McKie Elizabeth A, Reid Juliet L, Mistry Prafull C, DeWall Stephen L, Abberley Lee, Ambery Philip D, Gil-Extremera Blas
Respiratory R&D, GlaxoSmithKline, Uxbridge, United Kingdom.
Immunoinflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, United Kingdom.
PLoS One. 2016 Mar 1;11(3):e0150018. doi: 10.1371/journal.pone.0150018. eCollection 2016.
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.
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.
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.
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.
ClinicalTrials.gov NCT01648153.
有证据表明，慢性亚临床炎症在2型糖尿病（T2DM）的发病机制中起重要作用。白细胞介素（IL）-18的循环水平似乎与肥胖症和T2DM的许多微血管和大血管合并症相关。本研究旨在调查抑制IL-18在T2DM治疗中是否具有任何治疗益处。评估了抗IL-18单克隆抗体GSK1070806的初步疗效、安全性和耐受性、药代动力学及药效学。
这是一项多中心、随机、单盲（申办方未设盲）、安慰剂对照、平行组IIa期试验。招募年龄在18至70岁之间、仅接受二甲双胍单药治疗但T2DM控制不佳的肥胖患者。患者接受两剂安慰剂（n = 12）、GSK1070806 0.25 mg/kg（n = 13）或GSK1070806 5 mg/kg（n = 12）。主要终点是第29、57和85天空腹血糖的基线变化以及混合餐后试验（0 - 4小时）的加权平均血糖曲线下面积（AUC）。
37名患者被随机分配至三个治疗组之一。与安慰剂相比，GSK1070806各剂量对空腹血糖水平或加权平均血糖AUC（0 - 4小时）均无统计学显著影响。
GSK1070806耐受性良好，抑制IL-18并未使血糖控制得到任何改善。然而，由于研究局限性，不能排除IL-18抑制存在较小的、可能具有临床意义的效应。
ClinicalTrials.gov NCT01648153
