Pirfenidone: Anti-Scarring Drug for Diabetic Nephropathy

描述(由申请人提供)： 现有的治疗进展性糖尿病肾病的方法包括抗高血压药物，如血管紧张素转换酶抑制剂(ACEI)和血管紧张素II受体阻滞剂(ARB)。虽然最近的研究表明这种方法在1型和2型糖尿病患者中都是有效的，但这些药物在肾功能下降的患者中阻止糖尿病肾病的效力尚不清楚。尽管进一步修改肾素-血管紧张素-醛固酮系统可能被证明是有益的，但高剂量的这些药物很难用于因高钾导致肾功能下降的患者。低血压，以及药物引起的肾血流灌注减少。进行性糖尿病肾病在很大程度上是由于进行性肾小球硬化和肾小管间质纤维化，这一认识将注意力集中在这一过程的介体和阻滞剂上。我们先前的研究已经帮助确定了糖尿病肾脏进行性基质沉积的一个关键因素是转化生长因子-β(TGF-β)。然而，转化生长因子-β系统的直接抑制剂还不能用于临床试验。我们最近发现，口服药物吡非尼酮，在糖尿病肾病小鼠模型发病后给药，非常有效地阻止进行性肾小球硬化。在1型糖尿病和肾病患者中的试验数据表明，该药物耐受性良好。此外，最近在进展局灶性硬化症患者中进行的一项开放研究的初步数据表明，吡非尼酮可能会降低肾功能减退率。然而，吡非尼酮的作用模式尚不清楚。基于动物模型和小型临床研究中令人鼓舞的数据，我们进行了一项试验，以评估吡非尼酮在1型和2型糖尿病合并肾功能不全患者中的作用。我们正在进行的随机、双盲、安慰剂研究要求延长两年，这将使我们能够评估吡非尼酮是否会降低糖尿病肾病的进展速度。此外，这项临床研究还将确定是否可以将一系列的转化生长因子-β测定作为一个生物标记物，以识别可能出现肾功能快速下降的患者，并确定吡非尼酮的治疗益处是否确实是通过抑制转化生长因子-β系统来实现的。

DESCRIPTION (provided by applicant): Existing treatment approaches for progressive diabetic nephropathy include anti-hypertensive agents such as angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs). Although recent studies demonstrate the utility of this approach in both type 1 and type 2 diabetic patients, the potency of these agents to arrest diabetic nephropathy in patients with declining renal function is not clear. Although, further modifications of the renin-Angll-aldosterone system may prove to be beneficial, high doses of these agents are difficult to use in patients with declining renal function due to hyperkalemia. low blood pressure, and drug-induced reduction of renal perfusion. The recognition that progressive diabetic nephropathy is largely due to progressive glomerulosclerosis and tubulointerstitial fibrosis has focused attention on mediators and blockers of this process. Our prior studies have helped to establish that a key factor in the mediation of progressive matrix depositrion in the diabetic kidney is transforming growth factor-beta (TGF-beta). However, direct inhibitors of the TGF-beta system are not yet available for clinical trials. We have recently identified that an orally administered drug, pirfenidone, is extremely potent to block progressive glomerulosclerosis when administered after the onset of disease in a mouse model of diabetic nephropathy. Pilot data in patients with type 1 diabetes and nephropathy indicate that this drug is well tolerated. In addition, preliminary data from a recent open-label study in patients with advanced focal sclerosis suggests that pirfenidone may lower the rate of decline of renal function. However, the mode of action of pirfenidone is unclear. Based on the encouraging data in animal models and small clinical studies, we have undertaken a trial to evaluate the role of pirfenidone in patients with type 1 and type 2 diabetes and renal insufficiency. The requested two year renewal of our ongoing randomized, double-blind, placebo study will allow us to assess whether pirfenidone will lower the rate of progression of diabetic nephropathy. In addition, the clinical study will determine whether serial measures of TGF-beta may be used as a biomarker to identify patients who may have a rapid decline in renal function and to determine if the therapeutic benefit of pirfenidone is indeed via inhibition of the TGF-beta system.