Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Mirikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial. METHODS: We conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed. RESULTS: A total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. 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. CONCLUSIONS: Mirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizumab. (Funded by Eli Lilly; LUCENT-1 and LUCENT-2 ClinicalTrials.gov numbers, NCT03518086 and NCT03524092, respectively.).

Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Interleukin 23 contributes to the pathogenesis of ulcerative colitis (UC). We investigated the effects of mirikizumab, a monoclonal antibody against the p19 subunit of interleukin 23, in a phase 2 study of patients with UC. METHODS: We performed a trial of the efficacy and safety of mirikizumab in patients with moderate to severely active UC, enrolling patients from 14 countries from January 2016 through September 2017. Patients were randomly assigned to groups given intravenous placebo (N = 63), mirikizumab 50 mg (N = 63) or 200 mg (N = 62) with exposure-based dosing, or mirikizumab 600 mg with fixed dosing (N = 61) at weeks 0, 4, and 8. Of assigned patients, 63% had prior exposure to a biologic agent. Clinical responders (decrease in 9-point Mayo score, including ≥2 points and ≥35% from baseline with either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 who had received mirikizumab were randomly assigned to groups that received maintenance treatment with mirikizumab 200 mg subcutaneously every 4 weeks (N = 47) or every 12 weeks (N = 46). The primary endpoint was clinical remission (Mayo subscores of 0 for rectal bleeding, with 1-point decrease from baseline for stool frequency, and 0 or 1 for endoscopy) at week 12. A multiple testing procedure was used that began with the 600-mg dose group, and any nonsignificant comparison result ended the formal statistical testing procedure. RESULTS: At week 12, 15.9% (P = .066), 22.6% (P = .004), and 11.5% (P = .142) of patients in the 50-mg, 200-mg, and 600-mg groups achieved clinical remission, respectively, compared with 4.8% of patients given placebo. The primary endpoint was not significant (comparison to 600 mg, P > .05). Clinical responses occurred in 41.3% (P = .014), 59.7% (P < .001), and 49.2% (P = .001) of patients in the 50-mg, 200-mg, and 600-mg groups, respectively, compared with 20.6% of patients given placebo. At week 52, 46.8% of patients given subcutaneous mirikizumab 200 mg every 4 weeks and 37.0% given subcutaneous mirikizumab 200 mg every 12 weeks were in clinical remission. CONCLUSIONS: In a randomized trial of patients with UC, mirikizumab was effective in inducing a clinical response after 12 weeks. Additional studies are required to determine the optimal dose for induction of remission. Mirikizumab showed durable efficacy throughout the maintenance period. Clinicaltrials.gov, Number NCT02589665.