Evaluation of Cenerimod Efficacy and Safety in Adults with Moderate-to-Severe Systemic Lupus Erythematosus: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2024-515871-37-00
Protocol: ID-064A302
Sponsor: Viatris Innovation GmbH

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Diseases & Conditions

Systemic lupus erythematosus

Objectives

The primary objective of this study is to evaluate the **effectiveness** of cenerimod 4 mg in reducing disease activity in patients with moderate to severe **systemic lupus erythematosus** (SLE) compared to placebo. This is clinically relevant as SLE is a chronic autoimmune disease characterized by periods of increased disease activity, which can lead to significant morbidity. Effective management of disease activity is crucial in improving patient outcomes and quality of life.

Secondary objectives include:

Evaluating the effect of cenerimod 4 mg on controlling the disease compared to placebo.

Participants

The clinical trial involves a total of **328 participants** diagnosed with **moderate to severe systemic lupus erythematosus**. The study population includes both male and female subjects, with an age range spanning from young adults to older adults. Participants were selected based on specific criteria, including a confirmed diagnosis of systemic lupus erythematosus made at least six months prior to screening, and a modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K) score of 6 or higher. The trial population includes individuals currently undergoing treatment with one or more background medications for systemic lupus erythematosus, such as antimalarials, mycophenolate mofetil, azathioprine, methotrexate, oral corticosteroids, or belimumab. Lifestyle considerations, such as diet and physical activity, are not specified. The study also includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's effectiveness across diverse demographic groups.

Plans and Procedures

The clinical trial is a **Phase 3**, multicenter, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy, safety, and tolerability of **cenerimod** in adult subjects with moderate-to-severe **systemic lupus erythematosus** (SLE) on top of background therapy. The primary objective is to assess the effectiveness of cenerimod 4 mg at reducing disease activity compared to placebo. The trial is expected to run until May 2027, with recruitment having commenced in July 2023. Participants will be involved in the study for a maximum treatment period of 12 months.

The trial includes several key study visits. The initial visit is the inclusion (screening) visit, where participants must meet specific criteria, including a diagnosis of SLE made at least six months prior, a modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K) score of at least 6, and current treatment with stable SLE background medications. Randomization criteria include a clinical mSLEDAI-2K score of at least 4, a British Isles Lupus Assessment Group-2004 (BILAG) Grade B in two or more organ systems, and the presence of serological evidence of active SLE. Follow-up visits will occur regularly to monitor the participants' response to treatment, with primary and secondary endpoints assessed at Month 12 compared to baseline. The primary endpoint is the response on the Systemic Lupus Erythematosus Responder Index (SRI-4), while secondary endpoints include the response on the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) and time to first confirmation of a sustained mSLEDAI-2K response.

The end-of-study visit will conclude the participants' involvement, assessing the overall treatment effects and any adverse events. Participants may be terminated early from the study if they experience significant adverse effects, fail to adhere to the study protocol, or withdraw consent. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.

Treatment

The clinical trial involves the administration of **cenerimod**, an investigational medication, which is being evaluated for its efficacy, safety, and tolerability in adult subjects with moderate-to-severe **systemic lupus erythematosus** (SLE). Cenerimod is provided in the form of a film-coated tablet, with a dosage of 4 mg. The route of administration is oral, and the medication is to be taken once daily. The maximum treatment period for cenerimod is 12 weeks. The active substance, cenerimod, is of chemical origin and is manufactured by Idorsia Pharmaceuticals Ltd. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the cenerimod film-coated tablet in appearance and is administered orally at the same frequency and duration as the active treatment. The use of a placebo allows for the assessment of cenerimod's effectiveness in reducing disease activity compared to no active treatment. Participants will continue their background therapy for SLE during the trial, ensuring that the study evaluates the additive effect of cenerimod on top of standard-of-care treatments.

Efficacy

The efficacy of cenerimod in the treatment of moderate-to-severe **Systemic Lupus Erythematosus (SLE)** will be assessed through a series of predefined endpoints. The primary endpoint is the response on the Systemic Lupus Erythematosus Responder Index (SRI-4) at Month 12 compared to baseline. Secondary endpoints include the response on the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) at Month 12 compared to baseline, the time to first confirmation of a 4-month sustained mSLEDAI-2K response, and the time to first confirmation of a 4-month sustained response in mucocutaneous manifestations. These efficacy parameters will be measured and collected at specified timepoints, with the primary assessment occurring at the 12-month mark. The trial will utilize validated scales and laboratory tests to ensure the accuracy and reliability of the data collected. The analysis will focus on comparing the efficacy of cenerimod 4 mg to placebo in reducing disease activity in adult subjects with SLE, while subjects continue their background therapy. The study is designed as a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, ensuring a robust evaluation of the treatment's efficacy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Screening criteria: • Signed Informed Consent Form prior to any study-mandated procedure. • Diagnosis of Systemic Lupus Erythematosus (SLE) made at least 6 months prior to Screening, according to 2019 European League Against Rheumatism / American College of Rheumatology Criteria. • A modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K) score ≥ 6 and clinical mSLEDAI-2K score ≥ 4 with at least 2 points for musculoskeletal or mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers). The mSLEDAI-2K score does not include "leukopenia". • Currently treated with one or more of the following SLE background medications: - Antimalarials (≤ 400 mg/day hydroxychloroquine, ≤ 500 mg/day chloroquine, ≤ 100 mg/day quinacrine). - Mycophenolate mofetil (≤ 2 g/day) / mycophenolic acid (≤1.44 g/day). - Azathioprine (≤ 2 mg/kg/day). - Methotrexate (≤ 25 mg/week). - Oral Corticosteroids (OCS): if OCS is the only SLE background medication, ≥ 7.5 mg/day and ≤ 30 mg/day prednisone or equivalent; if OCS is not the only SLE background medication, ≤ 30 mg/day prednisone or equivalent. - Belimumab (≤10 mg/kg every 4 weeks intravenously [i.v.], or 200 mg/week subcutaneously [s.c.]). • Treatment with antimalarials, mycophenolate mofetil, mycophenolic acid, azathioprine, methotrexate or belimumab must have been started at least 90 days prior to Screening. • Treatment with OCS must have been started at least 30 days prior to Screening. • For women of childbearing potential (WoCBP): - Negative serum pregnancy test at Screening. - Agreement to undertake monthly urine pregnancy tests from Randomization up to 6 months after study treatment discontinuation. - Agreement to use a highly effective method of contraception from Screening (Visit 1) up to 6 months after study treatment discontinuation.
Randomization criteria: • A clinical mSLEDAI-2K score ≥ 4 with at least 2 points for musculoskeletal or mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers). • British Isles Lupus Assessment Group-2004 (BILAG) Grade B in 2 or more organ systems or a BILAG Grade A in 1 or more organ system. • Physician's Global Assessment (PGA) score ≥ 1.0 on a 0 to 3 visual analog scale. • Presence of at least one of the following biomarkers of serological evidence of active SLE (in a Screening sample as measured by central laboratory): - Anti-dsDNA antibodies elevated above normal, - Antinuclear antibodies with a titer of at least 1:160, - Anti-Smith antibody elevated above normal. • Currently treated with one or more of the following SLE background medications that must be stable for at least 30 days prior to Randomization (except OCS, which must be stable for at least 15 days prior to Randomization): - Antimalarials (≤ 400 mg/day hydroxychloroquine, ≤ 500 mg/day chloroquine, ≤ 100 mg/day quinacrine); - Mycophenolate mofetil (≤ 2 g/day) / mycophenolic acid (≤ 1.44 g/day); - Azathioprine (≤ 2 mg/kg/day); - Methotrexate (≤ 25 mg/week); - OCS: if OCS is the only SLE background medication, ≥ 7.5 mg/day and ≤ 30 mg/day prednisone or equivalent; if OCS is not the only SLE background medication: ≤ 30 mg/day prednisone or equivalent). - Belimumab (≤ 10 mg/kg every 4 weeks i.v. or ≤ 200 mg/week s.c.). • WoCBP must have a negative urine pregnancy test at Randomization.

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Exclusion Criteria

Pregnant, planning to become pregnant up to Final Study Visit, or lactating women.
Severe active central nervous system lupus or active severe or unstable neuropsychiatric SLE including but not limited to: aseptic meningitis; cerebral vasculitis; myelopathy; demyelination syndromes (ascending, transverse, acute inflammatory demyelinating polyradiculopathy); acute confusional state; impaired level of consciousness; psychosis; acute stroke or stroke syndrome; cranial neuropathy; status epilepticus; cerebellar ataxia; or mononeuritis multiplex: • That would make the subject unable to fully understand the ICF; OR • Where, in the opinion of the investigator/delegate, protocol-specified standard of care is insufficient and the use of a more aggressive therapeutic approach, such as adding i.v. cyclophosphamide and/or high dose i.v. pulse corticosteroid (CS) therapy or other treatments not permitted in the protocol is indicated.
History or presence of Mobitz type II or third-degree atrioventricular block, sick sinus syndrome, symptomatic bradycardia or syncope associated with cardiac disorders. • Subjects who experienced myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack, vascular thrombosis, decompensated heart failure requiring hospitalization, or heart failure defined by the New York Heart Association Class III/IV within 6 months prior to Screening. • Resting Heart Rate < 50 bpm as measured by the 12-lead ECG at Screening or at Randomization. • An elevated QT interval corrected according to Fridericia's formula (QTcF) interval of > 470 ms (females) / > 450 ms (males) at Screening or at Randomization.
History or presence of severe respiratory disease or pulmonary fibrosis, based on medical history, lung function, and chest X-ray (or CT scan as per local guidelines), performed at Screening or within 6 months prior to Screening. • History of clinically relevant bronchial asthma or chronic obstructive pulmonary disease that has required treatment with oral or parenteral CS for more than a total of 2 weeks within the last 6 months prior to Screening.
History or presence of malignancy (except for surgically excised and non-recurrent cutaneous basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma), lymphoproliferative disease, or history of total lymphoid irradiation within 10 years prior to Screening. • Presence of any of the following abnormalities detected during the ophthalmological evaluation and/or by optical coherence tomography (OCT) during screening: - Macular edema of any cause: diabetic, cystoid, tractional. - Foveal degeneration, macular hole, macular pseudohole, hereditary or degenerative maculopathies. - Active uveitis, papilledema. - Retinal neovascularization of any cause and in any location.• History of chronic liver or biliary disease (other than Gilbert's Syndrome) or subjects with alanine aminotransferase or aspartate aminotransferase > 3 × Upper Limit of Normal (ULN) or total bilirubin > 1.5 × ULN (unless in the context of known Gilbert's Syndrome). • Significant hematology abnormality at screening assessment: - lymphocyte count < 500/μL (0.5 × 10^9/L); - hemoglobin < 7 g/dL; - white blood cell count < 2000/μL (2.0 × 10^9/L); or - platelets < 25000/μL (25 × 10^9/L). • Estimated glomerular filtration rate < 15 mL/min/1.73 m^2.
Treatment with the following medications within 15 days or 5 half-lives of the medication (whichever is longer) prior to Randomization: - β-blockers, diltiazem, verapamil, digoxin, digitoxin, or any other antiarrhythmic or heart-rate -lowering systemic therapy. - QT-prolonging drugs with known risk of torsade de pointes irrespective of indication. • Treatment with the following medications within 30 days or 5 half-lives of the medication (whichever is longer) prior to Randomization: - Cyclophosphamide, cyclosporine, voclosporin, tacrolimus, sirolimus, etc. - Pulse methylprednisolone. - Vaccination with live vaccines. • Intra-articular, intramuscular or i.v. CS within 6 weeks prior to Randomization. • Treatment with anifrolumab within 6 months prior to Randomization. • Treatment with the following medications within 90 days or 5 half-lives of the medication (whichever is longer) prior to Randomization: - Leflunomide. - i.v. immunoglobulins. • Treatment with any investigational agent within 90 days or 5 half-lives of the drug (whichever is longer) prior to Randomization. • Treatment with B cell-depleting biological agents (e.g., rituximab or ocrelizumab) or biological immunosuppressive agents (e.g., anti-tumor necrosis factor [TNF], anti-interleukin [IL]-1, anti-IL6 therapies), within 12 months prior to Randomization. • Treatment with any of the following medications any time prior to Screening: - Alemtuzumab; - Sphingosine-1-phosphate receptor modulators (e.g., fingolimod). - Subjects previously randomized to cenerimod or placebo in any trial involving cenerimod.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Czechia	Not Recruiting	03 Jul 2023	10
Germany	Not Recruiting	03 Jul 2023	32
Poland	Not Recruiting	03 Jul 2023	27
Portugal	Not Recruiting	03 Jul 2023	12
Spain	Not Recruiting	03 Jul 2023	11