A Research Study to Evaluate the Efficacy and Safety of Cenerimod in Subjects Suffering From Systemic Lupus Erythematosus

A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study 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 goal of this clinical trial is to see how well cenerimod reduces symptoms of Systemic Lupus Erythematous in adult patients with moderate to severe symptoms. The main questions it aims to answer are:

• How well cenerimod works on top of the treatment already being administered.
• How safe cenerimod is for adult patients with Systemic Lupus Erythematosus.

Researchers will compare one dose of cenerimod and a placebo to see how well cenerimod works when it is added to the treatment already being administered.

In this research study approximately 210 participants will receive cenerimod and approximately 210 participants will receive placebo for 12 months.

Inclusion Criteria:

Inclusion criteria at screening:

• Signed Informed Consent Form (ICF) 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".

• British Isles Lupus Assessment Group-2004 (BILAG) Grade B in ≥ 2 organ systems or a BILAG Grade A in ≥ 1 organ system.

• Physician's Global Assessment (PGA) score ≥ 1.0 on a 0 to 3 visual analog scale.

• Currently treated with one or more of the following SLE background medications:

  • Anti-malarials (≤ 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.

Inclusion criteria at randomization:

• A clinical mSLEDAI-2K score ≥ 4 with at least 2 points for musculoskeletal or mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers).

• BILAG Grade B in 2 or more organ systems or a BILAG Grade A in 1 or more organ system.

• 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 (≤ 1.44g/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.

Main Exclusion Criteria:

• Pregnant, planning to be 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.

• A diagnosis of mixed connective tissue disease or any history of overlap syndromes of SLE with psoriasis, rheumatoid arthritis, erosive arthritis, scleroderma, autoimmune hepatitis or uncontrolled autoimmune thyroid disease.

• 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 (including live vaccines for COVID-19).

• Intra-articular, intramuscular or i.v. CS within 6 weeks 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 anifrolumab within 6 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.