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首页> 外文期刊>Journal of Clinical Medicine >Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade
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Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade

机译：地平线2020在糖尿病肾病中的应用：基于肾素血管紧张素系统封锁的附加疗法的临床试验管道

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Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways. Among agents currently undergoing trials that may modify the clinical practice on top of RAS blockade in a 5-year horizon, anti-inflammatory agents currently hold the most promise while anti-fibrotic agents have so far disappointed. Pentoxifylline, an anti-inflammatory agent already in clinical use, was recently reported to delay estimated glomerular filtration rate (eGFR) loss in chronic kidney disease (CKD) stage 3–4 diabetic kidney disease when associated with RAS blockade and promising phase 2 data are available for the pentoxifylline derivative CTP-499. Among agents targeting chemokines or chemokine receptors, the oral small molecule C-C chemokine receptor type 2 (CCR2) inhibitor CCX140 decreased albuminuria and eGFR loss in phase 2 trials. A dose-finding trial of the anti-IL-1β antibody gevokizumab in diabetic kidney disease will start in 2015. However, clinical development is most advanced for the endothelin receptor A blocker atrasentan, which is undergoing a phase 3 trial with a primary outcome of preserving eGFR. The potential for success of these approaches and other pipeline agents is discussed in detail.
机译：糖尿病肾病是终末期肾病的最常见原因。这暗示基于肾素-血管紧张素系统（RAS）阻断的当前治疗方法失败。最近在早期糖尿病肾病中帕立骨化醇和晚期糖尿病肾病中巴达洛酮甲基的3期临床试验分别未能达到主要终点或因安全性考虑而终止。然而，各种新颖的策略正在进行针对炎症，纤维化和信号通路的2期和3期随机对照试验。在目前正在进行的可能会在5年内改变RAS阻断作用的临床实践的药物中，抗炎药目前最有前途，而抗纤维化药物到目前为止却令人失望。己酮可可碱是一种已经在临床上使用的抗炎药，据报道，当与RAS阻滞和有希望的2期数据相关联时，其可延缓慢性肾脏病（CKD）3–4期糖尿病肾脏疾病的肾小球滤过率（eGFR）损失。可用于己酮可可碱衍生物CTP-499。在针对趋化因子或趋化因子受体的靶向药物中，口服小分子2型C-C趋化因子受体2型（CCR2）抑制剂CCX140在2期试验中降低了白蛋白尿和eGFR的损失。抗IL-1β抗体gevokizumab在糖尿病肾病中的剂量寻找试验将于2015年开始。但是，内皮素受体A阻断剂阿曲生坦的临床开发最为先进，该试验正在进行3期试验，主要结果是保留eGFR。详细讨论了这些方法和其他管道代理成功的潜力。

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