BACKGROUND This is the first-in-human study of icenticaftor, an oral potentiator of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel. Restoration of CFTR activity has shown significant clinical benefits, but more studies are needed to address all CFTR mutations. METHODS Safety, pharmacodynamics/pharmacokinetics of icenticaftor were evaluated in a randomized, double-blind, placebo-controlled study in healthy volunteers. Efficacy was assessed in adult CF patients with ≥1 pre-specified CFTR Class III or IV mutation (150 and 450 mg bid), or homozygous for F508del mutation (450 mg bid). Primary efficacy endpoint was change from baseline in lung clearance index (LCI2.5). Secondary endpoints included %predicted FEV1 and sweat chloride level. RESULTS Class IV mutations were present in 22 patients, Class III in 2 (both S549N), and 25 were homozygous for F508del. Icenticaftor was well-tolerated in healthy and CF subjects with no unexpected events or discontinuations in the CF groups. The most frequent study-drug related adverse events in CF patients were nausea (12.2%), headache (10.2%), and fatigue (6.1%). Icenticaftor 450 mg bid for 14 days showed significant improvements in all endpoints versus placebo in patients with Class III and IV mutations; mean %predicted FEV1 increased by 6.46%, LCI2.5 decreased by 1.13 points and sweat chloride decreased by 8.36 mmol/L. No significant efficacy was observed in patients homozygous for a single F508del. CONCLUSIONS Icenticaftor was safe and well-tolerated in healthy volunteers and CF patients, and demonstrated clinically meaningful changes in lung function and sweat chloride level in CF patients with Class III and IV CFTR mutations. ClinicalTrials.gov: NCT02190604.

中文翻译：

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囊性纤维化跨膜电导调节剂增强剂 (QBW251) 的安全性和有效性

背景 这是对 icenticaftor 的首次人体研究，icenticaftor 是一种囊性纤维化 (CF) 跨膜电导调节器 (CFTR) 通道的口服增效剂。CFTR 活性的恢复已显示出显着的临床益处，但需要更多的研究来解决所有 CFTR 突变。方法 在健康志愿者中进行的一项随机、双盲、安慰剂对照研究中评估了 icenticaftor 的安全性、药效学/药代动力学。在具有≥1 个预先指定的 CFTR III 或 IV 类突变（150 和 450 mg bid）或 F508del 突变纯合子（450 mg bid）的成年 CF 患者中评估疗效。主要疗效终点是肺清除指数（LCI2.5）相对于基线的变化。次要终点包括 % 预测 FEV1 和汗液氯化物水平。结果 22 名患者出现 IV 类突变，2 名患者出现 III 类突变（均为 S549N），和 25 是 F508del 的纯合子。Icenticaftor 在健康和 CF 受试者中具有良好的耐受性，在 CF 组中没有意外事件或停药。CF 患者中最常见的研究药物相关不良事件是恶心 (12.2%)、头痛 (10.2%) 和疲劳 (6.1%)。与安慰剂相比，Icenticaftor 450 mg bid 14 天在 III 类和 IV 类突变患者中的所有终点均显着改善；平均 % 预测 FEV1 增加 6.46%，LCI2.5 降低 1.13 点，汗液氯化物降低 8.36 mmol/L。在单一 F508del 纯合子的患者中未观察到显着疗效。结论 Icenticaftor 在健康志愿者和 CF 患者中安全且耐受性良好，并证明了具有 III 类和 IV 类 CFTR 突变的 CF 患者的肺功能和汗液氯化物水平有临床意义的变化。ClinicalTrials.gov：NCT02190604。