Cenerimod, a novel selective S1P₁ receptor modulator with unique signaling properties

Abstract

Sphingosine‐1‐phosphate receptor 1 (S1P1) modulators sequester circulating lymphocytes within lymph nodes, thereby preventing potentially pathogenic autoimmune cells from exiting into the blood stream and reaching inflamed tissues. S1P1 receptor modulation may thus offer potential to treat various autoimmune diseases. The first nonselective S1P1‐5 receptor modulator FTY720/fingolimod/Gilenya® has successfully demonstrated clinical efficacy in relapsing forms of multiple sclerosis. However, cardiovascular, hepatic, and respiratory side‐effects were reported and there is a need for novel S1P1 receptor modulators with better safety profiles. Here, we describe the discovery of cenerimod, a novel, potent and selective S1P1 receptor modulator with unique S1P1 receptor signaling properties and absence of broncho‐ and vasoconstrictor effects ex vivo and in vivo. Cenerimod dose‐dependently lowered circulating lymphocyte counts in rats and mice after oral administration and effectively attenuated disease parameters in a mouse experimental autoimmune encephalitis (EAE) model. Cenerimod has potential as novel therapy with improved safety profile for autoimmune diseases with high unmet medical need.

Modelling pharmacokinetics and pharmacodynamics of the selective S1P1 receptor modulator cenerimod in healthy subjects and systemic lupus erythematosus patients

“…Cenerimod (ACT‐334441 [molecular weight: 453.5 g/mol]) is a potent, orally active, selective modulator of the sphingosine‐1‐phosphate 1 (S1P 1 ) receptor . S1P 1 receptor modulators reduce the tissue availability of lymphocytes by blocking the egress of lymphocytes from lymphoid organs and are developed for the treatment of autoimmune disorders .…”

“…1 S1P 1 receptor modulators reduce the tissue availability of lymphocytes by blocking the egress of lymphocytes from lymphoid organs 2 and are developed for the treatment of autoimmune disorders. 3 To date, 2 S1P (1) receptor modulators have been granted marketing authorization for the treatment of multiple sclerosis. 4,5 Cenerimod is under clinical development for the treatment of systemic lupus erythematosus (SLE), a complex autoimmune disorder of chronic nature 6,7 that involves autoreactive T and B lymphocytes causing inflammation and tissue damage.…”

“…By contrast, too low LY counts are generally associated with an increased risk of infections. 9 Consequently, LY counts are frequently measured in studies with S1P (1) receptor modulators as surrogate for the immunomodulatory effect (efficacy) and as safety measure. Thereby, LY count thresholds for efficacy and safety proved useful to guide dose selection and benefit-risk evaluation of S1P (1) receptor modulators.…”

First use of cenerimod, a selective S1P1receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study

“…Cenerimod is a potent, orally active, selective S1P 1 receptor modulator with unique signalling properties 19. In the non-clinical setting, cenerimod did not induce bronchoconstriction or vasoconstriction, which are known adverse effects of S1P receptor modulators 19.…”

“…Cenerimod is a potent, orally active, selective S1P 1 receptor modulator with unique signalling properties 19. In the non-clinical setting, cenerimod did not induce bronchoconstriction or vasoconstriction, which are known adverse effects of S1P receptor modulators 19. A phase I study in healthy participants showed that cenerimod was well tolerated with no significant safety concerns across a range of doses from 0.5 to 4 mg once daily 20.…”