Background

Riociguat is a first-in-class soluble guanylate cyclase stimulator for which preclinical data suggested improvements in cystic fibrosis transmembrane conductance regulator (CFTR) function.

Methods

This international, multicenter, two-part, Phase II study of riociguat enrolled adults with cystic fibrosis (CF) homozygous for Phe508del CFTR. Part 1 was a 28-day, randomized, double-blind, placebo-controlled study in participants not receiving CFTR modulator therapy. Twenty-one participants were randomized 1:2 to placebo or oral riociguat (0.5 mg three times daily [tid] for 14 days, increased to 1.0 mg tid for the subsequent 14 days). The primary and secondary efficacy endpoints were change in sweat chloride concentration and percent predicted forced expiratory volume in 1 second (ppFEV₁), respectively, from baseline to Day 14 and Day 28 with riociguat compared with placebo.

Results

Riociguat did not alter CFTR activity (change in sweat chloride) or lung function (change in ppFEV₁) at doses up to 1.0 mg tid after 28 days. The most common drug-related adverse event (AE) was headache occurring in three participants (21%); serious AEs occurred in one participant receiving riociguat (7%) and one participant receiving placebo (14%). This safety profile was consistent with the underlying disease and the known safety of riociguat for its approved indications.

Conclusions

The Rio-CF study was terminated due to lack of efficacy and the changing landscape of CF therapeutic development. The current study⁠, within its limits of a small sample size, did not provide evidence that riociguat could be a valid treatment option for CF.

Clinical trial registration number: NCT02170025.

中文翻译：

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Riociguat 用于治疗 Phe508del 纯合成人囊性纤维化

背景

Riociguat 是一流的可溶性鸟苷酸环化酶刺激剂，其临床前数据表明囊性纤维化跨膜电导调节剂 (CFTR) 功能有所改善。

方法

这项国际、多中心、两部分、II 期研究 riociguat 招募了患有 Phe508del CFTR纯合子囊性纤维化 (CF) 的成年人。第 1 部分是一项为期 28 天、随机、双盲、安慰剂对照的研究，受试者为未接受 CFTR 调节剂治疗的参与者。21 名参与者以 1:2 的比例随机分配至安慰剂组或口服 riociguat（0.5 毫克，每天 3 次 [tid] 持续 14 天，随后 14 天增加到 1.0 mg tid）。主要和次要疗效终点分别是从基线到第 14 天和第 28 天，与安慰剂相比，从基线到第 14 天和第 28 天，汗液氯化物浓度和预测的 1 秒用力呼气量百分比 (ppFEV _{1 ) 的变化。}

结果

Riociguat在剂量高达 1.0 mg tid 28 天后没有改变 CFTR 活性（汗液氯化物的变化）或肺功能（ppFEV _{1的变化）。}最常见的药物相关不良事件 (AE) 是三名参与者 (21%) 发生的头痛；一名接受 riociguat 的参与者 (7%) 和一名接受安慰剂的参与者 (14%) 发生了严重的 AE。该安全性概况与潜在疾病和 riociguat 对其批准适应症的已知安全性一致。

结论

Rio-CF 研究因缺乏疗效和 CF 治疗发展的变化而终止。目前的研究在其小样本量的范围内，没有提供证据表明 riociguat 可能是 CF 的有效治疗选择。

临床试验注册号：NCT02170025。