Ulcerative colitis is a lifelong inflammatory disease affecting the rectum and colon to a variable extent. However, ulcerative colitis can highly affect a patient’s life, leading to long-term burdensome complications. According to study datas, the prevalence of ulcerative colitis was estimated to be 5 million cases around the world, and the incidence is increasing worldwide, in 2023. Ulcerative colitis is thought to occur in people with a genetic predisposition following environmental exposures. Moreover, gut epithelial barrier defects, the microbiota, and a dysregulated immune response are strongly implicated.
The therapeutic options have expanded substantially over the past decade with biologics (eg, anti-tumour necrosis factor (TNF), vedolizumab, and ustekinumab) and small molecules (eg, Janus kinase inhibitors and sphingosine-1-receptor modulators). Hence, we will introduce a FDA approved new active agent, Etrasimod (APD334).
Etrasimod is a potent, selective and orally available sphingosine-1-phosphate-1 (S1P1) receptor antagonist.
Etrasimod selectively targets S1P receptor subtypes 1, 4 and 5 which have been implicated in decreasing intestinal inflammation. Importantly, Etrasimod does not activate S1P2 or S1P3 receptor subtypes, which are associated with cardiac, pulmonary and tumor-related side effects.
In vitro, Etrasimod exhibits an IC50 value of 1.88 nM in CHO cells expressing HA tagged S1P1.
In addition, Etrasimod achieves good central exposure following oral dosing and possesses a favorable pharmacokinetic profile in multiple preclinical species. Besides, Etrasimod maintains the S1P1 activity in mice (EC50=0.44 nM), rats (EC50=0.32 nM), dogs (EC50=0.34 nM) and monkeys (EC50=0.32 nM). Furthermore, Etrasimod has a relatively low systemic clearance (<4% of hepatic blood flow) and high Cmax across all species. And, oral bioavailability is in the range of 40-100%, and the terminal phase half-life varied from 6 h in monkey, to as long as 29 h in dog.
In a word, Etrasimod is a promising active agent for ulcerative colitis research.
Reference:
[1] Buzard DJ, et al. ACS Med Chem Lett. 2014 Nov 4;5(12):1313-7.
[2] Le Berre C, et al. Lancet. 2023 Aug 12;402(10401):571-584.
[3] John W Adams, et al. FASEB J.2018 Oct 3.