Esophagus to Small Intestine
Lancet. 2024;404(10470):2423-2436
Efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn’s disease: A phase 3, multicentre, randomised, double-blind, placebo-controlled and active-controlled, treat-through study
Background: Mirikizumab, a humanised monoclonal antibody that inhibits interleukin-23p19, is effective in moderate-to-severe ulcerative colitis. The aim of this study was to evaluate the efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn’s disease. Methods: VIVID-1 was a global phase 3, randomised, double-blind, double-dummy, placebo-controlled and active-controlled, treat-through study. The study enrolled adult patients at 324 sites (hospitals or medical centres, clinical practices, and clinical research sites) in 33 countries across Europe, Asia, North America, Central America, South America, and Australia. Adult patients with moderately-to-severely active Crohn’s disease and previous inadequate response, loss of response, or intolerance to 1 or more approved biological therapies or conventional therapies were randomly assigned 6:3:2 to receive mirikizumab 900 mg intravenously at weeks 0, 4, and 8, then 300 mg subcutaneously every 4 weeks from weeks 12 to 52; ustekinumab about 6 mg/kg intravenously at week 0, then 90 mg subcutaneously every 8 weeks from weeks 8 to 52; or placebo. The coprimary endpoints assessing superiority of mirikizumab over placebo were composite endpoints: patient-reported outcome (PRO) clinical response at week 12 and endoscopic response at week 52 (endoscopic response-composite), and PRO clinical response at week 12 and Crohn’s Disease Activity Index (CDAI) clinical remission at week 52 (CDAI clinical remission-composite). The adjusted risk differences were calculated, and the comparison was performed by the Cochran-Mantel-Haenszel test. Non-responder imputation was used. Findings: Between July 23, 2019, and August 23, 2023, 1150 patients were randomly assigned and received study treatment (safety population); 1065 patients were included in the efficacy population and received mirikizumab (n = 579), ustekinumab (n = 287), or placebo (n = 199). Both coprimary endpoints were met: endoscopic response-composite was reached in 220 of 579 patients (38.0%) on mirikizumab versus 18 of 199 patients (9.0%) on placebo (99.5% confidence interval [CI]: 20.6–36.8; p < 0.0001); CDAI clinical remission-composite was reached in 263 of 579 patients (45.4%) on mirikizumab versus 39 of 199 patients (19.6%) on placebo (99.5% CI: 15.9–35.6; p < 0.0001). The incidence rates of overall adverse events and discontinuations in patients treated with mirikizumab were lower compared with placebo. The most common adverse event across the 3 groups was COVID-19. Serious adverse events were reported in 65 of 630 patients (10.3%) on mirikizumab, 33 of 309 patients (10.7%) on ustekinumab, and 36 of 211 patients (17.1%) on placebo. There were 3 deaths during VIVID-1, 1 in the ustekinumab group, and 2 in the placebo group, including 1 in a placebo non-responder who switched to mirikizumab after week 12. None of the deaths were considered related to the study drug. The safety of mirikizumab in Crohn’s disease was consistent with its known favourable profile.
Interpretation: Mirikizumab was safe and effective as induction and maintenance treatment for patients with moderately-to-severely active Crohn's disease who had intolerance, inadequate response, or loss of response to standard therapy.