美国斯坦福大学Richard Lafayette团队研究了靶向释放布地奈德制剂治疗IgA肾病患者的疗效与安全性。该研究于2023年8月14日发表在《柳叶刀》杂志上。

IgA肾病是一种慢性免疫介导的肾脏疾病，也是世界范围内肾衰竭的主要原因。肠道粘膜免疫系统与其发病机制有关，Nefecon是一种新型口服靶向释放布地奈德制剂，旨在在肠道粘膜水平发挥作用。研究组介绍了Nefecon在IgA肾病患者中的2年、临床3期NefIgArd试验结果。

在这项临床3期、多中心、随机、双盲、安慰剂对照试验中，招募患有原发性IgA肾病的成年患者（年龄≥18岁），估计肾小球滤过率（eGFR）为35-90 mL/min/1.73 m²，伴有持续性蛋白尿（尿蛋白-肌酐比值≥0.8 g/g或蛋白尿≥1 g/24 h）。患者被随机分配（1:1）接受16 mg/天的Nefecon口服胶囊或匹配的安慰剂，为期9个月，然后接受为期15个月的非研究药物观察随访。

根据基线蛋白尿（<2或≥2 g/24 h）、基线eGFR（<60或≥60 mL/min/1.73 m²）和地区（亚太、欧洲、北美或南美），通过交互反应技术系统进行随机分组。在为期2年的试验中，患者、研究人员和现场工作人员都双盲接受治疗任务。在整个试验过程中，积极的支持性护理也在继续。主要疗效终点是2年内eGFR的时间加权平均值。疗效和安全性分析在完整的分析集中进行（即，所有随机分配的患者）。

患者在2018年9月5日至2021年1月20日期间被招募参加NefIgArd试验，364名患者（每个治疗组182名）被随机分配到完整的分析集中。240名（66%）患者为男性，124名（34%）患者为女性，275名（76%）患者为白人。

2年内eGFR的时间加权平均值显示，与安慰剂相比，Nefecon的治疗效果具有统计学意义（差异为5.05 mL/min/1.73 m²，p<0.0001），Nefecon组和安慰剂组的时间加权平均变化分别为–2.47 mL/min和–7.52 mL/min。Nefecon治疗期间最常见的治疗突发不良事件是外周水肿（31例[17%]患者，安慰剂组7例[4%]）、高血压（22例[12%]与6例[3%]）、肌肉痉挛（22例%12%]与7例[4]）、痤疮（20例[11%]与2例[1]）和头痛（19例[10%]与14例[8%]）。没有与治疗相关的死亡报告。

研究结果表明，与安慰剂相比，Nefecon治疗9个月后减缓了eGFR的下降，并持久降低了蛋白尿，为IgA肾病患者的疾病改善效果提供了支持。Nefecon的耐受性也很好，局部作用的口服布地奈德产品具有预期的安全性。

附：英文原文

Title: Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial

Author: Richard Lafayette, Jens Kristensen, Andrew Stone, Jürgen Floege, Vladimir Tesa, Hernán Trimarchi, Hong Zhang, Necmi Eren, Alexander Paliege, Heather N Reich, Brad H Rovin, Jonathan Barratt

Issue&Volume: 2023-08-14

Abstract:

Background

IgA nephropathy is a chronic immune-mediated kidney disease and a major cause of kidney failure worldwide. The gut mucosal immune system is implicated in its pathogenesis, and Nefecon is a novel, oral, targeted-release formulation of budesonide designed to act at the gut mucosal level. We present findings from the 2-year, phase 3 NefIgArd trial of Nefecon in patients with IgA nephropathy.

Methods

In this phase 3, multicentre, randomised, double-blind, placebo-controlled trial, adult patients (aged ≥18 years) with primary IgA nephropathy, estimated glomerular filtration rate (eGFR) 35–90 mL/min per 1·73 m2, and persistent proteinuria (urine protein–creatinine ratio ≥0·8 g/g or proteinuria ≥1 g/24 h) despite optimised renin-angiotensin system blockade were enrolled at 132 hospital-based clinical sites in 20 countries worldwide. Patients were randomly assigned (1:1) to receive 16 mg/day oral capsules of Nefecon or matching placebo for 9 months, followed by a 15-month observational follow-up period off study drug. Randomisation via an interactive response technology system was stratified according to baseline proteinuria (<2 or ≥2 g/24 h), baseline eGFR (<60 or ≥60 mL/min per 1·73 m2), and region (Asia-Pacific, Europe, North America, or South America). Patients, investigators, and site staff were masked to treatment assignment throughout the 2-year trial. Optimised supportive care was also continued throughout the trial. The primary efficacy endpoint was time-weighted average of eGFR over 2 years. Efficacy and safety analyses were done in the full analysis set (ie, all randomly assigned patients). The trial was registered on ClinicalTrials.gov, NCT03643965, and is completed.

Findings

Patients were recruited to the NefIgArd trial between Sept 5, 2018, and Jan 20, 2021, with 364 patients (182 per treatment group) randomly assigned in the full analysis set. 240 (66%) patients were men and 124 (34%) were women, and 275 (76%) identified as White. The time-weighted average of eGFR over 2 years showed a statistically significant treatment benefit with Nefecon versus placebo (difference 5·05 mL/min per 1·73 m2 [95% CI 3·24 to 7·38], p<0·0001), with a time-weighted average change of –2·47 mL/min per 1·73 m2 (95% CI –3·88 to –1·02) reported with Nefecon and –7·52 mL/min per 1·73 m2 (–8·83 to –6·18) reported with placebo. The most commonly reported treatment-emergent adverse events during treatment with Nefecon were peripheral oedema (31 [17%] patients, vs placebo, seven [4%] patients), hypertension (22 [12%] vs six [3%]), muscle spasms (22 [12%] vs seven [4%]), acne (20 [11%] vs two [1%]), and headache (19 [10%] vs 14 [8%]). No treatment-related deaths were reported.

Interpretation

A 9-month treatment period with Nefecon provided a clinically relevant reduction in eGFR decline and a durable reduction in proteinuria versus placebo, providing support for a disease-modifying effect in patients with IgA nephropathy. Nefecon was also well tolerated, with a safety profile as expected for a locally acting oral budesonide product.

DOI: 10.1016/S0140-6736(23)01554-4

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01554-4/fulltext