Background

Voclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis, improved complete renal response rates in patients with lupus nephritis in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of lupus nephritis.

Methods

This multicentre, double-blind, randomised phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus with lupus nephritis according to the American College of Rheumatology criteria, and a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible. Patients were randomly assigned (1:1) to oral voclosporin (23·7 mg twice daily) or placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low-dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks defined as a composite of urine protein creatinine ratio of 0·5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] ≥60 mL/min/1·73 m² or no confirmed decrease from baseline in eGFR of >20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or for 7 or more days during weeks 44 through 52, just before the primary endpoint assessment. Safety was also assessed. Efficacy analysis was by intention-to-treat and safety analysis by randomised patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03021499.

Findings

Between April 13, 2017, and Oct 10, 2019, 179 patients were assigned to the voclosporin group and 178 to the placebo group. The primary endpoint of complete renal response at week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio 2·65; 95% CI 1·64–4·27; p<0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in 7 (4%) patients in the voclosporin group and in 8 (4%) patients in the placebo group. A total of six patients died during the study or study follow-up period (one [<1%] patient in the voclosporin group and five [3%] patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments.

Interpretation

Voclosporin in combination with MMF and low-dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low-dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active lupus nephritis.

Funding

Aurinia Pharmaceuticals.

中文翻译：

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voclosporin 与安慰剂治疗狼疮性肾炎的疗效和安全性（AURORA 1）：一项双盲、随机、多中心、安慰剂对照的 3 期试验

背景

Voclosporin 是一种被批准用于治疗成人狼疮性肾炎的新型钙调神经磷酸酶抑制剂，在一项 2 期试验中提高了狼疮性肾炎患者的完全肾脏反应率。本研究旨在评估沃罗孢素治疗狼疮性肾炎的疗效和安全性。

方法

这项多中心、双盲、随机 3 期试验在 27 个国家的 142 家医院和诊所进行。根据美国风湿病学会标准诊断为系统性红斑狼疮伴狼疮性肾炎的患者，以及 2 年内肾活检显示 III、IV 或 V 级（单独或与 III 或 IV 级联合）的患者是合格的。患者被随机分配 (1:1) 口服 voclosporin (23·7 mg，每日两次) 或安慰剂组，背景为霉酚酸酯 (1 g，每日两次) 和快速减量的低剂量口服类固醇，通过使用交互式网络响应系统。主要终点是 52 周时的完全肾脏反应，定义为尿蛋白肌酐比为 0·5 mg/mg 或更低、肾功能稳定（定义为估计肾小球滤过率 [eGFR] ≥60 mL/min/1· 73 米²或未确认 eGFR 从基线下降 > 20%），不给予急救药物，并且在第 44 至 52 周期间连续 3 天或更多天或 7 天或更多天每天不超过 10 mg 泼尼松当量，只是在主要终点评估之前。还评估了安全性。疗效分析是通过接受至少一剂研究治疗的随机患者进行的意向治疗和安全性分析。该试验已在 ClinicalTrials.gov 注册，NCT03021499。

发现

在 2017 年 4 月 13 日至 2019 年 10 月 10 日期间，179 名患者被分配到 voclosporin 组，178 名患者被分配到安慰剂组。与安慰剂组相比，沃罗孢素组在第 52 周达到完全肾脏反应的主要终点显着多于安慰剂组（179 名患者中的 73 [41%] vs178 名患者中的 40 名 [23%]；优势比2·65；95% CI 1·64–4·27；p<0·0001)。两组之间的不良事件概况是平衡的；沃罗孢素组 178 名患者中的 37 名（21%）和安慰剂组 178 名患者中的 38 名（21%）发生了严重不良事件。最常见的涉及感染的严重不良事件是肺炎，发生在 voclosporin 组的 7 名 (4%) 患者和安慰剂组的 8 名 (4%) 患者中。在研究或研究随访期间共有六名患者死亡（沃罗孢素组一名 [<​​1%] 患者和安慰剂组五名 [3%] 患者）。研究人员认为没有任何导致死亡的事件与研究治疗有关。

解释

与单独使用 MMF 和低剂量类固醇相比，Voclosporin 与 MMF 和低剂量类固醇联合使用导致临床和统计学上更优的​​完全肾脏反应率，并且具有相当的安全性。这一发现是治疗活动性狼疮肾炎患者的重要进展。

资金

奥瑞尼亚制药。