Long-term efficacy and safety of upadacitinib in patients with moderately to severely active ulcerative colitis: an interim analysis of the phase 3 U-ACTIVATE long-term extension study.

Background: The U-ACTIVATE long-term extension study aims to evaluate the long-term efficacy and safety of upadacitinib in patients with moderately to severely active ulcerative colitis. Here, we report interim results after 3 years of total treatment.

Methods: U-ACTIVATE is an ongoing, 288-week, phase 3, long-term extension study done at 307 centres across 43 countries (active sites on Dec 31, 2021, are presented as part of this interim analysis) and began on Jan 31, 2017. In brief, patients aged 16-75 years with a confirmed diagnosis of moderately to severely active ulcerative colitis for 90 days or more, an adapted Mayo score of 5-9, and an endoscopic subscore of 2 or 3 were eligible for the upadacitinib induction studies; patients who had a clinical response in the induction studies were eligible to enter the U-ACHIEVE maintenance study. Individuals who completed the U-ACHIEVE maintenance study were subsequently eligible for inclusion in the efficacy population of this long-term extension study. Patients in clinical remission per adapted Mayo score at week 52 of the maintenance study could continue their double-masked treatment upon entering the long-term extension study. Patients not in clinical remission originally randomly assigned to upadacitinib 15 mg were eligible to escalate to upadacitinib 30 mg, those originally randomly assigned to upadacitinib 30 mg continued on upadacitinib 30 mg, and those originally assigned to placebo were eligible to escalate to upadacitinib 15 mg in a masked way. We present data from weeks 48 and 96 of the long-term extension period. Key efficacy outcomes were clinical remission (per adapted Mayo score), endoscopic remission, maintenance of clinical remission, and maintenance of endoscopic remission, and are presented for those patients who had a clinical response after 8 weeks of upadacitinib 45 mg induction, completed 52 weeks of maintenance (U-ACHIEVE maintenance), and subsequently entered the long-term extension. Safety outcomes were treatment-emergent adverse events and adverse events of special interest, which were prespecified and were recorded in two populations: one comprising patients who received at least one dose of study drug in the long-term extension study and the other comprising all patients in the maintenance or long-term extension studies. Our primary approach for efficacy analysis was as-observed (ie, all observed data were used without imputation for missing data until patients switched to a different dose during the long-term extension study). This study is registered with ClinicalTrials.gov (NCT03006068).

Findings: 414 patients from the phase 3 upadacitinib U-ACHIEVE maintenance study were eligible to enter this long-term extension study for assessment of efficacy endpoints following treatment with upadacitinib. Of these individuals, 369 patients (231 [63%] male individuals and 138 [37%] female individuals) were treated with upadacitinib in the long-term extension study: 142 patients with upadacitinib 15 mg and 227 with upadacitinib 30 mg. In the as-observed population, 84 (71%) of 118 patients receiving upadacitinib 15 mg were in clinical remission at week 48, as were 130 (67%) of 193 receiving upadacitinib 30 mg; by week 96, 69 (76%) of 91 patients receiving upadacitinib 15 mg and 104 (74%) of 141 of those receiving upadacitinib 30 mg were in clinical remission. Most patients who entered the long-term extension in clinical remission maintained it in the as-observed analysis (week 48 upadacitinib 15 mg 62 [81%] of 77 and upadacitinib 30 mg 90 [81%] of 111; week 96 upadacitinib 15 mg 50 [78%] of 64 and upadacitinib 30 mg 69 [84%] of 82). In the as-observed population, 60 (49%) of 123 patients receiving upadacitinib 15 mg and 93 (46%) of 202 receiving upadacitinib 30 mg were in endoscopic remission at week 48; by week 96, 45 (47%) of 95 patients receiving upadacitinib 15 mg and 69 (45%) of 153 receiving upadacitinib 30 mg were in endoscopic remission. Most patients who entered the long-term extension in endoscopic remission maintained it in the as-observed analysis (week 48 upadacitinib 15 mg 28 [70%] of 40 and upadacitinib 30 mg 51 [76%] of 67; week 96 upadacitinib 15 mg 20 [65%] of 31 and upadacitinib 30 mg 37 [73%] of 51). In the long-term extension-only safety analysis, we assessed data from 467 patients, representing 1027·9 patient-years of continuous long-term extension exposure on a consistent upadacitinib dose. Treatment-emergent adverse events were recorded at 238·5 events per 100 patient-years for upadacitinib 15 mg and 233·4 events per 100 patient-years for upadacitinib 30 mg. Event rates of serious treatment-emergent adverse events were 11·7 events per 100 patient-years for upadacitinib 15 mg and 12·4 events per 100 patient-years for upadacitinib 30 mg. The most common adverse events of special interest were hepatic disorder, lymphopenia, creatine phosphokinase elevation, serious infection, neutropenia, and herpes zoster. Three treatment-emergent adverse events leading to death were reported in the long-term extension-only safety population.

Interpretation: This interim analysis supports the positive long-term risk-benefit profile for upadacitinib 15 mg and 30 mg among patients with moderately to severely active ulcerative colitis.

Funding: AbbVie.