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

Study design and dosing

The study protocol was approved by the relevant health authority in each country and by an institutional review board or an independent ethics committee at each site. Signed informed consent was obtained from each patient. The study was carried out in accordance with the principles of the International Council for Harmonisation Guidelines for Good Clinical Practice, the Declaration of Helsinki and all applicable national and local laws. This study is registered on ClinicalTrials.gov (NCT02472795).

This multicentre, double-blind, randomised, placebo-controlled 12-week study was conducted at 18 centres across Belarus, Bulgaria, Georgia, Russia, Ukraine and the USA. The study had two parts, part A and part B, which had the same study design: a 30-day screening period followed by a 12-week treatment period, a 6-week follow-up visit, and two telephone calls at 11 and 16 weeks after treatment discontinuation.

In part A, eligible patients were randomly assigned (1:1:1:1) to once daily oral administration of cenerimod 0.5, 1, 2 mg or placebo. After all patients had completed 4 weeks of treatment during part A, an Independent Data Monitoring Committee reviewed non-blinded data in an interim analysis to evaluate the safety profile of cenerimod and recommend whether the study could proceed to part B as planned (study design: online supplementary file 1). In part B, additional patients were randomised (3:1) to once daily oral administration of cenerimod 4 mg or placebo.

Randomisation was done using an interactive response technology system. The investigator, study site personnel, patients and sponsor personnel involved in the conduct of the study remained blinded to both the treatment allocation and to the interim analysis results until study closure.

Patients

Patients were eligible for inclusion in the study if they met the following criteria: were aged 18–65 years; fulfilled at least four of the American College of Rheumatology revised diagnostic criteria for SLE;21 were diagnosed at least 6 months before screening; had an SLE Disease Activity Index-2000 (SLEDAI-2K) score of at least two points for musculoskeletal or mucocutaneous manifestations; a history of, or positive serum test at screening for, antinuclear antibodies or anti-double-stranded DNA (dsDNA) antibodies; and were receiving background SLE medication (non-steroidal anti-inflammatory drugs, corticosteroids, antimalarials, mycophenolate mofetil, azathioprine or methotrexate) at stable doses for at least 30 days before randomisation. Patients were ineligible if they had severe lupus disease activity (SLEDAI-2K score >12 points), active lupus nephritis, central nervous system lupus or lupus vasculitis within 90 days prior to randomisation. Additional inclusion and exclusion criteria are described in online supplementary file 2.

Procedures

During the study, assessments were conducted at seven scheduled visits (baseline; day 1; weeks 2, 4 and 8 of treatment; at end of treatment (EOT; week 12) and at end of study (EOS; 6 weeks after EOT)). Additionally, patients were contacted via telephone 11 and 16 weeks after EOT to collect safety information, including serious adverse events (SAEs) and pregnancy status.

Assessments at each visit included blood sampling for haematology, clinical chemistry and biomarker analyses; safety and tolerability assessments (monitoring adverse events (AEs; coded using the Medical Dictionary for Regulatory Activities, version 19.0), vital signs, 12-lead electrocardiograms (ECGs), ophthalmic examinations (apart from day 1) and spirometry (apart from day 1) for forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC)); and disease activity assessments (apart from week 2) using the modified SLEDAI-2K (mSLEDAI-2K) to exclude leucopenia because of the mode of action of cenerimod.

During the treatment period, blood samples were collected before dosing at weeks 2, 4, 8 and 12, and at EOS. Trough plasma concentrations (C_trough) of cenerimod were determined using a validated liquid chromatography coupled to tandem mass spectrometry assay with a lower limit of quantification of 0.1 ng/mL.

Predefined day 1 safety assessments included heart rate monitoring and changes in 12-lead ECG variables (including heart rate and PR, QRS and QT intervals). These assessments were performed prior to the first dose and then hourly for 6 hours. Day 1 heart rate discharge criteria were the following: ECG-derived resting heart rate more than 45 beats per minute (bpm), and if heart rate was less than 50 bpm it could not be the lowest value post dose; systolic blood pressure (BP) more than 90 mm Hg; QT interval corrected by Fredericia's formula <500 ms; no persistent ECG abnormality (eg, atrioventricular block second degree or higher) or ongoing AE requiring continued hospitalisation. In addition, 24-hour Holter ECG values were assessed. Safety areas of interest, known through clinical experience to be a class effect of S1P receptor modulators, included: cardiovascular effects including heart rate (on day 1), PR interval, systolic and diastolic BP, pulmonary function, immunomodulation including malignancies and infections, macular oedema, liver function test elevation and teratogenicity. The predefined stopping criteria for safety areas of interest are summarised in online supplementary file 3.

Outcome measures

The primary PD endpoint was change in total lymphocyte count from baseline to EOT. Other study endpoints were changes in total lymphocyte count from baseline to each on-treatment assessment and at EOS; treatment-emergent AEs (TEAEs); SAEs; AEs of special interest (AESIs; (defined as per safety area of interest) to include the anticipated risks of treatment with cenerimod, known class effects, or the events related to SLE comorbidities (eg, cardiovascular AEs)); AEs representing a clinical manifestation of an SLE flare (in the investigator’s opinion); and AEs leading to treatment discontinuation (list of AESIs and additional safety endpoints: online supplementary file 4).

Exploratory evaluations of disease activity included changes from baseline to each post-baseline asse ssment in the mSLEDAI-2K score and in the mucocutaneous and/or musculoskeletal SLEDAI-2K subscore. Exploratory biomarker endpoints included changes in anti-dsDNA and blood lymphocyte subsets from baseline to EOT and EOS. Additional exploratory endpoints are described in online supplementary file 5.

Statistical analysis

Based on assumptions from phase I study results,20 a sample size of 64 patients (12 in each cenerimod dose group and 16 in the placebo group) was deemed adequate to provide an average power of at least 90% to show a significant dose–response relationship on lymphocyte count at a one-sided alpha significance level of 5%. This assumed no lymphocyte count reduction from baseline for placebo, and a maximum 70% reduction for any cenerimod dose. For statistical analysis, all four cenerimod treatment groups were compared with combined data from the placebo groups in parts A and B.

To assess any change in total lymphocyte count, an optimised contrast test according to the Multiple Comparison Procedure and Modelling (MCP-Mod) approach22 for each considered dose–response model was used. Five models were prespecified for consideration in MCP-Mod analyses: maximum effect (E_max) curves with 50% of the effective dose (ED₅₀) at 0.2, 0.4 and 1 mg, quadratic curve with E_max at 3 mg and sigmoid-E_max curve with ED₅₀ at 0.4 mg and ED₉₅ at 2 mg. Multiplicity-adjusted p-values were calculated using the Dunnett’s test. PD effects were analysed based on pairwise comparisons of reduction in total lymphocyte count from baseline for each cenerimod dose level with placebo, using an analysis of covariance (ANCOVA) model, adjusted for baseline total lymphocyte count. Statistical testing was based on a two-sided significance level of 5%.

Exploratory analyses of the change from baseline in mSLEDAI-2K score and SLEDAI-2K mucocutaneous and/or musculoskeletal score were performed using an ANCOVA, with treatment group and baseline score as factors. Mean treatment differences for each cenerimod dose compared with placebo and their corresponding two-sided 95% CIs were provided.

In general, analyses were conducted on the full analysis set (FAS) of all 67 randomised patients. Primary PD analyses were initially performed using the PD set, which included all patients who had received study treatment for at least 21 days and had valid baseline and post-baseline total lymphocyte count data. Consequently, the PD set excluded three patients from the FAS: two from the cenerimod 1 mg group and one from the placebo group. Furthermore, C_trough levels were discovered to be low, or below the lower limit of quantification (BLQ), in four patients randomised to the cenerimod 4 mg group, a finding incompatible with compliance with study treatment. These patients were excluded from the PD set to form a post hoc modified PD (mPD) set. Exploratory analyses on disease activity and biomarkers used the mPD set in addition to the FAS. All 67 randomised patients (ie, the FAS) reported receiving at least one dose of study treatment and were included in the safety set.

Study population

Between 1 June 2015 and 28 February 2017, 105 patients were screened and 67 were randomised to receive study treatment: 49 in part A (randomised 1:1:1:1 to receive cenerimod 0.5, 1, 2 mg or placebo) and 18 in part B (randomised 3:1 to receive cenerimod 4 mg or placebo; figure 1).

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Demographics and baseline characteristics of the study population are shown in table 1. Overall, 61 (91%) patients were female, 65 (97%) were Caucasian and 2 (3%) were African-American. Both African-American patients were in the placebo group. The median times from first SLE symptom and SLE diagnosis varied between groups, with the lowest median values in the cenerimod 0.5 mg group (3.7 and 2.4 years, respectively) and the highest median values in the cenerimod 1 mg group (8.2 and 6.2 years, respectively). Background medication was predominantly oral corticosteroids, antimalarials and/or immunosuppressants.

Change in lymphocyte count

A statistically significant dose–response relationship for change from baseline to EOT in total lymphocyte count was established in the mPD and PD sets, such that all five dose–response models were statistically significant (mPD set p<0.001 and PD set p<0.005, for all five models; figure 2).

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Analysis of the mPD set showed a statistically significant greater mean reduction (±SD) in total lymphocyte count from baseline to EOT with cenerimod 1 mg (0.96±0.68×10⁹/L), 2 mg (0.86±0.61×10⁹/L) and 4 mg (1.48±0.73×10⁹/L) compared with placebo (0.32±0.72×10⁹/L). The mean reduction from baseline to EOT with cenerimod 0.5 mg (0.26±0.48×10⁹/L) was not statistically significant. Average percentage changes in total lymphocyte count from baseline to EOT for the mPD set were −12% (0.5 mg), −48% (1 mg), −52% (2 mg), −69% (4 mg) and −5% (placebo). Analysis of the PD set showed a lower mean reduction (±SD) in total lymphocyte count from baseline to EOT in the 4 mg (0.87±1.24×10⁹/L) group, consistent with low or BLQ C_trough in four subjects.

Decreases in mean lymphocyte counts were observed in all cenerimod groups compared with placebo at all on-treatment assessments. This decrease was evident at week 2 and plateaued by week 8, before returning toward baseline values at EOS (figure 3).

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Changes in disease activity

In an exploratory analysis of efficacy using the mPD set, greater mean (±SD) decreases from baseline to EOT in mSLEDAI-2K scores were seen in both cenerimod 2 mg (2.31±2.93) and 4 mg (4.78±3.23) groups, compared with placebo (1.94±2.54) (figure 3; online supplementary file 6). The estimated placebo-adjusted treatment effect of the 4 mg dose, −2.420 (p=0.0306) at EOT was sustained for at least 6 weeks (ie, EOS −3.234; p=0.0060).

Biomarker results

In the mPD set, the observed changes from baseline to EOT in anti-dsDNA antibodies were −18.23 U/mL in the cenerimod 2 mg group, and −53.78 U/mL in the 4 mg group, compared with +12.88 U/mL in the placebo group (online supplementary file 7). These resulted in estimated treatment effects of −24.77 U/mL in the cenerimod 2mg group (95% CI −67.18 to 17.64; p=0.2468) and of −64.55 U/mL in the cenerimod 4 mg group (95% CI −111.7 to –17.43; p=0.0082).

Consistent dose-related decreases in T and B lymphocyte subsets in blood were observed with cenerimod 1, 2 and 4 mg in the FAS. The mean reduction from baseline in T lymphocyte count at EOT was greater with cenerimod 1 mg (0.57±0.80×10⁹/L), 2 mg (0.86±0.53×10⁹/L) and 4 mg (0.70±0.86×10⁹/L) than with placebo (0.19±0.66×10⁹/L), while mean reduction in the 0.5 mg group (0.12±0.30×10⁹/L) was comparable with placebo (see online supplementary file 8A). The mean reduction from baseline in total B lymphocyte count at EOT was greater with cenerimod 1 mg (0.12±0.21×10⁹/L), 2 mg (0.12±0.09×10⁹/L) and 4 mg (0.11±0.16×10⁹/L) than with placebo (0.03±0.07×10⁹/L), while mean reduction in the 0.5 mg group (0.03±0.06×10⁹/L) was similar to placebo (see online supplementary file 8B).

PK results

For all cenerimod groups, C_trough increased until steady-state conditions were reached at approximately week 4, although the large variability observed in the cenerimod 4 mg group led to fluctuations in C_trough between week 4 and week 12. At the EOS visit, C_trough were BLQ for all patients in the cenerimod 0.5, 1 and 2 mg groups and for two patients in the cenerimod 4 mg group (figure 4).

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Safety and tolerability

Cenerimod treatment was well tolerated at all doses tested (analysed for the safety set). The incidence of TEAEs was similar among cenerimod doses and was numerically lower than in the placebo group (cenerimod 0.5 mg: 41.7%; 1 mg: 41.7%; 2 mg: 46.2%; 4 mg: 38.5% and placebo: 58.8%; table 2). Drug-related AEs, considered by the investigator to be related to study treatment, occurred in similar numbers of patients across the placebo and cenerimod treatment groups, and there was no evidence of dose dependency. No drug-related SAEs were reported (table 2).

In total, three patients discontinued because of AEs. One patient receiving placebo developed severe treatment-emergent SAEs (cholecystitis chronic, pancreatitis chronic (twice) and postcholecystectomy syndrome), which led to discontinuation on day 34. This patient’s SAEs were judged to be a clinical manifestation of an SLE flare unrelated to study treatment. Another patient receiving placebo discontinued the study after a TEAE of dyspepsia on day 22. One patient, receiving cenerimod 1 mg, was diagnosed with a non-TEAE of severe autoimmune hepatitis pre dose on day 1. This AE was judged by the investigator to be related to an SLE flare and led to discontinuation on day 9.

Less than 10% of patients experienced an AESI (n=6; 9%); five patients had liver-related AEs and one had a pulmonary-related AE. Numbers of reported AESIs were comparable across the cenerimod and placebo treatment groups with no evidence of dose dependency (table 2 and online supplementary file 9). All laboratory values were below the defined thresholds for marked abnormality. The pulmonary-related AE was non-serious severe pneumonitis, which occurred in a patient receiving cenerimod 1 mg and was judged by the investigator to be unrelated to study treatment.

After the first dosing, cenerimod induced a dose-dependent, transient and minimal decrease in heart rate (figure 5). On day 1, 12-lead ECG measurements hourly from pre dose to 6 hour post dose revealed that no patient had a heart rate lower than 40 bpm at any time after baseline, and all patients had systolic BP higher than 90 mm Hg. No patient failed to meet the heart rate or BP discharge criteria at 6 hours. Cenerimod did not affect PR or QRS intervals, although one patient (receiving placebo) had an abnormal PR interval of more than 200 ms. From the week 2 visit onward, no evidence for an effect with cenerimod was seen in any of the 12-lead ECG variables. Mean and median changes from baseline in supine systolic and diastolic BP over the first 6 hours on day 1 showed no difference between cenerimod-treated and placebo-treated patients. No trends could be discerned, and there was no evidence of a dose effect.

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Mean and median changes from baseline in spirometry variables indicated a small decrease in pulmonary function by EOT for cenerimod-treated patients that was not clearly dose related (see online supplementary file 10). The largest median decrease from baseline to EOT in absolute FEV₁ and FVC was observed in the cenerimod 2 mg group (−0.17 and −0.15 L, respectively) compared with placebo (0.00 and −0.06 L, respectively). Decreases of more than 15% from baseline to EOT in FEV₁ were observed in five patients (two patients in the placebo group, one in each of the cenerimod 0.5, 1 and 2 mg groups). A decrease above 15% decrease from baseline to EOT in FVC was also observed in five patients (two in the placebo group, two in the cenerimod 0.5 mg and one in the 4 mg group). No decreases in FEV₁ or FVC of more than 15% from baseline to EOT were observed at more than one timepoint in any of the cenerimod-treated patients. There was no evidence of a dose-related effect and none of these decreases or changes from baseline to EOT were associated with clinical symptoms.

Cenerimod treatment did not affect rates of infection, physical findings or body weight, nor did it lead to clinically significant ophthalmological disorders. There were no trends in changes in supine systolic and diastolic BP between cenerimod-treated and placebo-treated patients at any assessment during the treatment duration. None of the safety events met the protocol predefined safety stopping criteria.