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A randomized, double-blind, parallel-group, multicenter, phase 2 study to investigate the safety and PD of cenerimod in Japanese subjects with moderate to severe systemic lupus erythematosus (SLE)

Phase 2 double blind study of cenerimod

17

In this study, a total of 17 SLE subjects received cenerimod, 9 in the cenerimod 2 mg group and 8 in the cenerimod 4 mg group. Approximately 90% of the subjects were female. The age (mean +/- standard deviation [S.D.]) was 41.2 +/- 11.9 years (cenerimod 2 mg group: 42.0 +/- 13.9 years, cenerimod 4 mg group: 40.4 +/- 10.0 years). Arthritis was the most common symptom found in multiple subjects on the SLEDAI-2K score endpoint at 76.5% (13/17 subjects). The total mSLEDAI-2K score (mean +/- S.D.) was 7.8 +/- 2.9 (cenerimod 2 mg group: 6.7 +/- 2.5, cenerimod 4 mg group: 9.1 +/- 3.0), with slightly higher disease activity in the cenerimod 4 mg group. Mean SLEDAI-2K total score and mean PGA score also tended to be higher in the cenerimod 4 mg group. SLE background treatments used in many subjects at baseline were hydroxychloroquine 88.2% (15/17 subjects), prednisolone 70.6% (12/17 subjects) and mycophenolate mofetil 47.1% (8/17 subjects).

In this study, 21 subjects were screened after informed consent was obtained, and 17 were randomized to receive the study treatment during the treatment period in a double-blind manner (cenerimod 2 mg group: 9 subjects; cenerimod 4 mg group: 8 subjects). Of these, 16 subjects (9 in the cenerimod 2 mg group and 7 in the cenerimod 4 mg group) completed all scheduled study procedures, and only 1 subject in the cenerimod 4 mg group prematurely discontinued the study treatment, and that subject completed the 6-month follow-up period.

The incidence of adverse events during the entire study period was 88.9% (8/9 cases) in the cenerimod 2mg group and 75.0% (6/8 cases) in the cenerimod 4mg group. There was no significant difference in the proportion of subjects who experienced AEs after receiving the study treatment between the two groups. Except for 1 subject in the cenerimod 4 mg group who discontinued treatment due to non-serious peripheral edema and increased hepatic enzymes, 16 patients completed the 3-month treatment period as per the study protocol. There were no deaths and no severe AEs causally related to the study treatment, including during the treatment period and the 6-month follow-up period after completion of treatment. One SAE (large intestine polyp) occurred in 1 subject in the cenerimod 2 mg group and 2 SAEs (colitis ulcerative and meningitis aseptic) occurred in 2 subjects in the cenerimod 4 mg group after the study treatment, but only one event (meningitis aseptic) was judged to be causally related to the study treatment in the cenerimod 4 mg group at follow-up period. There were no SAEs reported in two or more cases for the same event. No other characteristic AEs were observed, and no dose-dependent increase in the incidence of AEs was observed.

In this study, pharmacodynamic was considered a secondary endpoint and other efficacies was considered an exploratory endpoint. PHARMACODYNAMIC RESULTS: The change (mean +/- S.D.) in total lymphocyte count from baseline to the end of treatment (after 3 months of study treatment) was -0.734 +/- 0.208 * 10^9/L in the cenerimod 2 mg group and -0.777 +/- 0.578 * 10^9/L in the cenerimod 4 mg group, with the cenerimod 4 mg group tended to decrease more; however, the percent change (mean +/- S.D.) from baseline was -67.68 +/- 10.93% and -57.06 +/- 25.72%, respectively, and the dose-dependent decrease in total lymphocyte count was not clearly observed in this study. The change (mean +/- S.D.) in total lymphocyte count from baseline to the end of study (after 6 months of follow-up) and the percent change (mean +/- S.D.) were -0.018 +/- 0.203 * 10^9/L and -1.74 +/- 19.47% in the cenerimod 2 mg group, -0.028 +/- 0.263 * 10^9/L and -3.10 +/- 19.22% in the cenerimod 4 mg group, and recovered to baseline values in accordance with the clearance of cenerimod from the blood 6 months after the end of treatment. In the total lymphocyte count during the treatment period, 2 subjects in the cenerimod 2 mg group showed a decrease to less than 0.200 * 10^9/L, which corresponds to the criteria for discontinuation of treatment in this study, but the count recovered above the discontinuation criteria with continued treatment, and no characteristic trends in subject background or treatment status were observed. OTHER EFFICACY RESULTS: - DISEASE ACTIVITY The change (mean +/- S.D.) in mSLEDAI-2K total score from baseline to the end of treatment (after 3 months of study treatment) was -1.3 +/- 3.0 in the cenerimod 2 mg group and -2.4 +/- 2.7 in the cenerimod 4 mg group, and the change (mean +/- S.D.) from baseline to the end of study (after 6 months of follow-up) was -2.2 +/- 1.9 in the cenerimod 2 mg group and -5.1 +/- 3.4 in the cenerimod 4 mg group. This indicates that the effect of cenerimod on disease activity may persist long after treatment ends.

In this study, the primary and second endpoints were safety and pharmacodynamic, respectively. The results showed that cenerimod 2 or 4 mg was generally well-tolerated with no major safety issues, although there was a need to monitor the decrease in total lymphocyte counts during the treatment period. Pharmacodynamic showed a decrease in lymphocyte counts at both doses.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2011210019

Yokoyama Yoshinari

Idorsia Pharmaceuticals Japan Ltd

9-7-2 Akasaka Mitatoku, Tokyo

chiken.info-jp@idorsia.com

Yokoyama Yoshinari

Idorsia Pharmaceuticals Japan Ltd

9-7-2 Akasaka Mitatoku, Tokyo

+81-03-5962-5616

chiken.info-jp@idorsia.com

Complete

July. 01, 2021

Interventional

randomized controlled trial

double blind

dose comparison control

parallel assignment

treatment purpose

(1) Signed ICF prior to any study-mandated procedure.
(2) Diagnosis of SLE made at least 6 months prior to Screening, by fulfilling at least 4 of the 11 criteria for SLE as defined by the American College of Rheumatology (ACR) criteria.
(3) Male and female subjects, age 18 to 75 years old (both inclusive).
(4) A mSLEDAI-2K score >= 6 of at least 2 points for musculoskeletal or mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers).
Note: The mSLEDAI-2K score does not consider the factor leukopenia in SLEDAI-2K.

(1) Female subjects who are lactating or planning to become pregnant during the study.
(2) Active lupus nephritis (defined by proteinuria > 1.5 g/24 h, or equivalent using spot urine protein-to-creatinine ratio > 150 mg/mmol) or a renal biopsy demonstrating immune complex-mediated glomerulonephritis compatible with lupus nephritis within 90 days prior to Screening.
(3) Severe active central nervous system (CNS) lupus requiring therapeutic intervention (including aseptic meningitis, seizures, psychosis, cerebritis, cerebrovascular accident [CVA], organic brain syndrome, CNS vasculitis)
(4) Severe forms of vasculitis requiring systemic immunosuppressive treatment (including retinal vasculitis, coronary vasculitis, pulmonary vasculitis, mesenteric vasculitis) within 90 days prior to Screening.
(5) A diagnosis of mixed connective tissue disease or any history of overlap syndromes of SLE with rheumatoid arthritis, erosive arthritis, scleroderma or autoimmune hepatitis.

Both

Systemic lupus erythematosus

Administration of two doses of cenerimod (2 and 4 mg) given orally once daily for 3 months in adult subjects with moderate to severe SLE concurrently receiving SLE background treatment

Occurrence of treatment-emergent AEs/SAEs, and AEs of following special interest:
HR and rhythm-related AEs
Hypotension-related AEs
Hypertension-related AEs
etc.

Change from baseline to each post-baseline assessment up to EOS in total lymphocyte count

+81-11-706-7061

June. 15, 2021

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