Vanzacaftor-tezacaftor-deutivacaftor versus elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): results from two randomised, active-controlled, phase 3 trials.

Vanzacaftor-tezacaftor-deutivacaftor restored CFTR function in vitro and in phase 2 trials in participants aged 18 years and older resulting in improvements in CFTR function, as measured by sweat chloride concentrations and lung function as measured by spirometry.

Vanzacaftor-tezacaftor-deutivacaftor在体外和针对18岁及以上参与者进行的2期试验中恢复了CFTR功能，通过汗液氯化物浓度和通过肺活量计测量的肺功能的改善来衡量。

We aimed to evaluate the efficacy and safety of vanzacaftor-tezacaftor-deutivacaftor compared with standard of care elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older.

我们旨在评估vanzacaftor-tezacaftor-deutivacaftor与标准治疗elexacaftor-tezacaftor-ivacaftor在12岁及以上囊性纤维化患者中的疗效和安全性。

Methods

In two randomised, active-controlled, double-blind, phase 3 trials, individuals aged 12 years and older with stable cystic fibrosis with F508del-minimal function (SKYLINE Trial VX20-121-102) or with F508del-F508del, F508del-residual function, F508del-gating, or elexacaftor-tezacaftor-ivacaftor-responsive-non-F508del genotypes (SKYLINE Trial VX20-121-103) were enrolled at 126 and 159 international sites, respectively.

在两项随机、活性对照、双盲、3期试验中，分别在126个和159个国际地点招募了12岁及以上的稳定囊性纤维化患者，这些患者具有F508del-最小功能（SKYLINE试验VX20-121-102）或F508del-F508del、F508del残余功能、F508del-门控或elexacaftor-tezacaftor-ivacaftor反应性-非F508del基因型（SKYLINE试验VX20-121-103）。

Eligible individuals were entered into a 4-week run-in period, during which they received elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening.

符合条件的个体被纳入为期4周的启动期，在此期间，他们每天一次分别接受200毫克的elexacaftor、100毫克的tezacaftor和每12小时一次的150毫克ivacaftor，作为早晨的两片固定剂量组合片剂和晚上的一个ivacaftor片剂。

They were then randomly assigned (1:1) to either elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening, or vanzacaftor (20 mg once daily), tezacaftor (100 mg once daily), and deutivacaftor (250 mg once daily) as two fixed-dose combination tablets in the morning, for the 52-week treatment period.

然后，他们被随机分配（1:1），要么接受每天一次的elexacaftor（200毫克）、tezacaftor（100毫克）和每12小时一次的ivacaftor（150毫克），作为早晨的两片固定剂量组合片剂和晚上的一个ivacaftor片剂，要么接受每天一次的vanzacaftor（20毫克）、tezacaftor（100毫克）和每天一次的deutivacaftor（250毫克），作为早晨的两片固定剂量组合片剂，为期52周的治疗期。

All participants received matching placebo tablets to maintain the treatment blinding.

所有参与者均接受了匹配的安慰剂片剂，以保持治疗的盲法。

Randomisation was done using an interactive web-response system and stratified by age, FEV1 % predicted, sweat chloride concentration, and previous CFTR modulator use, and also by genotype for Trial VX20-121-103.

使用交互式网络响应系统进行随机分组，并根据年龄、FEV1%预测值、汗液氯化物浓度以及既往CFTR调节剂使用情况进行分层，对于VX20-121-103试验，还根据基因型进行分层。

The primary endpoint for both trials was absolute change in FEV1 % predicted from baseline (most recent value before treatment on day 1) through week 24 (with non-inferiority of vanzacaftor-tezacaftor-deutivacaftor shown if the lower bound of the 95% CI for the primary endpoint was -3·0 or higher).

两项试验的主要终点是基线（治疗前第1天的最近一次值）至第24周时FEV1%预测值的绝对变化（如果主要终点的95%置信区间下限为-3.0或更高，则显示vanzacaftor-tezacaftor-deutivacaftor的非劣效性）。

Efficacy was assessed in all participants with the intended CFTR genotype who were randomly assigned to treatment and received at least one dose of study treatment during the treatment period.

在治疗期间，所有被随机分配治疗并至少接受一次研究治疗剂量的预期CFTR基因型的参与者中评估了疗效。

Safety was assessed in all participants who received at least one dose of study drug during the treatment period.

在治疗期间，所有至少接受过一次研究药物剂量的参与者均进行了安全性评估。

These trials are registered with ClinicalTrials.gov, NCT05033080 (Trial VX20-121-102) and NCT05076149 (Trial VX20-121-103), and are now complete.

这些试验已在ClinicalTrials.gov上注册，注册号为NCT05033080（试验VX20-121-102）和NCT05076149（试验VX20-121-103），目前试验已经完成。

Results

In Trial VX20-121-102 between Sept 14, 2021, and Oct 18, 2022, 488 individuals were screened, of whom 435 entered the 4-week run-in period, and subsequently 398 were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=202) or vanzacaftor-tezacaftor-deutivacaftor (n=196).

在2021年9月14日至2022年10月18日进行的VX20-121-102试验中，共有488名个体接受了筛查，其中435人进入了为期4周的启动期，随后有398人被随机分配并至少接受了一剂elexacaftor-tezacaftor-ivacaftor（n=202）或vanzacaftor-tezacaftor-deutivacaftor（n=196）。

Median age was 31·0 years (IQR 22·6-38·5), 163 (41%) of 398 participants were female, 235 (59%) were male, and 388 (97%) were White.

中位年龄为31.0岁（四分位数间距22.6-38.5），398名参与者中有163名（41%）为女性，235名（59%）为男性，388名（97%）为白人。

In Trial VX20-121-103, between Oct 27, 2021, and Oct 26, 2022, 699 individuals were screened, of whom 597 entered the 4-week run-in period, and subsequently 573 participants were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=289) or vanzacaftor-tezacaftor-deutivacaftor (n=284).

在VX20-121-103试验中，从2021年10月27日至2022年10月26日，共有699名个体接受了筛查，其中597人进入了为期4周的启动期，随后有573名参与者被随机分配并至少接受了一次elexacaftor-tezacaftor-ivacaftor（n=289）或vanzacaftor-tezacaftor-deutivacaftor（n=284）的治疗。

Median age was 33·1 years (IQR 24·5-42·2), 280 (49%) of 573 participants were female, 293 (51%) were male, and 532 (93%) were White.

中位年龄为33.1岁（四分位数间距24.5-42.2），573名参与者中有280名（49%）为女性，293名（51%）为男性，532名（93%）为白人。

The absolute change in least squares mean FEV1 % predicted from baseline through week 24 for Trial VX20-121-102 was 0·5 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·3 (0·3) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference of 0·2 percentage points [95% CI -0·7 to 1·1]; p<0·0001), and for Trial VX20-121-103, was 0·2 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·0 (0·2) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference 0·2 percentage points [95% CI -0·5 to 0·9]; p<0·0001).

在VX20-121-102试验中，从基线至第24周，vanzacaftor-tezacaftor-deutivacaftor组的FEV1 %预测值的最小二乘均值的绝对变化为0.5（标准误0.3）个百分点，而elexacaftor-tezacaftor-ivacaftor组为0.3（0.3）个百分点（最小二乘均值治疗差异为0.2个百分点[95%置信区间-0.7至1.1]；p<0.0001），在VX20-121-103试验中，vanzacaftor-tezacaftor-deutivacaftor组为0.2（标准误0.3）个百分点，而elexacaftor-tezacaftor-ivacaftor组为0.0（0.2）个百分点（最小二乘均值治疗差异为0.2个百分点[95%置信区间-0.5至0.9]；p<0.0001）。

Most adverse events were mild or moderate, with the most common being infective pulmonary exacerbation (133 [28%] of 480 participants in the pooled vanzacaftor-tezacaftor-deutivacaftor group vs 158 [32%] of 491 in the pooled elexacaftor-tezacaftor-ivacaftor group), cough (108 [23%] vs 101 [21%]), COVID-19 (107 [22%] vs 127 [26%]), and nasopharyngitis (102 [21%] vs 95 [19%]).

大多数不良事件为轻度或中度，最常见的包括感染性肺部加重（在合并的vanzacaftor-tezacaftor-deutivacaftor组480名参与者中有133人[28%]，而在合并的elexacaftor-tezacaftor-ivacaftor组491名参与者中有158人[32%]），咳嗽（108人[23%]对比101人[21%]），COVID-19（107人[22%]对比127人[26%]），以及鼻咽炎（102人[21%]对比95人[19%]）。

interpretation

Vanzacaftor-tezacaftor-deutivacaftor is non-inferior to elexacaftor-tezacaftor-ivacaftor in terms of FEV1 % predicted, and is safe and well tolerated.

Vanzacaftor-tezacaftor-deutivacaftor 在FEV1%预测值方面不劣于elexacaftor-tezacaftor-ivacaftor，并且安全且耐受性良好。

Once daily dosing with vanzacaftor-tezacaftor-deutivacaftor reduces treatment burden, potentially improving adherence, compared with the twice daily regimen of the current standard of care.

每日一次的vanzacaftor-tezacaftor-deutivacaftor治疗减轻了治疗负担，与当前标准治疗的每日两次给药方案相比，可能提高了依从性。

The restoration of CFTR function and the potential variants treated are also considerations that should be compared with currently available CFTR modulators.

CFTR功能的恢复以及可能治疗的变异体也是应该与目前可用的CFTR调节剂进行比较的考虑因素。

funding

Vertex Pharmaceuticals.

Vertex制药公司。