Etrasimod as induction and maintenance treatment for patients with moderately to severely active ulcerative colitis in East Asia (ENLIGHT UC): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study.
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BACKGROUND: Etrasimod is an oral, once-daily sphingosine 1-phosphate (S1P) receptor modulator for the treatment of active ulcerative colitis. In the randomised, placebo-controlled, double-blind phase 3 ENLIGHT UC study, also known as the ES101002 study, we aimed to evaluate the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis in East Asia. METHODS: Using a central interactive web response system, in the 12-week induction period, adults (aged 18-75 years, inclusive) with moderately to severely active ulcerative colitis (modified Mayo score [MMS] 4-9 with an endoscopic subscore ≥2 and a rectal bleeding subscore ≥1) and an inadequate response, loss of response, or intolerance to at least one ulcerative colitis treatment were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients and study staff were masked to treatment assignment. Patients were enrolled from 52 hospitals across China, Taiwan, and Souh Korea. Randomisation was stratified by previous treatment status and baseline disease activity. Patients who had an MMS clinical response at induction period week 12 were re-randomly assigned (1:1) to once-daily oral etrasimod 2 mg or placebo for the 40-week maintenance period. Randomisation was stratified by induction period treatment, previous exposure to biologicals or JAK inhibitors, and concomitant use of oral corticosteroids at induction period baseline. The primary efficacy outcome was MMS clinical remission (stool frequency subscore=0 [or stool frequency subscore=1 with a ≥1 point decrease from induction period baseline], rectal bleeding subscore=0, and endoscopic subscore ≤1 [excluding friability]), assessed in the induction and maintenance periods separately (at induction period week 12 and maintenance period week 40). The primary efficacy analyses used the full analysis set (FAS), which included all patients who were randomly assigned and received at least one dose of study treatment for the induction period, and all re-randomly assigned patients who showed clinical response at induction period week 12 and received at least one dose of study treatment for the maintenance period. The safety analyses for each treatment period used the safety analysis set (SAF), which included all patients who received any amount of study drug in the corresponding treatment period. ENLIGHT UC is registered with ClinicalTrials.gov (NCT04176588) and the study is complete. FINDINGS: 606 patients were screened between Sept 25, 2019, and April 27, 2023, and 340 were randomly assigned for the induction period and treated (FAS: 228 patients [88 female and 140 male] assigned to etrasimod and 112 patients [44 female and 68 male] assigned to placebo). 157 patients who showed clinical response in the induction period were re-randomly assigned and treated in the maintenance period (FAS: 77 patients [35 female and 42 male] assigned to etrasimod and 80 patients [32 female and 48 male] assigned to placebo). A significantly greater proportion of patients treated with etrasimod than those treated with placebo, showed clinical remission at induction week 12 (57 [25·0%] of 228 patients vs six [5·4%] of 112 patients; adjusted difference 20·4%; 95% CI 13·4%-27·4%; p<0·0001) and maintenance period week 40 (37 [48·1%] of 77 patients vs 10 [12·5%] of 80 patients; adjusted difference 35·9%; 95% CI 22·5%-49·2%; p<0·0001). In the induction period, the most frequently reported treatment-emergent adverse event (TEAE) was increased ALT (22 [10%] in the etrasimod group vs one [1%] in the placebo group). In the maintenance period, the most frequently reported TEAE was upper respiratory tract infection (14 [18%] in the etrasimod group vs 14 [17%] in the placebo group). Across the induction and maintenance periods, most TEAEs were mild to moderate in severity. Five (2%) of 228 patients treated with etrasimod and four (4%) of 112 patients treated with placebo discontinued study treatment due to TEAEs during the induction period, and one (1%) of 77 patients treated with etrasimod and one (1%) of 81 patients treated with placebo discontinued study treatment due to TEAEs during the maintenance period. No grade 4 or higher TEAE, malignancies, or deaths were reported. INTERPRETATION: Etrasimod was effective and well tolerated as an oral induction and maintenance treatment in patients with moderately to severely active ulcerative colitis in East Asia. FUNDING: Everest Medicines. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.