Randomised clinical trial: a phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis

Abstract

Background: Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis.

Aim: To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis.

Methods: We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches.

Results: Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation.

Conclusion: This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis.

Figure 1

Study design. The study included single and multiple ascending intravenous (IV) dose groups as well as an adaptive subcutaneous (SC) dose group. Patients were randomised 5:1 (GS‐5745:placebo) in the single dose and 8:2 (GS‐5745:placebo) in the multiple‐dose groups to treatment with 0.3, 1.0, 2.5 and 5.0 mg/kg GS‐5745 or placebo. Patients in the adaptive SC dose group were randomised to treatment with 150 mg GS‐5745. Patients in the single IV dose groups had a single infusion on Day 1, whereas patients in the multiple IV dose groups had three infusions separated by 2 weeks, on Days 1, 15 and 29. Patients in the SC dose group received five weekly injections on Days 1, 8, 15, 22 and 29. Adverse events were assessed at all clinic visits and blood sampling for pharmacokinetic sampling was performed as described in the Methods section. Endoscopies and biopsies for endoscopic, histological and molecular analyses were performed on Days 1 and 36.

Figure 2

Patient disposition. Of 124 patients screened for eligibility, 74 were randomised to single or multiple doses of GS‐5745 or placebo; 24 were randomised to a single intravenous infusion (n = 20 GS‐5745, n = 4 placebo), 40 were randomised to multiple intravenous infusions (n = 32 GS‐5745, n = 8 placebo) and 10 were randomised to multiple subcutaneous injections of GS‐5745. Of the randomised patients, the following proportions completed study treatment: 24/24 (100%) in the single intravenous dose group, 37/40 (92.5%) in the multiple intravenous dose group (one patient treated with GS‐5745 and two patients treated with placebo discontinued due to an adverse event), and 9/10 (90%) in the multiple subcutaneous GS‐5745 dose group (1 patient withdrew consent). Of the patients who completed study treatment, the following proportions completed the study: 22/24 (91.7%) in the single intravenous dose group (one patient each treated with GS‐5745 discontinued the study due to an adverse event or at the discretion of the investigator), 33/37 (89.2%) in the multiple intravenous dose group (1 patient treated with GS‐5745 discontinued the study due to an adverse event, and two patients in the GS‐5745 group and one patient in the placebo group withdrew consent), and 9/9 (100%) in the multiple subcutaneous GS‐5745 dose group.

Figure 3

Dose‐dependent GS‐5745 plasma concentrations over time. GS‐5745 displayed typical nonlinear pharmacokinetic profiles with nonparalleled terminal phases across intravenous dose levels in the multiple‐dose cohorts.

Figure 4

Individual patient changes in the Mayo Clinic Score from baseline to Day 36. Overall, 28 of 42 patients (67%) treated with GS‐5745 had an improvement, 6 of 42 (14%) had a worsening, and 8 of 42 (19%) had no change (or were missing a complete Mayo Clinic score) in the complete Mayo Clinic score through Day 36. For patients treated with placebo, three of eight patients (38%) had an improvement, one of eight (13%) had a worsening and four of eight (50%) had no change (or were missing a complete Mayo Clinic score).