Colon to Rectum
Lancet. 2022;399(10341):2113–28
Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: Results from 3 phase 3, multicenter, double-blind, randomized trials
Background: There is a great unmet need for advanced therapies that provide rapid, robust, and sustained disease control for patients with ulcerative colitis. The authors assessed the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis.
Methods: This phase 3, multicenter, randomized, double-blind, placebo-controlled clinical program consisted of 2 replicate induction studies (U-ACHIEVE induction [UC1] and U-ACCOMPLISH [UC2]) and a single maintenance study (U-ACHIEVE maintenance [UC3]). The studies were conducted across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 199 clinical centers in 39 countries (UC1), 204 clinical centers in 40 countries (UC2), and 195 clinical centers in 35 countries (UC3). Patients aged 16–75 years with moderately to severely active ulcerative colitis (Adapted Mayo score 5–9; endoscopic subscore 2 or 3) for at least 90 days were randomly assigned (2:1) to oral upadacitinib 45 mg once daily or placebo for 8 weeks (induction studies). Patients who achieved clinical response following 8-week upadacitinib induction were re-randomly assigned (1:1:1) to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks (maintenance study). All patients were randomly assigned using web-based interactive response technology. The primary end points were clinical remission per Adapted Mayo score at week 8 (induction) and week 52 (maintenance). The efficacy analyses in the 2 induction studies were based on the intention-to-treat population, which included all randomized patients who received at least 1 dose of treatment. In the maintenance study, the primary efficacy analyses reported in this manuscript were based on the first 450 (planned) clinical responders to 8-week induction therapy with upadacitinib 45 mg once daily. The safety analysis population in the induction studies consisted of all randomized patients who received at least 1 dose of treatment; in the maintenance study, this population included all patients who received at least 1 dose of treatment as part of the primary analysis population.
Findings: Between October 23, 2018, and September 7, 2020, 474 patients were randomly assigned to upadacitinib 45 mg once daily (n = 319) or placebo (n = 155) in UC1. Between December 6, 2018, and January 14, 2021, 522 patients were randomly assigned to upadacitinib 45 mg once daily (n = 345) or placebo (n = 177) in UC2. In UC3, a total of 451 patients (21 from the phase 2b study, 278 from UC1, and 152 from UC2) who achieved a clinical response after 8 weeks of upadacitinib induction treatment were randomly assigned again to upadacitinib 15 mg (n = 148), upadacitinib 30 mg (n = 154), and placebo (n = 149) in the primary analysis population. Statistically significantly more patients achieved clinical remission with upadacitinib 45 mg (83 of 319 patients [26%] in UC1 and 114 of 341 patients [34%] in UC2) than in the placebo group (7 of 154 patients [5%] in UC1 and 7 of 174 patients [4%] in UC2; p < 0.0001; adjusted treatment difference 21.6% [95% confidence interval {CI}: 15.8–27.4] for UC1 and 29.0% [95% CI: 23.2–34.7] for UC2). In the maintenance study, clinical remission was achieved by statistically significantly more patients receiving upadacitinib (15 mg: 63 of 148 [42%]; 30 mg: 80 of 154 [52%]) than those receiving placebo (18 of 149 [12%]; p < 0.0001; adjusted treatment difference, 30.7% [95% CI: 21.7–39.8] for upadacitinib 15 mg vs. placebo and 39.0% [95% CI: 29.7–48.2] for upadacitinib 30 mg vs. placebo). The most commonly reported adverse events (AEs) in UC1 were nasopharyngitis (15 of 319 [5%] in the upadacitinib 45-mg group vs. 6 of 155 [4%] in the placebo group), creatine phosphokinase elevation (15 [4%] vs. 3 [2%]), and acne (15 [5%] vs. 1 [1%]). In UC2, the most frequently reported AE was acne (24 of 344 [7%] in the upadacitinib 45-mg group vs. 3 of 177 [2%] in the placebo group). In both induction studies, serious AEs and AEs leading to discontinuation of treatment were less frequent in the upadacitinib 45-mg group than in the placebo group (serious AEs: 8 [3%] vs. 9 [6%] in UC1 and 11 [3%] vs. 8 [5%] in UC2; AEs leading to discontinuation: 6 [2%] vs. 14 [9%] in UC1 and 6 [2%] vs. 9 [5%] in UC2). In UC3, the most frequently reported AEs (≥ 5%) were worsening of ulcerative colitis (19 of 148 [13%] in the upadacitinib 15-mg group vs. 11 of 154 [7%] in the upadacitinib 30-mg group vs. 45 of 149 [30%] in the placebo group), nasopharyngitis (18 [12%] vs. 22 [14%] vs. 15 [10%]), creatine phosphokinase elevation (9 [6%] vs. 13 [8%] vs. 3 [2%]), arthralgia (9 [6%] vs. 5 [3%] vs. 15 [10%]), and upper respiratory tract infection (7 [5%] vs. 9 [6%] vs. 6 [4%]). The proportion of serious AEs (10 [7%] vs. 9 [6%] vs. 19 [13%]) and AEs leading to discontinuation (6 [4%] vs. 10 [6%] vs. 17 [11%]) was lower in both upadacitinib groups than in the placebo group. Events of cancer, adjudicated major adverse cardiac events, or venous thromboembolism were reported infrequently. There were no treatment-related deaths.
Interpretation: Upadacitinib demonstrated a positive efficacy and safety profile and could be an effective treatment option for patients with moderately to severely active ulcerative colitis.