A Study to Investigate the Efficacy and Safety of an Anti-Interleukin-18 Monoclonal Antibody in the Treatment of Type 2 Diabetes Mellitus.

OBJECTIVE: Evidence suggests that chronic subclinical inflammation plays an important role in the pathogenesis of type 2 diabetes (T2DM). Circulating levels of interleukin (IL)-18 appear to be associated with a number of micro- and macrovascular comorbidities of obesity and T2DM. This study was designed to investigate whether inhibition of IL-18 had any therapeutic benefit in the treatment of T2DM. Preliminary efficacy, safety and tolerability, pharmacokinetics, and pharmacodynamics of the anti-IL-18 monoclonal antibody, GSK1070806, were assessed. RESEARCH DESIGN AND METHODS: This was a multicentre, randomized, single-blind (sponsor-unblinded), placebo-controlled, parallel-group, phase IIa trial. Obese patients of either sex, aged 18-70 years, with poorly controlled T2DM on metformin monotherapy were recruited. Patients received two doses, of placebo (n = 12), GSK1070806 0.25 mg/kg (n = 13) or GSK1070806 5 mg/kg (n = 12). The primary end-point was the change from baseline in fasting plasma glucose and weighted mean glucose area under the curve (AUC)(0-4 hours) postmixed meal test on Days 29, 57, and 85. RESULTS: Thirty-seven patients were randomized to one of the three treatment arms. There were no statistically significant effects of GSK1070806 doses on fasting plasma glucose levels, or weighted mean glucose AUC(0-4 hours) compared with placebo. CONCLUSIONS: GSK1070806 was well tolerated, and inhibition of IL-18 did not lead to any improvements in glucose control. However, because of study limitations, smaller, potentially clinically meaningful effects of IL-18 inhibition cannot be excluded. TRIAL REGISTRATION: ClinicalTrials.gov NCT01648153.

First administration of the Fc-attenuated anti-ß amyloid antibody GSK933776 to patients with mild Alzheimer's disease: a randomized, placebo-controlled study.

OBJECTIVE: To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the Fc-inactivated anti-ß amyloid (Aß) monoclonal antibody (mAb) GSK933776 in patients with mild Alzheimer's disease (AD) or mild cognitive impairment (MCI). METHODS: This was a two-part, single blind, placebo-controlled, first-time-in-human (FTIH) study of single (n = 18) and repeat dose (n = 32) intravenous GSK933776 0.001-6 mg/kg (ClinicalTrials.gov: NCT00459550). Additional safety data from an open-label, uncontrolled, single dose study of intravenous GSK933776 1-6 mg/kg (n = 18) are included (ClinicalTrials.gov: NCT01424436). RESULTS: There were no cases of amyloid-related imaging abnormalities-edema (ARIA-E) or -hemorrhage (ARIA-H) after GSK933776 administration in both studies. Three patients across the two studies developed anti-GSK933776 antibodies. Plasma GSK933776 half-life (t1/2) was 10-15 days after repeat dosing. After each of three administrations of GSK933776, plasma levels of total Aß42 and Aß increased whereas plasma levels of free Aß decreased dose dependently; no changes were observed for placebo. For total Aß42 the peak:trough ratio was ≤2 at doses ≥3 mg/kg; for total Aß the ratio was ≤2 at 6 mg/kg. CSF concentrations of Aß showed increases from baseline to week 12 for Aß X-38 (week 12:baseline ratio: 1.65; 95%CI: 1.38, 1.93) and Aß X-42 (week 12:baseline ratio: 1.18; 95%CI: 1.06, 1.30) for values pooled across doses. CONCLUSION: In this FTIH study the Fc-inactivated anti-Aß mAb GSK933776 engaged its target in plasma and CSF without causing brain ARIA-E/H in patients with mild AD or MCI. TRIAL REGISTRATION: ClinicalTrials.gov NCT00459550.