Clinical Pearls & Morning Reports
Published June 28, 2023
Current therapies for ulcerative colitis are limited by increased risks of infection or cancer, nonresponse to primary therapy, or loss of clinical benefit over time. D’Haens et al. conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately-to-severely active ulcerative colitis (LUCENT-1, a 12-week induction trial, and LUCENT-2, a 40-week maintenance trial). Read the NEJM Original Article here.
Q: What is mirikizumab?
A: Interleukin-23, a proinflammatory factor, has two components: the p40 subunit, which is shared with interleukin-12, and the unique p19 subunit. Mirikizumab, a humanized IgG4-variant monoclonal antibody that specifically binds to subunit p19 of interleukin-23, showed efficacy in a phase 2 trial involving patients with ulcerative colitis.
Q: How did mirikizumab compare with placebo among patients with ulcerative colitis in LUCENT-1, the 12-week induction trial?
A: The primary end point in the induction trial was clinical remission at week 12. At week 12, the percentage of patients with clinical remission was higher in the mirikizumab group than in the placebo group (24.2% vs. 13.3%, P<0.001). Results favored the mirikizumab group for the major secondary end points of clinical response, endoscopic remission, remission of symptoms at weeks 4 and 12, clinical response in patients who had previous treatment failure with a biologic agent or tofacitinib, histologic–endoscopic mucosal improvement, and bowel-movement urgency (P<0.001 for all comparisons).
A: The primary end point in the maintenance trial was clinical remission at week 40. At week 40, 49.9% of the patients in the mirikizumab group and 25.1% of those in the placebo group had clinical remission (P<0.001). The percentages of patients with glucocorticoid-free clinical remission, maintenance of clinical remission, endoscopic remission, histologic–endoscopic mucosal remission, and bowel-urgency remission, were all significantly greater in the mirikizumab group than in the placebo group. Among mirikizumab-treated patients who were in clinical remission at week 40, a total of 97.8% were not taking glucocorticoids. The improvement from baseline in the Urgency Numeric Rating Scale score (an 11-point scale that patients used to describe the severity of their daily bowel urgency) remained stable throughout the maintenance trial in the mirikizumab group, whereas patients in the placebo group in the maintenance trial lost some of the improvement that had been gained during the induction trial.
A: Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer. Elevations in liver-enzyme levels were more frequent in the mirikizumab groups than in the placebo groups. Elevations in liver-enzyme levels have been observed with interleukin-23 subunit p19 inhibitors that are approved for other indications. During the maintenance trial, depression was more common in the mirikizumab group than in the placebo group (in four patients vs. none). Nasopharyngitis and arthralgias were also more frequent in the mirikizumab groups than in the placebo groups.