Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients With Ulcerative Colitis

Gastroenterology. 2020 Feb;158(3):550-561. doi: 10.1053/j.gastro.2019.10.035. Epub 2019 Nov 9.

Abstract

Background & aims: Etrasimod (APD334) is an oral, selective sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We assessed the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis (UC).

Methods: In a phase 2, proof-of-concept, double-blind, parallel-group study, adult outpatients with modified Mayo Clinic scores (MCSs) (stool frequency, rectal bleeding, and endoscopy findings) of 4-9, endoscopic subscores of 2 or more, and rectal bleeding subscores of 1 or more were randomly assigned to groups given once-daily etrasimod 1 mg (n = 52), etrasimod 2 mg (n = 50), or placebo (n = 54) for 12 weeks. The study was performed from October 15, 2015, through February 14, 2018, at 87 centers in 17 countries. The primary endpoint was an increase in the mean improvement in modified MCS from baseline to week 12. Secondary endpoints included the proportion of patients with endoscopic improvement (subscores of 1 or less) from baseline to week 12. Exploratory endpoints, including clinical remission, are reported in the article, although the study was statistically powered to draw conclusions only on the primary endpoint.

Results: At week 12, the etrasimod 2 mg group met the primary and all secondary endpoints. Etrasimod 2 mg led to a significantly greater increase in mean improvement in modified MCS from baseline than placebo (difference from placebo, 0.99 points; 90% confidence interval, 0.30-1.68; P = .009), and etrasimod 1 mg led to an increase in mean improvement from baseline in modified MCS of 0.43 points more than placebo (90% confidence interval, reduction of 0.24 to increase of 1.11; nominal P = .15). Endoscopic improvement occurred in 41.8% of patients receiving etrasimod 2 mg vs 17.8% receiving placebo (P = .003). Most adverse events were mild to moderate. Three patients had a transient, asymptomatic, low-grade atrioventricular block that resolved spontaneously all patients had evidence of atrioventricular block before etrasimod exposure.

Conclusions: In patients with moderately to severely active ulcerative colitis, etrasimod 2 mg was more effective than placebo in producing clinical and endoscopic improvements. Further clinical development is warranted. Clinicaltrials.gov, Number: NCT02447302.

Keywords: Immunomodulatory Therapy; Inflammatory Bowel Disease; S1P Receptor Modulator; Ulcerative Colitis.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / administration & dosage*
  • Acetates / adverse effects
  • Adult
  • Asymptomatic Diseases / epidemiology
  • Atrioventricular Block / chemically induced
  • Atrioventricular Block / epidemiology*
  • Colitis, Ulcerative / complications
  • Colitis, Ulcerative / diagnosis
  • Colitis, Ulcerative / drug therapy*
  • Colitis, Ulcerative / immunology
  • Colon / diagnostic imaging
  • Colon / drug effects
  • Colon / pathology
  • Colonoscopy
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Gastrointestinal Hemorrhage / diagnosis
  • Gastrointestinal Hemorrhage / epidemiology
  • Gastrointestinal Hemorrhage / etiology
  • Gastrointestinal Hemorrhage / prevention & control*
  • Humans
  • Indoles / administration & dosage*
  • Indoles / adverse effects
  • Induction Chemotherapy / adverse effects
  • Induction Chemotherapy / methods
  • Intestinal Mucosa / diagnostic imaging
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / pathology
  • Male
  • Middle Aged
  • Placebos / administration & dosage
  • Placebos / adverse effects
  • Proof of Concept Study
  • Rectum
  • Severity of Illness Index
  • Sphingosine-1-Phosphate Receptors / immunology
  • Sphingosine-1-Phosphate Receptors / metabolism
  • Treatment Outcome

Substances

  • Acetates
  • Indoles
  • Placebos
  • Sphingosine-1-Phosphate Receptors
  • etrasimod

Associated data

  • ClinicalTrials.gov/NCT02447302