Background

Data obtained in human lung tissue and preclinical models suggest that oxidative stress and increased apoptosis signal-regulating kinase 1 (ASK1) activity might have a prominent role in the pathobiology of pulmonary arterial hypertension (PAH). The purpose of this study was to determine the efficacy, safety, and tolerability of the ASK1 inhibitor selonsertib compared with placebo in patients with PAH.

Methods

We did a randomised, double-blind, placebo-controlled, phase 2 trial at 46 centres located in Canada, France, Germany, Italy, the Netherlands, Spain, the UK, and the USA. Participants were aged 18–75 years and had an established diagnosis of idiopathic or hereditary PAH, or PAH associated with connective tissue disease, drugs or toxins, human immunodeficiency virus, or repaired congenital heart defects. Patients were stratified by PAH aetiology and background therapy, and randomly assigned (1:1:1:1) using an interactive voice-response or web-response system to placebo or selonsertib 2 mg, 6 mg, or 18 mg administered orally once daily. Both placebo and selonsertib were in tablet form. The primary efficacy endpoint was change in pulmonary vascular resistance, measured by right heart catheterisation, from baseline to week 24 in the full analysis set. Pair-wise comparisons between each of the selonsertib groups and the placebo group were made with a stratified Wilcoxon (van Elteren) rank sum test for participants without major protocol deviations who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02234141.

Findings

Between Dec 3, 2014, and Nov 13, 2015, 151 patients were enrolled and randomly assigned. Of 150 participants who received selonsertib or placebo, 134 (89%) completed 24 weeks of the randomly assigned treatment; all were on background PAH therapy (138 [92%] on combination therapy). 90 (60%) patients were in functional class II and 60 (40%) in functional class III. Mean baseline pulmonary vascular resistance was 772 (SD 334) dyn·s/cm⁵. Change in pulmonary vascular resistance was 6·0 dyn·s/cm⁵ (SD 28·0; n=31) for placebo, and 35·0 (35·4) dyn·s/cm⁵ (n=35; p=0·21 vs placebo) for 2 mg selonsertib, −28·0 (30·2) dyn·s/cm⁵ (n=34; p=0·27 vs placebo) for 6 mg selonsertib, and −21·0 (37·9) dyn·s/cm⁵ (n=36; p=0·60 vs placebo) for 18 mg selonsertib. The most frequent adverse events were headache (17 [15%]), abnormal dreams (eight [7%]), nausea (seven [6%]), and diarrhoea (seven [6%]) in the selonsertib groups, and headache (six [16%]), nausea (five [14%]), and diarrhoea (two [5%]) in the placebo group. Serious adverse events occurred in 23 (20%) of 113 selonsertib-treated patients and seven (19%) of 37 patients who received placebo.

Interpretation

Selonsertib once daily for 24 weeks did not lead to a significant reduction in pulmonary vascular resistance or to clinical improvement in patients with PAH, but appeared to be safe and well tolerated. Although these data do not support the clinical use of selonsertib in PAH, further study of the potential of targeting the ASK1–p38 pathway in PAH is warranted.

Funding

Gilead Sciences.

中文翻译：

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Selonsertib 用于成人肺动脉高压 (ARROW)：一项随机、双盲、安慰剂对照的 2 期试验

背景

在人肺组织和临床前模型中获得的数据表明，氧化应激和增加的细胞凋亡信号调节激酶 1 (ASK1) 活性可能在肺动脉高压 (PAH) 的病理生物学中起重要作用。本研究的目的是确定 ASK1 抑制剂 selonertib 与安慰剂相比对 PAH 患者的疗效、安全性和耐受性。

方法

我们在位于加拿大、法国、德国、意大利、荷兰、西班牙、英国和美国的 46 个中心进行了一项随机、双盲、安慰剂对照的 2 期试验。参与者年龄在 18 至 75 岁之间，已确诊为特发性或遗传性 PAH，或与结缔组织病、药物或毒素、人类免疫缺陷病毒或修复的先天性心脏缺陷相关的 PAH。根据 PAH 病因和背景治疗对患者进行分层，并使用交互式语音响应或网络响应系统随机分配 (1:1:1:1) 安慰剂或 selonertib 2 mg、6 mg 或 18 mg，每天一次口服给药. 安慰剂和 selonertib 均为片剂形式。主要疗效终点是肺血管阻力的变化，通过右心导管术测量，在完整分析集中从基线到第 24 周。每个 selonertib 组和安慰剂组之间的成对比较是通过分层 Wilcoxon (van Elteren) 秩和检验对接受至少一剂研究药物的参与者进行的，这些参与者没有出现重大协议偏差。该试验已在 ClinicalTrials.gov 注册，NCT02234141。

发现

在 2014 年 12 月 3 日至 2015 年 11 月 13 日期间，151 名患者被纳入并随机分配。在接受 selonertib 或安慰剂的 150 名参与者中，134 名 (89%) 完成了 24 周的随机分配治疗；所有患者均接受背景 PAH 治疗（138 [92%] 接受联合治疗）。90 名 (60%) 患者处于功能 II 级，60 名 (40%) 患者处于功能 III 级。平均基线肺血管阻力为 772 (SD 334) dyn·s/cm ⁵。肺血管阻力变化为 6·0 dyn·s/cm ⁵ (SD 28·0; n=31) 安慰剂组和 35·0 (35·4) dyn·s/cm ⁵ (n=35; p= 0·21 vs安慰剂) 2 mg selonertib, -28·0 (30·2) dyn·s/cm ⁵ (n=34; p=0·27 vs安慰剂) 用于 6 mg selonsertib，-21·0 (37·9) dyn·s/cm ⁵ (n=36；p=0·60 vs安慰剂) 用于 18 mg selonsertib。selonertib 组最常见的不良事件是头痛 (17 [15%])、梦境异常 (8 [7%])、恶心 (7 [6%]) 和腹泻 (7 [6%])，以及头痛安慰剂组（6 [16%]）、恶心（5 [14%]）和腹泻（2 [5%]）。113 名接受 selonertib 治疗的患者中有 23 名 (20%) 和接受安慰剂的 37 名患者中有 7 名 (19%) 发生了严重不良事件。

解释

Selonsertib 每天一次，持续 24 周并未导致肺血管阻力显着降低或 PAH 患者的临床改善，但似乎是安全且耐受性良好的。尽管这些数据不支持在 PAH 中临床使用 selonertib，但有必要进一步研究靶向 PAH 中 ASK1-p38 通路的潜力。

资金

吉利德科学。