Unique pharmacological properties of etrasimod among S1P receptor modulators

• Published in: FEBS open bio 2025-01, Vol.15 (1), p.108-121
• Main Authors: Gaidarov, Ibragim, Komori, H. Kiyomi, Stepniak, Dariusz T., Bruinsma, Karin, Dang, Huong, Chen, Xiaohua, Anthony, Todd, Gatlin, Joel, Karimi‐Naser, Lisa, Ton, Anh‐Tuan, Indersmitten, Tim, Miller, Paul E., Ghetti, Andre, Abi‐Gerges, Najah, Unett, David, Al‐Shamma, Hussien, Rabbat, Christopher J., Crosby, Catherine, Adams, John W.
• Format: Article
• Language: English
• Subjects: Arrestin; Cell culture; Cell growth; Clinical trials; Endothelial cells; etrasimod; Fatty acids; Heart rate; Inflammatory bowel diseases; Inflammatory Diseases; Internalization; Intracellular signalling; Lymphatic system; Lymphocytes; pharmacodynamics; Pharmacokinetics; Pharmacology; Potassium; Potassium channels (inwardly-rectifying); Proteins; sphingosine 1‐phosphate receptor modulator; Ulcerative colitis; Umbilical vein
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.13907

Etrasimod (ADP334) is an oral, once‐daily, selective sphingosine 1‐phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis and in development for the treatment of immune‐mediated inflammatory diseases. Interaction between S1P and its five receptor subtypes (S1P1–S1P5) plays a role in several physiologic systems, including the cardiovascular and immune systems. Since differences in S1PR binding and downstream intracellular signaling could contribute to distinct profiles of drug efficacy and safety, we directly compared the S1P1–5 selectivity profile of etrasimod to three marketed S1PR modulators: fingolimod, ozanimod, and siponimod. Using both heterologous expression systems and human umbilical vein endothelial cells that spontaneously express S1P1, we profiled key S1P1 downstream signaling pathways and found that etrasimod had similar potency to the other tested S1PR modulators in promoting β‐arrestin recruitment and S1P1 internalization. However, etrasimod was notably less potent than other S1PR modulators in assays measuring S1P1‐mediated G protein activation (GTPγS binding and cAMP inhibition). Relatively lower potency of etrasimod in inducing G protein signaling corresponded to significantly diminished activation of human cardiac G protein‐coupled inwardly rectifying potassium channels when compared to ozanimod. Together with pharmacokinetic properties, this pharmacologic profile of etrasimod may contribute to the positive benefit risk profile of etrasimod observed during the phase III ELEVATE UC 52 and ELEVATE UC 12 trials in patients with moderately to severely active ulcerative colitis. Several S1P receptor modulators are being studied for treating immune‐mediated inflammatory diseases, each showing distinct selectivity and signaling activities. Downstream of S1P1, etrasimod showed similar potency to other S1P receptor modulators in promoting β‐arrestin recruitment and S1P1 internalization but was less potent in G protein activation, which may contribute to its favorable benefit–risk profile in treating conditions such as ulcerative colitis.