in short succession, three large phase III trials meeting their primary outcome of efficacy were published or announced (table 1).…”