Phase 2 Study of Avacopan for Treatment of C3G, IND 132321, Orphan Designation 16-5590

项目摘要 补体3肾小球病（C3 G）是一种罕见病，包括C3肾小球肾炎 （C3 GN）和密切相关的致密存款病（DDD），肾小球肾炎的形式。这种疾病 由于旁路补体途径的异常调节， 补体激活临床表现从轻度蛋白尿到肾脏迅速恶化不等 大约一半的C3 G患者在10年内转移到终末期肾病。 诊断.目前没有批准的C3 G药物目前的治疗建议 包括用血管紧张素转换酶（ACE）/血管紧张素受体阻滞剂控制高血压 （ARB）经验性使用血浆置换或输注。这些治疗方法都不能解决 补体系统失调。因此，对于新颖的药物存在显著未满足的医学需求。 治疗C3 G的药物 Avacopan是一种口服活性药物，其特异性抑制C5 a受体（补体的一部分）， 系统），并已在1期和2期人体临床试验中显示出安全有效， AAV，目前正在3期AAV试验中进行测试。更重要的是，引人注目的临床， 实验室和肾活检反应已经在C3 G患者中观察到， 同情使用协议总而言之，这些发现为人类提供了强有力的理由 临床试验，以测试avacopan作为C3 G的新型治疗的安全性和有效性。本研究将 在11个国家的40个临床试验机构招募了44名C3 G患者。这项研究的主要目标是 根据肾活检的组织学变化评价avacopan与安慰剂相比的疗效 在治疗前和治疗期间。本研究的次要目标包括评价： 1根据不良事件的发生率，avacopan与安慰剂相比的安全性， 临床实验室测量值和生命体征的变化; 2肾脏疾病实验室参数的变化，包括估计的肾小球滤过率 速率（eGFR）、蛋白尿和单核细胞趋化蛋白-1（MCP-1）的尿排泄 1)Avacopan与安慰剂相比; 3基于简明健康调查表第2版（SF-36 v2）的健康相关生活质量变化， Avacopan与安慰剂相比的EuroQOL-5D-5L（EQ-5D-5L）; 4 Avacopan在C3 G患者中的药代动力学特征。 此外，探索性评价研究了替代治疗标志物较基线的变化， 可在血浆/血清中评估补体途径参与和其它炎症标志物 或尿液中的浓度。

Project Summary Complement 3 Glomerulopathy (C3G) is an orphan disease which includes C3 glomerulonephritis (C3GN) and the closely related dense deposit disease (DDD), forms of glomerulonephritis. This disease results from abnormal regulation of the alternative complement pathway resulting in unrestrained complement activation. The clinical presentation varies from mild proteinuria to rapid renal deterioration and about half of the individuals with C3G move the End Stage Renal Disease within in 10 years of diagnosis. There are no approved drugs for C3G currently The current treatment recommendations include control of hypertension with angiotensin-converting enzyme (ACE)/angiotensin receptor blocker (ARBs) to empirical use of plasma exchange or infusion. None of these treatments address the dysregulation of the complement system. Hence, there is a significant unmet medical need for novel drugs to treat C3G. Avacopan is an orally active drug that specific inhibitor of the C5a receptor (part of the complement system) and has been shown to be safe and efficacious in Phase 1 and Phase 2 human clinical trials in AAV, and is currently being tested in a Phase 3 AAV trial. More importantly, compelling clinical, laboratory, and kidney biopsy responses have been observed in C3G patients treated with avacopan under a compassionate use protocol. Taken together, these findings provide a strong justification for a human clinical trial to test the safety and efficacy of avacopan as a novel treatment of C3G. This study will enroll 44 patients with C3G at 40 clinical sites in 11 countries. The primary goal of the study is to evaluate the efficacy of avacopan compared to placebo based on histologic changes in kidney biopsies taken before and during treatment. Secondary goals of this study include the evaluation of: 1 The safety of avacopan compared to placebo based on the incidence of adverse events, changes in clinical laboratory measurements, and vital signs; 2 Changes in laboratory parameters of renal disease including estimated glomerular filtration rate (eGFR), proteinuria, and urinary excretion of monocyte chemoattractant protein-1 (MCP- 1) with avacopan compared to placebo; 3 Health-related quality-of-life changes based on Short Form-36 version 2 (SF-36 v2) and EuroQOL-5D-5L (EQ-5D-5L) with avacopan compared to placebo; 4 The pharmacokinetic profile of avacopan in patients with C3G. Additionally, exploratory evaluations studying changes from baseline in markers of alternative complement pathway involvement and other markers of inflammation may be assessed in plasma/serum or urine over the course of the treatment period.