Upadacitinib: The New Jak Inhibitor in Town

Abstract

Danese S, Vermeire S, Zhou W, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicenter, double-blind, randomized trials. Lancet. 2022;399:2113–2128. Upadacitinib is an oral small molecule that has preferential inhibition of JAK1 that also inhibits JAK2, JAK3, and tyrosine kinase. Danese et al performed 3 phase III multicenter, double-blind, randomized trials assessing the efficacy and safety of upadacitinib as induction and maintenance therapy in patients with moderate to severe active ulcerative colitis. The 2 induction studies were UC1 and UC2, with each randomizing in a 2:1 ratio over 300 patients to upadacitinib 45 mg every other day, and over 150 patients to placebo. Patients who had a clinical response after 8 weeks of upadacitinib were eligible to enter UC3 (a maintenance study), where approximately 150 patients were each randomized to either upadacitinib 15 mg or 30 mg every other day or placebo for 52 weeks. The primary end points were clinical remission defined by an adapted Mayo score of ≤2, with a stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and an endoscopic subscore of ≤1 without friability. Secondary end points included improvements in endoscopic score, endoscopic remission, clinical response, histological improvement, bowel urgency, abdominal pain, inflammatory bowel disease questionnaire scores, mucosal healing and change in baseline in the Functional Assessment of Chronic Illness therapy score. Significantly more patients achieved clinical remission with upadacitinib 45 mg compared with placebo at 8 weeks (26% vs 5%, Δ 21% in UC1; 33% vs 4%, Δ 29% in UC2). In UC3, upadacitinib 15 mg and 30 mg was significantly superior to placebo in maintaining clinical remission at 52 weeks (42% and 52% vs 12%, Δ31% and Δ39%, respectively). All secondary end points were achieved in UC3 in the 15-mg and 30-mg groups compared with placebo. Upadacitinib showed similar safety and withdrawal profiles when compared with placebo. Events of cancer, adjudicated major adverse cardiac events, or venous thromboembolism were reported infrequently. There were no treatment-related deaths. The study limitations include the lack of data beyond 52 weeks. It also did not allow any dose optimization or de-escalation, and hence the benefits of these strategies remain unknown. Despite these limitations, upadacitinib demonstrated a positive efficacy and safety profile and could be an effective treatment option for patients with moderately to severely active ulcerative colitis. Excitingly, phase III trials have also reported positive signals for upadacitinib in achieving both induction and maintenance in patients with Crohn’s disease (Gastroenterology 2020;158:2123–2138) and hence real-world and long-term data will be paramount to help position this drug appropriately. This study highlights the potential of selective JAK inhibition and provides signals that optimizing JAK selectivity may culminate in more efficacious and safe drugs in inflammatory bowel disease.