Elexacaftor/tezacaftor/ivacaftor for cystic fibrosis and rare CFTR variants: in vitro translation to a phase 3, double-blind, randomized, placebo-controlled trial, and real-world study.

In multiple clinical and real-world studies, elexacaftor/tezacaftor/ivacaftor was shown to be safe and highly effective in people with CF carrying at least one F508del-CFTR (∼80% of people with CF).

在多项临床和现实世界研究中，elexacaftor/tezacaftor/ivacaftor在携带至少一个F508del-CFTR的囊性纤维化患者中显示出安全性和高效性（约占囊性纤维化患者的80%）。

Background

To characterize the response of rare, non-F508del CFTR variants to elexacaftor/tezacaftor/ivacaftor in vitro, and in clinical and real-world studies.

为了表征罕见的非F508del CFTR变异体对elexacaftor/tezacaftor/ivacaftor的反应，在体外以及临床和真实世界研究中。

Methods

We engineered Fischer rat thyroid (FRT) cells each of which express 1 of 620 rare exonic CFTR variants present in public databases and evaluated their in vitro response to elexacaftor/tezacaftor/ivacaftor.

我们设计了Fischer大鼠甲状腺(FRT)细胞，每个细胞表达公共数据库中存在的620种罕见外显子CFTR变异体中的1种，并评估了它们对elexacaftor/tezacaftor/ivacaftor的体外反应。

We evaluated efficacy and safety of elexacaftor/tezacaftor/ivacaftor in a 24-week randomized, placebo-controlled, Phase 3 trial (445-124) in participants with 1 of 18 rare variants and no F508del and in a real-world study (CFD-016) in people carrying 82 rare variants and no F508del.

我们在一项为期24周的随机、安慰剂对照、III期试验（445-124）中评估了elexacaftor/tezacaftor/ivacaftor的疗效和安全性，该试验针对携带18种罕见变异且无F508del的参与者，以及在一项真实世界研究（CFD-016）中针对携带82种罕见变异且无F508del的人群。

measurements_and_main_results

In FRT cells, 518 of 620 (84%) rare variants responded to elexacaftor/tezacaftor/ivacaftor.

在FRT细胞中，620个罕见变异中有518个（84%）对elexacaftor/tezacaftor/ivacaftor有反应。

In 445-124, mean improvements were seen in the primary endpoint of percent predicted FEV1 (9.2 percentage points [95% CI: 7.2, 11.3; P < .0001]), and secondary endpoints of sweat chloride (-28.3 mmol/L [95% CI: -32.1, -24.5 mmol/L; P < .0001]) and CFQ-R RD (19.5 points [95% CI: 15.5, 23.5; P < .0001]).

在445-124研究中，主要终点指标预测的FEV1百分比平均提高了9.2个百分点[95%置信区间：7.2, 11.3; P < .0001]，次要终点指标汗液氯化物降低了28.3毫摩尔/升[95%置信区间：-32.1, -24.5毫摩尔/升; P < .0001]，以及CFQ-R RD提高了19.5分[95%置信区间：15.5, 23.5; P < .0001]。

In CFD-016, improvements in lung function were seen after treatment initiation.

在CFD-016研究中，治疗开始后观察到肺功能的改善。

Conclusions

In vitro, clinical, and real-world data support elexacaftor/tezacaftor/ivacaftor treatment in people carrying a range of CFTR variants and no F508del.

体外、临床和真实世界数据支持携带多种CFTR变异且无F508del的人群接受elexacaftor/tezacaftor/ivacaftor治疗。

The response of 84% of rare CFTR variants that produce protein to protein-stabilizing therapy suggests variants in many regions of the protein causes disease via protein destabilization.

84%的罕见CFTR变异产生蛋白质对蛋白质稳定疗法的反应表明，蛋白质不稳定可能是许多区域的变异导致疾病的途径。