Colon to Rectum
Lancet Gastroenterol Hepatol. 2023;8(11):976–89
Efficacy and safety of upadacitinib maintenance therapy for moderately to severely active ulcerative colitis in patients responding to 8-week induction therapy (U-ACHIEVE Maintenance): Overall results from the randomized, placebo-controlled, double-blind, phase 3 maintenance study
Background: Upadacitinib is an oral, selective, and reversible Janus kinase (JAK) inhibitor with demonstrated efficacy in patients with moderately to severely active ulcerative colitis in a phase 2b induction trial, 2 phase 3 induction trials (U-ACHIEVE Induction and U-ACCOMPLISH), and a primary analysis of the first 451 patients entering a subsequent maintenance trial (U-ACHIEVE Maintenance). Here, the authors present overall results from the entire U-ACHIEVE Maintenance population.
Methods: In this randomized, placebo-controlled, double-blind, phase 3 maintenance study done across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 251 clinical centers in 44 countries, patients aged 16–75 years with moderately to severely active ulcerative colitis (adapted Mayo score 5–9, centrally assessed endoscopic subscore of 2 or 3) for 90 days or more were randomly assigned (2:1) to double-blind upadacitinib 45 mg once daily or placebo induction therapy in the phase 2b induction trial or 2 phase 3 induction trials. Patients with a clinical response per adapted Mayo score after 8 weeks were randomly reassigned (1:1:1) using web-based interactive response technology to 52-week double-blind maintenance therapy with placebo, upadacitinib 15 mg, or upadacitinib 30 mg once daily. Efficacy was analyzed at week 52 in the intention-to-treat population, which included all patients randomly reassigned who received at least 1 dose of study drug. The primary end point was clinical remission per adapted Mayo score. Safety through week 52 was assessed with exposure-adjusted event rates (EAERs; events per 100 patient-years) in upadacitinib 45 mg once daily 8-week induction responders who were enrolled per protocol for 44-week or 52-week maintenance therapy (i.e., the intention-to-treat population plus patients who received up to 44 weeks’ maintenance therapy under earlier protocol amendments) and received at least 1 dose of study drug.
Findings: Between September 3, 2016, and January 14, 2021, 987 patients received the upadacitinib 45 mg once daily induction therapy in the phase 2b trial, U-ACHIEVE Induction, or U-ACCOMPLISH. 681 patients with a clinical response to the induction therapy (319 from U-ACHIEVE Induction, 341 from U-ACCOMPLISH, and 21 from the phase 2b induction trial) received placebo (n = 223), upadacitinib 15 mg once daily (n = 225), or upadacitinib 30 mg once daily (n = 233) in U-ACHIEVE Maintenance and were included in this analysis. A greater proportion of patients achieved the primary end point with upadacitinib 15 mg (40.4%) and 30 mg once daily (53.6%) versus placebo (10.8%; both p < 0.0001 vs. placebo). For safety, 746 patients were analyzed, representing 552.9 patient-years of exposure; the most common grade 3–4 treatment-emergent adverse events were worsening of ulcerative colitis in 9 patients (4%) with placebo, and COVID-19 pneumonia and cryptococcal pneumonia in 2 patients (1%) each with upadacitinib 30 mg once daily. Higher EAERs of the following treatment-emergent events of special interest were observed with upadacitinib versus placebo: herpes zoster (6.0 events per 100 patient-years with upadacitinib 15 mg once daily and 7.3 events per 100 patient-years with upadacitinib 30 mg once daily versus none per 100 patient-years with placebo [12 and 16 vs. no events], respectively), hepatic disorders (17.0 and 9.2 vs. 5.9 events per 100 patient-years [34 and 20 vs. 8 events], respectively), creatine phosphokinase elevation (8.0 and 10.1 vs. 3.7 events per 100 patient-years [16 and 22 vs. 5 events], respectively), and neutropenia (5.5 and 8.7 vs. 5.2 events per 100 patient-years [11 and 19 vs. 7 events], respectively). One (< 1% of patients) adjudicated major adverse cardiovascular event occurred with placebo and 1 (< 1% of patients) with upadacitinib 30 mg once daily (EAERs 0.7 and 0.5 events per 100 patient-years, respectively). Two (1% of patients) venous thromboembolic events occurred with upadacitinib 15 mg once daily and 2 (1% of patients) with upadacitinib 30 mg once daily (EAERs 1.0 and 0.9 events per 100 patient-years, respectively). All adjudicated major adverse cardiovascular events and venous thromboembolic events with upadacitinib occurred in patients with relevant known risk factors.
Interpretation: Consistent with the primary analysis done among a smaller population, both maintenance doses of upadacitinib showed a positive benefit-risk profile in patients with moderately to severely active ulcerative colitis. Upadacitinib represents an effective treatment option for this population, for whom a large unmet need persists.