Vanzacaftor-tezacaftor-deutivacaftor for children aged 6-11 years with cystic fibrosis (RIDGELINE Trial VX21-121-105): an analysis from a single-arm, phase 3 trial.

Restoring normal CFTR function early in life has the potential to prevent manifestations of cystic fibrosis.

在生命早期恢复正常的CFTR功能有可能预防囊性纤维化的表现。

We aimed to evaluate the safety, tolerability, efficacy, and pharmacokinetics of vanzacaftor-tezacaftor-deutivacaftor in children with cystic fibrosis aged 6-11 years.

我们旨在评估6-11岁囊性纤维化儿童使用vanzacaftor-tezacaftor-deutivacaftor的安全性、耐受性、疗效和药代动力学。

Methods

In this multicentre, single-arm, phase 3 trial (RIDGELINE Trial VX21-121-105), participants were enrolled across 33 clinical sites that care for children with cystic fibrosis in eight countries (Australia, France, Germany, Netherlands, Sweden, Switzerland, the UK, and the USA).

在这项多中心、单臂、3期试验（RIDGELINE试验VX21-121-105）中，参与者在八个国家（澳大利亚、法国、德国、荷兰、瑞典、瑞士、英国和美国）的33个囊性纤维化儿童护理临床站点进行了招募。

Eligible participants were aged 6-11 years with at least one elexacaftor-tezacaftor-ivacaftor-responsive CFTR variant, FEV1 % predicted of 60% or higher, and stable cystic fibrosis as determined by investigators.

符合条件的参与者年龄为6-11岁，至少有一个对elexacaftor-tezacaftor-ivacaftor有反应的CFTR变异，FEV1%预计值为60%或更高，并且由研究者确定为稳定的囊性纤维化。

Before study treatment, participants were either on stable elexacaftor-tezacaftor-ivacaftor for at least 28 days before screening or received the combination for a 4-week run-in period.

在研究治疗前，参与者要么在筛选前至少28天内使用稳定的elexacaftor-tezacaftor-ivacaftor，要么接受了为期4周的组合治疗作为启动期。

Participants then received vanzacaftor-tezacaftor-deutivacaftor (<40 kg bodyweight: vanzacaftor 12 mg, tezacaftor 60 mg, and deutivacaftor 150 mg orally as three fixed-dose combination tablets once daily; ≥40 kg bodyweight: vanzacaftor 20 mg, tezacaftor 100 mg, and deutivacaftor 250 mg orally as two fixed-dose combination tablets once daily (manufactured by Patheon Pharmaceuticals, Cincinnati, OH, USA) from day 1 for 24 weeks.

参与者随后接受vanzacaftor-tezacaftor-deutivacaftor治疗（体重<40公斤：vanzacaftor 12 mg，tezacaftor 60 mg，deutivacaftor 150 mg，每天一次口服三个固定剂量组合片剂；体重≥40公斤：vanzacaftor 20 mg，tezacaftor 100 mg，deutivacaftor 250 mg，每天一次口服两个固定剂量组合片剂（由Patheon Pharmaceuticals, Cincinnati, OH, USA制造），从第1天开始，持续24周。

The primary endpoint was safety and tolerability, as measured by adverse events, vital signs, clinical laboratory values, electrocardiograms, and pulse oximetry.

主要终点是安全性与耐受性，通过不良事件、生命体征、临床实验室值、心电图和脉搏血氧测量。

Endpoints were analysed in all participants who received at least one dose of vanzacaftor-tezacaftor-deutivacaftor.

终点事件分析包括所有至少接受了一剂vanzacaftor-tezacaftor-deutivacaftor治疗的参与者。

This trial is registered with ClinicalTrials.gov, NCT05422222, and evaluation of the 6-11-year-old cohort is complete.

该试验已在ClinicalTrials.gov上注册，注册号为NCT05422222，对6-11岁年龄组的评估已经完成。

Results

Between Feb 6 and May 18, 2023, 83 children were screened, of whom five were not eligible, and 78 children aged 6-11 years received at least one dose of vanzacaftor-tezacaftor-deutivacaftor.

2023年2月6日至5月18日期间，共有83名儿童接受了筛查，其中5名不符合条件，其余78名年龄在6-11岁之间的儿童至少接受了一剂vanzacaftor-tezacaftor-deutivacaftor。

Median age was 9·3 years (IQR 7·6-10·4), 34 (44%) of 78 participants were female, 44 (56%) were male, 71 (91%) were White, one (1%) was Black or African American, and one (1%) was of multiple races.

中位年龄为9.3岁（四分位数间距7.6-10.4岁），78名参与者中有34名（44%）为女性，44名（56%）为男性，71名（91%）为白人，1名（1%）为黑人或非裔美国人，另有1名（1%）为多种族。

The analysis for these data was completed on Dec 15, 2023.

这些数据的分析已于2023年12月15日完成。

Median exposure of participants to vanzacaftor-tezacaftor-deutivacaftor was 168 days (IQR 166-170). 75 (96%) of 78 participants had adverse events, all of which were mild or moderate; the most common events were generally consistent with cystic fibrosis manifestations, including, cough (36 [46%]), pyrexia (16 [21%]), headache (14 [18%]), infective pulmonary exacerbation of cystic fibrosis (13 [17%]), and oropharyngeal pain (13 [17%]).

参与者对vanzacaftor-tezacaftor-deutivacaftor的中位暴露时间为168天（四分位数间距166-170天）。78名参与者中有75名（占96%）出现了不良事件，所有这些不良事件均为轻度或中度；最常见的事件通常与囊性纤维化表现一致，包括咳嗽（36例，占46%）、发热（16例，占21%）、头痛（14例，占18%）、囊性纤维化感染性肺部恶化（13例，占17%）和口咽痛（13例，占17%）。

Serious adverse events occurred in six (8%) participants (two had infective pulmonary exacerbation, one of whom also had failure to thrive; one participant each had adenovirus infection, constipation, pulmonary function test decreased, and cough), and one (1%) participant discontinued due to adverse events of cough and fatigue that were considered possibly related to study drug.

六名（8%）参与者出现了严重不良事件（其中两人出现感染性肺部恶化，其中一人还伴有生长迟缓；一人出现腺病毒感染，一人便秘，一人肺功能测试下降，一人咳嗽），一名（1%）参与者因考虑可能与研究药物相关的咳嗽和疲劳不良事件而停药。

interpretation

Vanzacaftor-tezacaftor-deutivacaftor was safe and well tolerated and maintained FEV1 % predicted from elexacaftor-tezacaftor-ivacaftor baseline with further improved CFTR function.

Vanzacaftor-tezacaftor-deutivacaftor 安全且耐受性良好，并且从elexacaftor-tezacaftor-ivacaftor基线期维持了FEV1%预测值，并进一步改善了CFTR功能。

Improvements in CFTR function compared with baseline elexacaftor-tezacaftor-ivacaftor values demonstrate the potential opportunity to restore normal physiology early and prevent development or progression of cystic fibrosis.

与基线时的elexacaftor-tezacaftor-ivacaftor值相比，CFTR功能的改善显示了早期恢复正常生理机能的潜在机会，并有可能预防或阻止囊性纤维化的发生或进展。

Nearly all participants had sweat chloride below the diagnostic threshold for cytstic fibrosis (<60 mmol/L) and more than half had normal levels (<30 mmol/L).

几乎所有参与者在汗液氯化物水平上都低于囊性纤维化的诊断阈值（<60 mmol/L），超过一半的人达到了正常水平（<30 mmol/L）。

Additional long-term data in children with cystic fibrosis are being collected in an open-label extension study to demonstrate clinical benefits and safety.

正在收集囊性纤维化儿童的额外长期数据，以在开放标签扩展研究中展示临床益处和安全性。

These findings will inform health-care providers and people with cystic fibrosis regarding the benefits of early initiation of CFTR modulators.

这些发现将为医疗保健提供者和囊性纤维化患者提供关于早期开始CFTR调节剂治疗的益处的信息。

funding

Vertex Pharmaceuticals.

Vertex制药公司。