Randomised clinical trial: a placebo-controlled study of intravenous golimumab induction therapy for ulcerative colitis.

BACKGROUND: Tumour necrosis factor alpha (TNFα)-antagonism effectively treats ulcerative colitis (UC). The golimumab clinical programme evaluated subcutaneous (SC) and intravenous (IV) induction, and SC maintenance regimens, in TNFα-antagonist-naïve patients with moderate-to-severe active UC despite conventional treatment. AIM: To evaluate dose-response relationship, select IV golimumab induction doses for continued development, and evaluate the safety and efficacy of selected doses. METHODS: Adults with Mayo scores of 6-12 and endoscopic subscores ≥2 were enrolled into this multicentre, randomised, double-blind, placebo-controlled, integrated Phase 2/3 dose-finding/dose-confirming study. In Phase 2, 176 patients were randomised (1:1:1:1) to a single IV infusion of placebo, 1-, 2- or 4-mg/kg golimumab. While Phase 2 data were analysed to select doses for continued development, 71 additional patients were randomised. Phase 3 enrolment stopped after 44 additional patients were randomised (1:1:1) to placebo, 2- or 4-mg/kg golimumab. Due to insufficient power for the Phase 3 primary endpoint analysis (clinical response at week 6), efficacy analyses are considered exploratory and include all randomised patients. RESULTS: No dose-response was observed in Phase 2; however, higher serum golimumab exposure was associated with greater proportions of patients achieving more favourable clinical outcomes, clinical response and greater improvement in Mayo scores compared with placebo-treated patients and those with lower serum concentrations. Among all randomised patients, numerically greater proportions were in clinical response at week 6 in the 2- and 4-mg/kg golimumab groups compared with placebo [44.0% (33/75) and 41.6% (32/77) vs. 30.1% (22/73)]. CONCLUSIONS: Efficacy with single-dose golimumab IV induction was lower than expected and less than observed in the SC induction study. No new safety findings were observed. ClinicalTrials.gov Number, NCT00488774.

Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis.

OBJECTIVES: Infliximab, an IgG1 monoclonal antibody (mab), has large inter-individual serum concentration variability. The objective was to determine the extent of the association of baseline albumin concentration and infliximab disposition in patient with ulcerative colitis. METHOD: Data from 728 patients with ulcerative colitis from two clinical trials were analyzed to evaluate trends between infliximab pharmacokinetics and serum albumin, or liver or kidney function. Response in the placebo and treated groups were compared by baseline serum albumin concentrations (SAC) groups. RESULTS: Patients with higher SAC maintained higher infliximab concentrations, lower clearance, and longer half-life than patients with lower SAC. When analyzed by SAC quartiles, patients in the highest quartile had several-fold greater trough infliximab concentrations when compared with those in the lowest quartile. These observations were consistent in both studies and at different dose levels. Generally, clinical response in patients did not vary with SAC when the SAC was within the normal range, apparently because serum infliximab concentrations remained at therapeutic levels. However, patients with SAC lower than the normal laboratory reference range had much lower median serum infliximab concentrations and lower response rates compared with patients within normal SAC. Infliximab pharmacokinetics did not correlate with SGOT or creatinine clearance. CONCLUSIONS: It is hypothesized that the common rescue pathway for both albumin and IgG involving the neonatal Fc receptor may be responsible for the relationship between serum albumin and serum infliximab levels. Baseline albumin level may serve as a valuable and convenient measure of mab pharmacokinetic expectations in these patients.