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First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study.

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.

SUBMITTER: Hermann V

PROVIDER: S-EPMC6861098 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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First use of cenerimod, a selective S1P<sub>1</sub> receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study.

Hermann Viktoria V Batalov Anastas A Smakotina Svetlana S Juif Pierre-Eric PE Cornelisse Peter P

Lupus science & medicine 20191109 1

<h4>Objective</h4>To investigate the pharmacodynamics, pharmacokinetics and safety of cenerimod-a potent, oral, selective sphingosine 1-phosphate 1 receptor modulator-in patients with SLE.<h4>Methods</h4>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 randomise ...[more]

PMID: 31798918

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Project description:BACKGROUND:Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. METHODS:In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585. FINDINGS:Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were -0·73 log IU/mL in group 1 (95% CI 0·17-1·31; p=0·03) and -1·54 log IU/mL in group 2 (1·21-1·93; p<0·0001). Lonafarnib serum concentrations correlated with HDV RNA change (r(2)=0·78, p<0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days [SE 0·24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 [SE 0·06] vs 0·739 [0·05], p<0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. INTERPRETATION:Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. FUNDING:National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc.

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Dataset Information

First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study.

Publications

First use of cenerimod, a selective S1P<sub>1</sub> receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study.

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