Clinical Pearls & Morning Reports
Published May 24, 2023
Crohn’s disease is a chronic and relapsing inflammatory bowel disease characterized by transmural inflammation within the gastrointestinal tract. New treatment options with novel mechanisms of action that provide adequate symptomatic and endoscopic control for patients with moderate-to-severe disease are needed. Loftus et al. conducted three phase 3 trials that evaluated the efficacy and safety of upadacitinib in patients with moderate-to-severe Crohn’s disease. Read the NEJM Original Article here.
Q: What kind of drug is upadacitinib?
A: Activation of signal transducers and activators of transcription (STATs) that are mediated by Janus kinases (JAKs) in T cells play an important pathogenic role in Crohn’s disease. Upadacitinib, an oral, reversible JAK inhibitor, has been approved for the treatment of ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, and ankylosing spondylitis.
Q: What were the primary end points of the three trials in this phase 3 program?
A: U-EXCEL and U-EXCEED consisted of a 12-week double-blind, placebo-controlled induction treatment period. U-ENDURE was a 52-week double-blind, placebo-controlled maintenance trial for patients who had a clinical response to 12 weeks of upadacitinib induction treatment in U-EXCEL or U-EXCEED. The primary end points for induction (week 12) and maintenance (week 52) were clinical remission (defined as a Crohn’s Disease Activity Index [CDAI] score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]) and endoscopic response.
A: In this set of trials involving patients with moderate-to-severe Crohn’s disease, upadacitinib induction and maintenance therapy was superior to placebo with respect to the primary end points of clinical remission and endoscopic response as well as the majority of secondary end points, including quality-of-life outcomes. In U-EXCEL, a significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo met the primary end points at week 12 of CDAI clinical remission (49.5% vs. 29.1%, P<0.001) and endoscopic response (45.5% vs. 13.1%, P<0.001). In U-EXCEED, a significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo met the primary end points at week 12 of CDAI clinical remission (38.9% vs. 21.1%, P<0.001) and endoscopic response (34.6% vs. 3.5%, P<0.001). In U-ENDURE, with respect to CDAI clinical remission at week 52, maintenance treatment with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) was superior to placebo (15.1%) (P<0.001 for both comparisons). An endoscopic response at week 52 was significantly more likely among patients who received 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than among those who received placebo (7.3%) (P<0.001 for both comparisons).
A: Results were not significant for the occurrence of Crohn’s disease–related hospitalization during the induction period and resolution of extraintestinal manifestations at week 12. Adverse events that are associated with JAK inhibition, including serious infections, opportunistic infections, anemia, neutropenia, and creatine kinase elevation, were observed more frequently in patients who received upadacitinib than in those who received placebo. An ongoing long-term extension trial of U-ENDURE is evaluating these patients for up to 5 years.