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

项目摘要 补体3肾小球疾病(C3G)是一种孤儿疾病，包括C3肾小球肾炎 (C3GN)和与之密切相关的致密沉着病(DDD)，这是肾小球肾炎的形式。这种病 由于替代补体途径的异常调节导致了不受抑制的 补体激活。临床表现多种多样，从轻度蛋白尿到迅速的肾脏恶化。 大约一半的C3G患者在10年内发展为终末期肾脏疾病 诊断。目前还没有批准用于C3G的药物，目前的治疗建议 包括使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 (ARBS)到经验性地使用血浆交换或输液。这些治疗方法都不能解决 补体系统调节失调。因此，对小说的医学需求还远远没有得到满足 治疗C3G的药物。 阿瓦科潘是一种口服活性药物，可特异性抑制C5a受体(补体的一部分 系统)，并已被证明是安全和有效的在第一阶段和第二阶段的人体临床试验 AAV，目前正在进行AAV第三阶段试验。更重要的是，令人信服的临床， 实验室和肾脏活检的反应已观察到的C3G患者的治疗下 一种富有同情心的用法。综上所述，这些发现为人类 临床试验，以测试阿瓦科潘作为一种新的治疗C3G的安全性和有效性。这项研究将 在11个国家和地区的40个临床地点招募44名C3G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文华可潘与安慰剂的疗效 在治疗前和治疗期间服用。本研究的次要目标包括评估： 1根据不良事件的发生率，与安慰剂相比，文冠果的安全性。 临床实验室测量和生命体征的变化； 2肾脏疾病实验室参数的变化，包括估计的肾小球滤过率 单核细胞趋化蛋白-1(MCP-1)排泄率(EGFR)、蛋白尿和尿液 1)与安慰剂相比，使用牛油果； 3基于简表-36版本2(SF-36 v2)的健康相关生活质量变化 EuroQol-5D-5L(EQ-5D-5L)，与安慰剂比较； 4Avacopan在C3G患者体内的药动学研究。 此外，探索性评估研究替代标记物较基线的变化 可在血浆/血清中评估补体途径的参与和其他炎症标志物 或在治疗过程中的尿液。

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.