Colon to Rectum
Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): Two randomized, double-blind, placebo-controlled, phase 3 studies
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 S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these 2 phase 3 trials, the authors aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis.
Methods: In 2 independent randomized, multicenter, 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 centers in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centers in 37 countries. Randomization 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 end points were the proportion of pa-tients 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.
Findings: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and January 28, 2021. Patients in ELEVATE UC 12 were enrolled be-tween September 15, 2020, and August 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 (74/274 patients [27%] vs. 10/135 patients [7%]; p < 0.0001) and at week 52 (88/274 patients [32%] vs. 9/135 pa-tients [7%]; p < 0.0001). In ELEVATE UC 12, 55 of 222 patients (25%) in the etrasimod group had clinical remission compared with 17 of 112 patients (15%) in the placebo group at the end of the 12-week induction period (p = 0.026). Adverse events were reported in 206 of 289 patients (71%) in the etrasimod group and 81 of 144 patients (56%) in the placebo group in ELEVATE UC 52 and 112 of 238 patients (47%) in the etrasi-mod group and 54 of 116 patients (47%) 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 pa-tients with ulcerative colitis.