Colon to Rectum
Lancet Gastroenterol Hepatol. 2022;7(7):648–57
AJM300 (carotegrast methyl), an oral antagonist of α4-integrin, as induction therapy for patients with moderately active ulcerative colitis: A multicenter, randomized, double-blind, placebo-controlled, phase 3 study
Background: AJM300 is an oral, small-molecule α4-integrin antagonist. The authors assessed the efficacy and safety of AJM300 in patients with moderately active ulcerative colitis.
Methods: This multicenter, randomized, double-blind, placebo-controlled, phase 3 study consisted of 2 phases: a treatment phase and an open-label retreatment phase. The study was done at 82 hospitals and clinics in Japan. Patients with a Mayo Clinic score of 6–10, endoscopic subscore ≥ 2, rectal bleeding subscore ≥ 1, and an inadequate response or intolerance to mesalazine were enrolled. Patients were randomly allocated (1:1) via a website to either AJM300 (960 mg) or placebo by the minimization method, which was adjusted centrally by dynamic assignment against the Mayo Clinic score (≥ 6 to ≤ 7, ≥ 8 to ≤ 10 points), any use of corticosteroids, anti-tumor necrosis factor-alpha antibody, or immunosuppressants during the disease-active period (yes vs. no), duration of induction therapy until randomization (< 4 weeks vs. ≥ 4 weeks) as the minimization factors. Patients, investigators, site staff, assessors, and the sponsor were masked to treatment assignments. The study drug was administered orally, 3 times daily, for 8 weeks, and continued for up to 24 weeks if endoscopic remission was not achieved or rectal bleeding did not stop. The primary end point was the proportion of patients with a clinical response at week 8, and was analyzed in the full analysis set. Clinical response was defined as a reduction in Mayo Clinic score ≥ 30% and ≥ 3, a reduction in rectal bleeding score ≥ 1 or rectal bleeding subscore ≤ 1, and an endoscopic subscore ≤ 1 at week 8.
Findings: Between June 6, 2018, and July 22, 2020, 203 patients were randomly assigned to AJM300 (n = 102) or placebo (n = 101). At week 8, 46 patients (45%) in the AJM300 group and 21 patients (21%) in the placebo group had a clinical response (odds ratio = 3.30, 95% confidence interval: 1.73–6.29; p = 0.00028). During the 8-week treatment and 16-week extension treatment periods, adverse events (AEs) occurred in 39 of 101 patients (39%) in the placebo group and 39 of 102 patients (38%) in the AJM300 group. No difference in the incidence of AEs between groups or after repeated administration of AJM300 was found. The most common AE was nasopharyngitis (11/101 patients [11%] in the placebo group and 10/102 patients [10%] in the AJM300 group). The most common treatment-related AE was also nasopharyngitis (4/101 patients [4%] in the placebo group and 3/102 patients [3%] in the AJM300 group). Most AEs were mild-to-moderate in severity. No deaths were reported. A serious AE was reported in the AJM300 group (1 patient with anal abscess), but this was judged to be unrelated to study drug.
Interpretation: AJM300 was well tolerated and induced a clinical response in patients with moderately active ulcerative colitis who had an inadequate response or intolerance to mesalazine. AJM300 could be a novel induction therapy for the treatment of patients with moderately active ulcerative colitis.