ABSTRACT
Introduction: Upadacitinib (UPA), an oral selective and reversible JAK inhibitor, recently demonstrated significantly greater therapeutic efficacy compared to placebo (PBO) in patients with moderate to severe ulcerative colitis (UC) during a Phase 3 program.1,2,3 We evaluated the efficacy of dose escalation to UPA 30 mg QD (UPA30) among patients who demonstrated an inadequate response to UPA 15 mg QD (UPA15) during the long-term extension (LTE) study U-ACTIVATE. Results were based on non-responder imputation (NRI-NC) with 95% confidence intervals (CI) calculated by normal approximation to binomial distribution. F020For patients enrolled from U-ACHIEVE Maintenance due to loss of response, inadequate response was defined as: SFS + RBS value that remains unchanged or has increased from wk 0 on two consecutive visits at least 7 days apart. a Non-responder imputation with no special data handling for missing due to COVID-19 was applied. 95% CI calculated by normal approximation to binomial distribution. b Clinical remission per Adapted Mayo score: SFS≤1 and not greater than baseline (of induction), RBS=0, and endoscopic subscore (ES) ≤ 1. c Clinical remission per Adapted Mayo score and CS-free clinical remission (clinical remission at wk 48 and CS-free for ≥90 days prior to wk 48 among patients with clinical remission at the end of the induction therapy). d Endoscopic improvement: ES ≤ 1 e Endoscopic remission: ES= 0.
ABSTRACT
Introduction: Upadacitinib (UPA), an oral JAK inhibitor, showed significantly greater efficacy vs placebo (PBO) in induction treatment of patients (pts) with moderately-to-severely active ulcerative colitis (UC) in two phase 3 induction trials, U-ACHIEVE and U-ACCOMPLISH. We evaluated efficacy of UPA in pts who had an inadequate response (IR), loss of response, or intolerance to biologic therapies (Bio-IR) or were non-Bio-IR. Methods: U-ACHIEVE and U-ACCOMPLISH, multicentre, double-blind, placebo (PBO)-controlled trials, randomized pts with moderately to severely active UC to UPA 45 mg QD or PBO for 8 weeks (wks). Randomization was stratified by status of previous biologic failure, ie an inadequate response (IR), loss of response, or intolerance to biologic therapies (Bio-IR or bio-failure) vs non-Bio-IR (nonbio-IR or non-bio-failure), baseline corticosteroid use (yes or no), and baseline adapted Mayo score (≤7 or>7). Efficacy endpoints included primary endpoint of clinical remission (adaptedMayo score) at Wk 8 and ranked secondary endpoints of clinical response (partial adapted Mayo score at Wk 2 and adapted Mayo score at Wk 8), endoscopic improvement (Mayo endoscopic subscore 0 or 1), endoscopic remission (Mayo endoscopic subscore 0) and histologic-endoscopic mucosal improvement at Wk 8 (HEMI;endoscopic subscore ≤1 and Geboes score ≤3.1). Results using non-responder imputation incorporating multiple imputation for missing data due to COVID-19 are reported. Results: In both studies, approximately half the pts were Bio-IR (Table 1). In both Bio-IR and non-Bio-IR pts, significantly higher proportion of pts receiving UPA achieved primary endpoint of clinical remission versus PBO;the magnitude of clinical remission at Wk 8 was greater in non-Bio-IR pts (UPA, 35% vs PBO, 9%;treatment difference [95% CI]: 26.0% [16.0, 36.1]) versus Bio-IR (UPA, 18% vs PBO, 0%;17.5% [11.4, 23.6]) in U-ACHIEVE and non-Bio-IR (UPA, 38% vs PBO, 6%;31.6% [22.8, 40.5]) versus Bio-IR (UPA, 30% vs PBO, 2%;27.1% [19.6, 34.7];Table 1) in U-ACCOMPLISH. Results were generally similar for ranked secondary endpoints (Table 1). UPA 45 mg QD was well-tolerated and no new safety signals were observed. Conclusion: UPA 45 mg QD is an effective induction treatment for pts with moderately to severely active UC. A significantly higher proportion of pts in both Bio-IR and non-Bio-IR groups receiving UPA achieved primary and secondary endpoints versus PBO. The magnitude of difference was greater among pts who were non-Bio-IR versus Bio-IR.