Clinical Overview: Etrasimod for Ulcerative Colitis


Etrasimod is an advanced synthetic compound classified as a selective modulator of Sphingosine 1-phosphate (S1P) receptors, specifically targeting S1P1, S1P4, and S1P5 receptors .

In October 2023, the FDA granted approval for etrasimod under the brand name Velsipty (Pfizer), intended for the treatment of adults suffering from moderately to severely active ulcerative colitis (UC).1 This approval was grounded in positive outcomes stemming from Pfizer's ELEVATE UC phase 3 registrational program, which encompassed the ELEVATE UC 52 and ELEVATE UC 12 clinical trials. These trials examined the effectiveness of a 2-mg daily dose of etrasimod, revealing remission rates of 32% in the UC 52 trial and 26% in the UC 12 trial.2

Etrasimod partially and temporarily inhibits the ability of lymphocytes to exit lymphoid organs, leading to a decrease in the quantity of lymphocytes in the peripheral blood. The precise mechanism through which etrasimod delivers therapeutic benefits in UC remains uncertain but could potentially include the reduction of lymphocyte migration into the intestines.3

female doctor holding shield and graphic virtual visualization of Intestine organ in hands.

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Etrasimod is an advanced synthetic compound classified as a selective modulator of Sphingosine 1-phosphate (S1P) receptors, specifically targeting S1P1, S1P4, and S1P5 receptors while showing no detectable activity on S1P2 and S1P3 receptors. S1P receptors are molecules involved in lysophospholipid signaling within cell membranes, and they play a crucial role in retaining circulating peripheral lymphocytes in lymph nodes.3

Consequently, S1P receptor modulators, such as etrasimod, have been extensively studied for their potential in treating immune-mediated conditions like ulcerative colitis. This condition often features an elevated presence of inflammatory T cells within the gastrointestinal tract, leading to widespread mucosal inflammation. It is noteworthy that antigen-activated T cells in peripheral lymphoid organs can temporarily reduce S1P receptor levels to facilitate the movement of immune cells into the intestinal mucosa.3

In the ELEVATE UC 52 and ELEVATE UC 12 trials, adults diagnosed with active moderate-to-severe UC, who had either not responded adequately or experienced intolerance to at least 1 approved ulcerative colitis treatment, were randomly allocated in a 2:1 ratio to receive either a daily oral dose of 2 mg etrasimod or a placebo.2

ELEVATE UC 52 and ELEVATE UC 12 initially screened 821 patients and 606 patients, respectively, with 433 and 354 eventually undergoing random assignment. In the ELEVATE UC 52 trial, the full analysis set included 289 patients given etrasimod and 144 who received a placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod, and 116 were assigned to the placebo.2

In ELEVATE UC 52, a significantly higher percentage of patients in the etrasimod group achieved clinical remission compared to those in the placebo group at the conclusion of the 12-week induction period (74 out of 274 patients [27%] vs. 10 out of 135 patients [7%]; p<0.0001) and at week 52 (88 out of 274 patients [32%] vs. 9 out of 135 patients [7%]; p<0.0001). In ELEVATE UC 12, 55 out of 222 patients (25%) in the etrasimod group attained clinical remission, compared to 17 out of 112 patients (15%) in the placebo group at the end of the 12-week induction period (p=0.026).2

Adverse events were reported in 206 out of 289 patients (71%) in the etrasimod group and 81 out of 144 patients (56%) in the placebo group in ELEVATE UC 52. In ELEVATE UC 12, 112 out of 238 patients (47%) in the etrasimod group and 54 out of 116 patients (47%) in the placebo group reported adverse events. Notably, there were no reported deaths or malignancies.2

Etrasimod proved to be both effective and well-tolerated when used as both an induction and maintenance therapy in individuals with moderately to severely active UC. This treatment option presents a distinctive blend of qualities that could potentially address the long-standing unmet requirements of patients with UC. Numerous treatments for UC require ongoing parenteral administration or carry the risk of severe infections and malignancies. Consequently, there is a demand for UC treatment options that are both safe and effective when taken orally. This medication offers a potential option for patients to attain clinical remission without relying on steroids, which have served as a short-term treatment for inflammatory bowel disease flares for many years.3

One distinction between etrasimod and ozanimod (Zeposia; Bristol Myers Squibb) lies in their dosing approaches. Ozanimod requires a titration process in which the dose is gradually escalated over the initial few days, whereas etrasimod maintains a consistent daily dosage of 2 mg.4

S1P receptor modulators have possible adverse effects. Etrasimod might lead to a temporary reduction in heart rate and atrioventricular (AV) conduction when treatment begins. In UC-1 and UC-2, the mean (standard deviation) decrease in heart rate was 7.2 (8.98) beats per minute at 2 to 3 hours following the initial dose of etrasimod on Day 1. When administered at twice the maximum recommended dose, etrasimod does not induce clinically significant prolongation of the QTc interval. Additionally, subjects treated with etrasimod experienced decreases in absolute FEV1.4

Contraindications to therapy include having a myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack, decompensated heart failure leading to hospitalization, or exhibiting Class III or IV heart failure within the preceding 6 months. Furthermore, a history or current presence of Mobitz type II second-degree or third-degree AV block, sick sinus syndrome, or sino-atrial block is contraindicated unless the patient is equipped with a functional pacemaker.4


1. U.S. FDA Approves Pfizer’s VELSIPITY for Adults with Moderately to Severely Active Ulcerative Colitis (UC). Accessed October 19, 2023.

2. Sandborn WJ, Vermeire S, Peyrin-Biroulet L, et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. The Lancet. 2023. doi:

3. Al-Shamma H, Lehmann-Bruinsma K, Carroll C, et al. The Selective Sphingosine 1-Phosphate Receptor Modulator Etrasimod Regulates Lymphocyte Trafficking and Alleviates Experimental Colitis. J Pharmacol Exp Ther. 2019 Jun;369(3):311-317. doi: 10.1124/jpet.118.254268.

4. Velsipity (etrasimod). [prescribing information]. New York, NC: Pfizer, Inc.; October 2023.

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