Background

Previous in vitro organoid data showed A455E–CFTR, a rare CFTR mutation with 4.1% prevalence in the Netherlands, responds to lumacaftor/ivacaftor (LUM/IVA). We explored LUM/IVA's clinical efficacy in people with CF and ≥1 A455E–CFTR mutation.

Methods

Participants aged ≥12 years were randomized to 1 of 2 treatment sequences (LUM/IVA→placebo or placebo→LUM/IVA) with an 8–week washout period between. Primary endpoint was absolute change in ppFEV₁ from study baseline through 8 weeks. Additional endpoints were change in sweat chloride concentration (SwCl) and CFQ–R respiratory domain score. Correlations between organoid–based measurements and clinical endpoints were investigated.

Results

Twenty participants were randomized at 2 sites in the Netherlands. Mean absolute change in ppFEV₁ from study baseline through Week 8 showed a treatment difference of 0.1 percentage points (95% CI, –2.5 to 2.7; P = 0.928) between LUM/IVA (within–group mean change, 2.7) and placebo (within–group mean change, 2.6). The mean absolute change in SwCl concentration from study baseline through Week 8 showed a treatment difference of –7.8 mmol/L between LUM/IVA and placebo (P = 0.004), while the absolute change in CFQ–R respiratory domain score showed a treatment difference of 3.5 between LUM/IVA and placebo (P = 0.469). The in vitro organoid–based assay demonstrated a concentration–dependent swelling increase with LUM/IVA. Exploratory correlation analyses between organoid swelling and ppFEV₁ and SwCl outcomes showed correlation coefficients of 0.49 and –0.11, respectively.

Conclusions

In this exploratory study, LUM/IVA elicited an in vitro response in organoid swelling and in vivo response in SwCl in participants with CF and ≥1 A455E–CFTR mutation. The primary endpoint (ppFEV₁) did not show a statistically significant difference between LUM/IVA and placebo; correlations between in vitro and in vivo responses were not established (NCT03061331).

中文翻译：

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Lumacaftor/ivacaftor 用于具有 A455E–CFTR 突变的囊性纤维化患者

背景

先前的体外类器官数据显示A455E-CFTR 是一种罕见的CFTR突变，在荷兰的患病率为 4.1%，对 lumacaftor/ivacaftor (LUM/IVA) 有反应。我们探讨了 LUM/IVA 在 CF 和 ≥1 A455E–CFTR突变患者中的临床疗效。

方法

年龄≥12 岁的参与者被随机分配到 2 个治疗序列中的 1 个（LUM/IVA→安慰剂或安慰剂→LUM/IVA），中间有 8 周的清除期。主要终点是 ppFEV ₁从研究基线到 8 周的绝对变化。其他终点是汗液氯化物浓度 (SwCl) 和 CFQ-R 呼吸域评分的变化。研究了基于类器官的测量与临床终点之间的相关性。

结果

20 名参与者随机分布在荷兰的 2 个地点。_{从研究基线到第 8 周，ppFEV 1}的平均绝对变化显示 LUM/IVA（组内平均变化，2.7）和安慰剂之间的治疗差异为 0.1 个百分点（95% CI，–2.5 至 2.7；P  = 0.928）。组内平均变化，2.6）。从研究基线到第 8 周，SwCl 浓度的平均绝对变化显示 LUM/IVA 和安慰剂之间的治疗差异为 –7.8 mmol/L ( P  = 0.004)，而 CFQ-R 呼吸领域评分的绝对变化显示治疗差异LUM/IVA 和安慰剂之间的 3.5 ( P = 0.469）。基于体外类器官的测定表明，LUM/IVA 会导致浓度依赖性肿胀增加。类器官肿胀与 ppFEV ₁和 SwCl 结果之间的探索性相关分析显示相关系数分别为 0.49 和 –0.11。

结论

在这项探索性研究中，LUM/IVA 在 CF 和≥1个 A455E–CFTR突变的参与者中引发了类器官肿胀的体外反应和 SwCl 的体内反应。主要终点（ppFEV ₁）在 LUM/IVA 和安慰剂之间没有显示出统计学上的显着差异；未建立体外和体内反应之间的相关性（NCT03061331）。