POS0168 POST-HOC ANALYSIS OF SUSTAINED RESPONSE OVER TIME IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS TREATED WITH CENERIMOD IN CARE (PHASE 2 B) STUDY

Abstract

Background:

The sphingolipid S1P is a signaling molecule with pleiotropic effects involved in several immune-mediated inflammatory diseases such as multiple sclerosis, ulcerative colitis, and SLE. It acts through 5 different receptors, S1P₁ to S1P₅. Cenerimod is a selective S1P₁ receptor modulator that blocks T- and B-cell egress from lymphoid organs and has the potential to reduce the abnormal immune response in SLE and decrease disease activity [1]. SLEDAI-2K is an established SLE outcome measure and one of the health authority guideline-recommended clinical endpoints to assess disease activity. In studies involving cenerimod, the SLEDAI-2K scale has been modified (mSLEDAI-2K) to exclude leukopenia since cenerimod reduces circulating lymphocyte count as part of its mechanism of action [2, 3]. In pivotal clinical trials, the change in SLEDAI-2K is usually measured after 1 or 2 years of treatment; however, little is known about the persistence of SLEDAI-2K improvement, i.e., the proportion of patients with sustained responses lasting several months. The CARE study, NCT03742037, a multicentre, randomized, double-blind, placebo-controlled phase 2b trial, evaluated the efficacy, safety, and tolerability of 4 doses of cenerimod (0.5, 1, 2, and 4 mg) versus placebo in adults with moderate-to-severe SLE receiving standard of care background therapy [3]. The primary endpoint was change from baseline to month 6 in mSLEDAI-2K. The treatment effect, in 427 randomized subjects, was largest with 4 mg, with an LSM (standard error) estimate of - 4.04 (0.38) vs - 2.85 (0.38) in the placebo group, resulting in a difference to placebo of -1·19 (P=0·029). Patients in the 0.5, 1, 2 mg, and placebo arms continued the study drug for an additional 6 months. Patients assigned to cenerimod 4 mg arm were randomly assigned (1:1) to either cenerimod 2 mg or placebo for another 6 months, designated herein as cenerimod Ex-4 mg group. All patients who had received cenerimod 4 mg for the first 6 months were included in the analysis irrespective of their treatment assignment in the next 6 months to either 2 mg or placebo. Safety outcomes were monitored for 12 months.

Objectives:

This post-hoc analysis was performed to assess sustained responses in mSLEDAI-2K vs placebo over a period of 12 months.

Methods:

Sustained response in mSLEDAI-2K (defined as a decrease of ≥4 points from baseline for 4 consecutive monthly assessments) and time to first confirmation of 4-month sustained response in mSLEDAI-2K were evaluated. The treatment effect was estimated for each treatment group vs placebo using a Cox proportional hazards model stratified by baseline oral corticosteroid and mSLEDAI-2K. Hazard ratios and 95% confidence interval were derived from the model. The analysis was performed over the 12-month period and the initial randomization was used as the basis for group allocation.

Results:

427 patients were randomized, 85 patients each in the 0.5, 1, and 4 mg arms and 86 patients each in the 2 mg and placebo arms. Median age was 42 years (range 18–72), 406 (95%) were female, and 337 (79%) White. A sustained response in mSLEDAI-2K score was observed in 63.5% of the patients in the cenerimod Ex-4mg group as compared to 50.0% of those in the placebo group. The median time is the time by when the event has occurred in 50% of the study subjects. The median time to the first confirmation of a 4-month sustained response in mSLEDAI-2K was estimated at 304 days in cenerimod Ex-4mg group vs 334 days in placebo group. The hazard ratio was estimated at 1.43 in cenerimod Ex-4mg group, suggesting that this group has a 43% greater chance of experiencing a 4-month sustained response in mSLEDAI-2K as compared to the placebo group (Figure 1).

Conclusion:

This analysis showed that over a period of 12 months, patients in the cenerimod Ex-4 mg group were 1.43 times more likely to achieve a 4-month sustained response than those receiving placebo. The ongoing confirmatory Phase 3 program OPUS (NCT05648500 and NCT05672576) will further evaluate the safety and efficacy of 4 mg cenerimod in adults with SLE.

REFERENCES:

[1] Hoyler TF, Strasser DS, Berkani O, et al. LO-016 The multifaceted immunomodulatory properties of cenerimod, a selective S1P1 receptor modulator, target three key aspects of SLE pathogenesis. Archives of Disease in childhood; 2023. [2] Hermann V, Batalov A, Smakotina S, Juif PE, Cornelisse P. First use of cenerimod, a selective S1P(1) receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study. Lupus Sci Med 2019; 6(1): e000354. [3] Askanase AD, D'Cruz D, Kalunian K, et al. Cenerimod, a sphingosine-1-phosphate receptor modulator, versus placebo in patients with moderate-to-severe systemic lupus erythematosus (CARE): an international, double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Rheumatol 2025; 7(1): e21-e32.

Acknowledgements:

The Authors acknowledge Arghya Bhattacharya, PhD (Viatris) for medical writing support.

Disclosure of Interests:

Anca Askanase: None declared, Ouali Berkani Idorsia Pharmaceuticals, Idorsia Pharmaceuticals, Cecile Dubois Idorsia Pharmaceuticals, Idorsia Pharmaceuticals. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.