A Randomized, Placebo-Controlled Trial of MDX-1100, an Anti-IP-10 Antibody, for Moderately to Severely Active Ulcerative Colitis

Abstract

MDX-1100 (MDX) is a fully human monoclonal antibody to IP-10, a CXC chemokine ligand that mediates T-cell migration via its receptor CXCR-3, and also seems to inhibit proliferation and migration of gut epithelial cells. This phase IIa, placebo-controlled trial evaluated the safety and efficacy of MDX in patients with moderately to severely active ulcerative colitis (UC) and an inadequate response and/or intolerance to medical therapy. We included 109 adult patients with Mayo scores of 6–10 and endoscopic subscore ≥2 who were randomized to MDX 10 mg/kg or placebo every 2 weeks for 4 doses. The primary end point was clinical response at day 57, defined as reduction from baseline in Mayo score ≥3 points (≥30%), and decrease in rectal bleeding subscore ≥1 point or absolute rectal bleeding subscore ≤1 point. Clinical remission was defined as Mayo score ≤2 points and no individual subscore >1 point. The prespecified statistical analyses (SAP) defined patients as nonresponders if <3 diary entries were present during the 7 days before assessment. More conventional analyses where any diary entry within a 3-day window before assessment contributed to the Mayo score were performed post hoc. In the SAP analyses at day 57, clinical response rates were 53% vs 35% in MDX vs placebo (Fisher exact P = .083). Clinical remission and mucosal healing rates were 18% vs 17% and 42% vs 35%, in MDX vs placebo. In the post hoc conventional Mayo score analyses, clinical response, remission, and mucosal healing rates were 60% vs 37% (P = .02), 24% vs 19%, and 42% vs 35%, in MDX vs placebo. When the response results were stratified according to MDX trough serum concentrations (SSCmin), there were increasing rates of response (53%, 63%, and 88%), remission (12%, 25%, and 44%), and mucosal healing (29%, 44%, and 69%) in the low, mid, and high tertile, of SSCmin. Logistic regression showed that increase in SSCmin led to increase in clinical response, remission, and mucosal healing with odds ratios of 3.77 (P = .017), 2.85 (P = .071), and 3.08 (P = .03), respectively. The proportions of patients with adverse events were low and comparable between the 2 groups. A greater proportion of patients had infection (12.7% vs 5.8%) and serious infection (5.5% vs 1.9%) in the MDX vs placebo. MDX-1100 was effective in inducing response with modest efficacy in patients with moderate to severe UC at the test dose of 10 mg/kg. Patients with higher MDX plasma levels had greater clinical benefits. There was a slightly higher rate of infections in the MDX group compared with placebo. MDX-1100 is a novel biologic agent focused on a new target in mucosal inflammation with evidence of clinical efficacy in UC.