A Multicenter,Open-label,Single Arm,Multiple-dose Study to Evaluate the Safety,Tolerability,Pharmacokinetics and Pharmacodynamics of Cenerimod in Adult Chinese Participants With Moderate-to-severe Systemic Lupus Erythematosus (SLE) on Top of Background Therapy
A Multicenter,Open-label,Single Arm,Multiple-dose Study to Evaluate the Safety,Tolerability,Pharmacokinetics and Pharmacodynamics of Cenerimod in Adult Chinese Participants With Moderate-to-severe Systemic Lupus Erythematosus (SLE) on Top of Background Therapy
The goal of this clinical trial is to learn about the safety, how the body processes the drug, and its effects of a drug called cenerimod in adult Chinese participants (aged 18-75) with moderate to severe Systemic Lupus Erythematosus (SLE) who are already receiving standard background therapy.
The main questions it aims to answer are:
Participants will:
Inclusion Criteria:
Signed and dated ICF prior to any study-mandated procedure.
Male and female Chinese participants aged from 18 to 75 years old (inclusive) at the time of signing the ICF.
Diagnosis of SLE made at least 6 months prior to Screening, according to 2019 European League Against Rheumatism / American College of Rheumatology Criteria.
An 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).
Note: The mSLEDAI-2K score does not include "leukopenia". The clinical mSLEDAI-2K is the mSLEDAI-2K assessment score without the inclusion of points attributable to hematuria, proteinuria, pyuria, urinary casts, low complement, increased DNA binding, and thrombocytopenia.
PGA score ≥ 1.0 on a 0 to 3 VAS.
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 corticosteroid(s) (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:
Belimumab (≤ 10 mg/kg every 4 weeks intravenously [i.v.] or ≤ 200 mg/week subcutaneously [s.c.]).
Telitacicept (≤ 240 mg/week subcutaneously). Treatment with antimalarials, mycophenolate mofetil, mycophenolic acid, azathioprine, methotrexate, belimumab, or telitacicept 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):
On Day 1 before dosing,A clinical mSLEDAI-2K score ≥ 4 with at least 2 points for musculoskeletal or mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers).
On Day 1 before dosing,PGA score ≥ 1.0 on a 0 to 3 VAS.
On Day 1 before dosing,Presence of at least one of the following biomarkers of serological evidence of active SLE (in a Screening sample as measured by central laboratory):
On Day 1 before dosing,Currently treated with one or more of the following SLE background medications that must be stable for at least 30 days prior to Day 1 (except OCS, which must be stable for at least 15 days prior to Day 1):
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:
If OCS is not the only SLE background medication:
Belimumab (≤ 10 mg/kg every 4 weeks i.v. or
≤ 200 mg/week s.c.);
Telitacicept (≤ 240 mg/week subcutaneously).
On Day 1 before dosing,WoCBP must have a negative urine pregnancy test.
Exclusion Criteria:
Pregnant, planning to be become pregnant up to 6 months after the last dose of cenerimod in this study, or lactating women.
Active severe SLE-driven renal disease (within 90 days prior to Screening or during Screening) where, in the judgment of the investigator, protocol-specified SLE background therapy is insufficient and the use of a more aggressive therapeutic approach or other treatments not permitted in the protocol is indicated.
Urine protein/creatinine ratio> 3000 mg/g (i.e., > 339.45 mg/mmol) at Screening assessment based on central assessment.
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:
Severe forms of vasculitis (e.g., retinal vasculitis, coronary vasculitis, pulmonary vasculitis, mesenteric vasculitis) requiring systemic immunosuppressive treatment within 90 days prior to Screening or during Screening.
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.
Participants 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 (see Appendix 14) within 6 months prior to Screening.
Resting HR < 50 beats per minute as measured by the 12-lead ECG at Screening or at Day 1 prior to study treatment administration.
An elevated QTcF interval of > 470 ms (females) / > 450 ms (males) at Screening or at Day 1 prior to study treatment administration.
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.
Have had household contact with a person with active Tuberculosis (TB) and did not receive appropriate and documented prophylaxis for TB.
Have evidence of active TB or latent TB
Active TB: Have evidence of active TB, defined in this study as the following:
Exception 1: participants with a history of active TB who have documented evidence of appropriate treatment, have no history of re-exposure since their treatment was completed, have no clinical features of active TB, and have a Screening chest X-ray with no evidence of active TB may be enrolled if other entry criteria met. Such participants would not be required to undergo the IGRA test, but must have a chest X- ray at Screening (i.e., chest imaging performed within the past 6 months will not be accepted).
Latent TB: Have evidence of untreated/inadequately or inappropriately treated latent TB, defined in this study as the following:
Exception 2: participants with a history of latent TB who have documented evidence of appropriate treatment, have no history of re-exposure since their treatment was completed, have no clinical features of active TB, and have a Screening chest X-ray with no evidence of active TB may be enrolled if other entry criteria met. Such participants would not be required to undergo the IGRA test, but must have a chest X- ray at Screening (i.e., chest imaging performed within the past 6 months will not be accepted).
Ongoing bacterial, viral, parasitic, or fungal infection that is of clinical concern according to the investigator or any of the following:
Positive results for serological markers for hepatitis A, B, C, and E indicating acute or chronic infection:
Participants who have congenital or acquired severe immunodeficiency or known human immunodeficiency virus (HIV) infection or positive HIV testing.
Negative IgG antibody test for varicella-zoster virus.
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.
History or presence of homologous (allogenic) bone marrow or solid organ transplantation.
Presence of macular edema or active uveitis detected by optical coherence tomography (OCT) during Screening.
Documented poorly controlled diabetes mellitus (i.e., glycated hemoglobin > 8.0% at Screening as reported by the central laboratory or unstable blood sugar control/treatment adherence as per investigator's judgment) or diabetes mellitus complicated with organ involvement, such as diabetic nephropathy or retinopathy as assessed by investigator.
History of chronic liver or biliary disease (other than Gilbert's Syndrome) or participants with alanine aminotransferase or aspartate aminotransferase > 3 × upper limit of normal or total bilirubin > 1.5 ×upper limit of normal (unless in the context of known Gilbert's Syndrome).
Significant hematology abnormality at screening assessment:
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 Day 1:
Treatment with the following medications within 30 days or 5 half-lives of the medication (whichever is longer) prior to Day 1:
Intra-articular, intramuscular or i.v. CS within 6 weeks prior to Day 1.
Treatment with the following medications within 90 days or 5 half-lives of the medication (whichever is longer) prior to Day 1:
Treatment with any investigational agent within 90 days or 5 half-lives of the drug (whichever is longer) prior to Day 1.
Treatment with B cell-depleting biological agents (e.g., rituximab or ocrelizumab) or biological immunosuppressive agents (e.g., anti-tumor necrosis factor, anti-interleukin- [IL]1, anti-IL-6 therapies), within 12 months prior to Day 1.
Treatment with anifrolumab within 6 months prior to Day 1.
Treatment with any of the following medications any time prior to Screening:
Recent clinically significant drug or alcohol abuse as per investigator's judgment.
Known allergy to S1P receptor modulators or any of the cenerimod formulation excipients.
Any other clinically relevant medical condition that would put the participant at risk if participating in the study, or any other diseases that may confound the disease activity assessments.
Participants with body weight < 40 kg at Screening or Day 1.