Lancet. 2023 Apr 8;401(10383):1159-1171.doi: 10.1016/S0140-6736(23)00061-2. Epub 2023 Mar 2.

William J Sandborn ¹, Séverine Vermeire ², Laurent Peyrin-Biroulet ³, Marla C Dubinsky ⁴, Julian Panes ⁵, Andres Yarur ⁶, Timothy Ritter ⁷, Filip Baert ⁸, Stefan Schreiber ⁹, Sheldon Sloan ¹⁰, Fabio Cataldi ¹⁰, Kevin Shan ¹⁰, Christopher J Rabbat ¹⁰, Michael Chiorean ¹¹, Douglas C Wolf ¹², Bruce E Sands ¹³, Geert D'Haens ¹⁴, Silvio Danese ¹⁵, Martina Goetsch ¹⁶, Brian G Feagan ¹⁷

Author information

¹Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. Electronic address: wsandborn@health.ucsd.edu.

²Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.

³Department of Gastroenterology, University of Lorraine, Inserm, NGERE, F-54000 Nancy, France; Groupe Hospitalier Privé Ambroise Paré-Hartmann, Paris IBD Center, Nully-sur-Seine, France.

⁴Department of Gastroenterology, Feinstein IBD Center, Mount Sinai, New York, NY, USA.

⁵Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.

⁶Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

⁷Department of Research and Education, GI Alliance Research, Southlake, TX, USA.

⁸Department of Gastroenterology, AZ Delta, Roeselare, Belgium.

⁹University Hospital Schleswig-Holstein, Department Internal Medicine I, Kiel University, Kiel, Germany.

¹⁰Arena Pharmaceuticals, San Diego, CA, USA; a wholly-owned subsidiary of Pfizer Inc, New York, NY, USA.

¹¹Division of Gastroenterology and Hepatology, IBD Center, Swedish Medical Center, Seattle, WA, USA.

¹²Atlanta Gastroenterology Associates, Atlanta, GA, USA.

¹³Dr Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

¹⁴Inflammatory Bowel Disease Centre, University of Amsterdam, Amsterdam, Netherlands.

¹⁵Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy.

¹⁶Arena Pharmaceuticals Development GmbH, Zug, Switzerland; a wholly-owned subsidiary of Pfizer Inc, New York, NY, USA.

¹⁷Department of Medicine, University of Western Ontario/Alimentiv Inc, London, ON, Canada.

Abstract

Background: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P_2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis.

Methods: In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively.

Findings: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported.

Interpretation: Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis.

Funding: Arena Pharmaceuticals.