Abstract
Aims
We evaluated long-term safety and efficacy of lumacaftor (LUM)/ivacaftor (IVA) in children aged 12 to <24 months with cystic fibrosis (CF) homozygous for F508del.
Methods
This international, 96-week, phase 3, open-label study enrolled children who completed parent study 809-122 (after 2-week washout) or were LUM/IVA-naïve. The primary end-point was safety and tolerability. The secondary efficacy end-point was change from baseline in sweat chloride concentration.
Results
52 children (39 from 809-122; 13 LUM/IVA-naïve) participated. Mean±sd exposure to LUM/IVA was 597±162 days. All children had at least one adverse event, which were mostly mild (32.7%) or moderate (55.8%) in severity and consistent with common manifestations of CF or early childhood illnesses. One child (1.9%) discontinued study drug due to a treatment-emergent adverse event of increased alanine/aspartate aminotransferases that resolved after discontinuation. 12 (23.1%) children had serious adverse events, none of which was considered related to LUM/IVA. At week 96, mean absolute change from pre-treatment baseline in sweat chloride concentration was −21.0 (95% CI −27.6 to −14.3) mmol·L−1. Growth parameters, which did not change significantly, were in the normal range throughout the 96-week treatment period. Improvements from baseline were observed in mean fecal elastase-1, fecal calprotectin, and serum immunoreactive trypsinogen.
Conclusions
LUM/IVA remained generally safe and well-tolerated over 96 weeks. Improvements in sweat chloride concentration and markers of pancreatic function and intestinal inflammation were consistent with the parent study. These results demonstrate the long-term safety and efficacy of LUM/IVA in the 12 to 24-month-old population.
Shareable abstract
In a 2-year clinical study, LUM/IVA was generally safe and well-tolerated by children with CF who initiated treatment between the ages of 12 and <24 months, with sustained improvements in sweat chloride concentration and markers of pancreatic function https://bit.ly/4wfMtYl
Introduction
Cystic fibrosis (CF) results from pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that decrease quantity and/or function of CFTR protein on epithelial cell surfaces [1–4]. CF symptoms manifest early in life, with newborns and young children often presenting with exocrine pancreatic insufficiency in the neonatal period and evidence of early lung function impairment [5–8]. For this reason, newborn screening for early diagnosis [9–11] and subsequent early clinical intervention are important opportunities to alter the trajectory of disease progression.
CFTR modulators are small molecules that address the underlying cause of CF [12–14]. Ivacaftor (IVA) is a potentiator that enhances gating properties of the CFTR channel [15], while CFTR correctors such as lumacaftor (LUM), tezacaftor (TEZ), elexacaftor (ELX), and vanzacaftor (VNZ) improve processing and trafficking of CFTR proteins to the cell surface [16, 17]. Triple-combination CFTR modulator regimens, such as ELX/TEZ/IVA and VNZ/TEZ/D-IVA, have been shown to be safe and provide significant clinical benefits to children aged ≥2 years, adolescents, and adults with CF and at least one F508del allele [18–22].
For children with CF as young as 12 months homozygous for F508del (F/F genotype), the most common CFTR variant found in people with CF of Northern European ancestry [12], the dual CFTR modulator LUM/IVA has been shown to be safe and efficacious [23–25] . In a 24-week study in children aged 12 to <24 months (study 809-122), reductions in sweat chloride concentration were observed following initiation of LUM/IVA [23], suggesting improved CFTR function. Children in this study also remained in normal range for growth parameters (body mass index (BMI), weight, length, and z-scores) and some showed improving trends in biomarkers of pancreatic function and intestinal inflammation. These results suggest early initiation of LUM/IVA may alter the long-term trajectory of CF disease in young children.
To understand the longer-term safety and clinical impact of extended LUM/IVA treatment in younger children, we conducted a 96-week open-label extension study in children with the F/F genotype who initiated LUM/IVA between the ages of 12 and <24 months. At the time of this study, LUM/IVA was the only modulator available for children with CF <2 years of age without a CFTR gating variant.
Methods
Patients, trial design, and oversight
VX19-809-124 (study 809-124; NCT04235140) was a 96-week, phase 3, single-arm, open-label study enrolling children with CF and the F/F genotype who were aged 12 to <24 months at time of LUM/IVA treatment initiation. Children who previously completed parent study 809-122 or were LUM/IVA-naïve and between 12 and <24 months of age at day 1 of this study were eligible. Prior to first dose of LUM/IVA in this study, children who previously completed parent study 809-122 had a 2-week washout period to establish a pre-LUM/IVA treatment baseline (figure 1). Additional inclusion and exclusion criteria and complete dosing information are found in the supplementary material.
FIGURE 1.
Study design. LUM: lumacaftor; IVA: ivacaftor; OE: ophthalmological examinations. #: LUM/IVA-naïve participants (by age group: 18 to <24 months and 12 to <18 months) were able to enroll in study 809-124 once minimum enrolment was met for study 809-122 (n=10 children in each age group) and after an assessment of safety data from study 809-122 through week 12 for five or more children in each age group; ¶: for rollover children, the day 1 visit was the same day as the safety follow-up visit in study 809-122; +: for LUM/IVA-naïve participants, doses were determined by weight at screening; §: the safety follow-up visit was not required for participants transitioning to commercial LUM/IVA.
The trial was designed by Vertex Pharmaceuticals (Boston, MA, USA) in collaboration with the authors. Informed consent was obtained from legally authorised guardians of all participants. The clinical trial protocol and informed consent forms were approved by independent ethics committees of each region or site. Safety was monitored by an independent data safety monitoring committee. Data collection and analysis were performed by Vertex Pharmaceuticals in collaboration with the authors and the 809–124 Study Group. Authors had full access to trial data after the final database lock, critically edited the manuscript, and approved it for submission. Investigators vouch for the accuracy and completeness of the data generated at their respective sites, and the investigators and Vertex Pharmaceuticals vouch for the fidelity of the trial to the protocol.
Outcome measures
The primary and secondary objectives of this study were to evaluate the safety and pharmacodynamics of long-term LUM/IVA treatment, respectively, rather than comparative efficacy. The primary end-point was safety and tolerability as assessed by adverse events, clinical laboratory values (serum chemistry and haematology), standard 12-lead ECGs, vital signs, pulse oximetry, and ophthalmological examinations. The secondary end-point was the absolute change in sweat chloride concentration from baseline at week 96. Exploratory efficacy end-points were absolute change from baseline at week 96 in growth parameters (body mass index (BMI), BMI-for-age z-score, weight, weight-for-age z-score, length, length-for-age z-score, and weight-for-length z-score) and markers of pancreatic function and intestinal inflammation (fecal elastase-1, fecal calprotectin, and serum immunoreactive trypsinogen concentrations). Amylase and lipase were collected as part of safety profile.
Statistical analysis
No formal sample size calculations were performed. The study was designed to enrol ∼50 children to provide data for assessment of long-term safety in the target patient population. Data were analysed using descriptive statistics. Raw and change from baseline values were summarised descriptively for continuous end-points; number of children and percentages were summarised for categorical end-points. Baseline was defined as the most recent non-missing measurement (scheduled or unscheduled) collected on or before the first dose of LUM/IVA in this extension study, following the 2-week washout period for children who previously completed parent study 809-122. Baseline for sweat chloride concentration was defined as either the most recent non-missing measurement (scheduled or unscheduled) collected on or before the first dose of LUM/IVA, following a 2-week washout period, for children who rolled over from study 809-122 or the average of values at screening and the pre-treatment measurement on day 1 of this study for LUM/IVA-naïve participants. No adjustments for multiplicity were performed and there was no hypothesis testing. Data were analysed using SAS version 9.4 or higher.
Results
Population
This trial was conducted at 22 sites in the United States of America and Canada between 24 February 2020 and 21 August 2023. 52 children (39 rolled-over from study 809-122 and 13 LUM/IVA-naïve) were enrolled and received at least one dose of LUM/IVA. Mean±sd exposure to LUM/IVA was 597±162 days. 14 (26.9%) children prematurely discontinued study drug treatment: seven transitioned to commercial drug; four declined further dosing not due to adverse event (two self-discontinued to qualify for an ELX/TEZ/IVA clinical trial, one thought study procedures were too difficult, and one no longer wished to participate in the study); two had an adverse event (one of which was not treatment-emergent); and one was lost to follow-up (figure 2). Mean±sd age at treatment initiation was 18.8±3.32 months, and mean baseline sweat chloride concentration was 101.6±8.9 mmol·L−1 (table 1). Clinical characteristics, including sweat chloride concentration, fecal elastase-1, serum immunoreactive trypsinogen, and fecal calprotectin, for children who rolled-over from study 809-122 were generally consistent with the LUM/IVA-untreated parent study baseline following the 2-week washout period.
FIGURE 2.
Participant disposition. LUM: lumacaftor; IVA: ivacaftor. #: one of the two children discontinued study drug treatment and the study due to an adverse event of granulomatous liver disease that was not treatment-emergent.
TABLE 1.
Demographics and clinical characteristics at baseline#
| Participants | 52 |
| Sex | |
| Male | 28 (53.8) |
| Female | 24 (46.2) |
| Age at treatment initiation, months | 18.8±3.32 |
| Age group at treatment initiation | |
| 12 to <18 months | 18 (34.6) |
| 18 to <24 months | 34 (65.4) |
| Ethnicity | |
| Hispanic or Latino | 1 (1.9) |
| Not Hispanic or Latino | 43 (82.7) |
| Not collected, per local regulations | 8 (15.4) |
| Race ¶ | |
| White | 42 (80.8) |
| Black or African American | 1 (1.9) |
| Asian | 1 (1.9) |
| American Indian or Alaska Native | 2 (3.8) |
| Native Hawaiian or other Pacific Islander | 1 (1.9) |
| Not collected, per local regulations | 8 (15.4) |
| Other | 1 (1.9) |
| Weight, kg | 12.2±1.6 n=47 |
| Weight-for-age, z-score | 0.27±0.91 n=47 |
| Length, cm | 85.6±3.8 n=47 |
| Length-for-age, z-score | −0.23±0.93 n=47 |
| BMI, kg·m−2 | 16.59±1.50 n=47 |
| BMI-for-age, z-score | 0.58±1.04 n=47 |
| Sweat chloride,+ mmol·L−1 | 101.6±8.9 n=35 |
Data are presented as N, n (%) or mean±sd. BMI: body mass index. #: baseline value was defined as the most recent nonmissing measurement (scheduled or unscheduled) collected on or before the first dose of lumacaftor (LUM)/ivacaftor (IVA) in study 809-124; ¶: if a participant was reported to have multiple races, then the participant was counted under each reported race; +: baseline for sweat chloride concentration was defined as either the most recent nonmissing measurement (scheduled or unscheduled) collected on or before the first dose of LUM/IVA, following a 2-week washout period, for children who rolled over from study 809-122 or the average of values at screening and the pre-treatment measurement on day 1 of this study for LUM/IVA-naïve participants.
Safety
All children had at least one adverse event, most of which were mild (32.7%) or moderate (55.8%) in severity. The most commonly reported adverse events (occurring in >20% of participants) were cough, infective pulmonary exacerbation, upper respiratory tract infection, constipation, pyrexia, rhinorrhoea, vomiting, COVID-19 and ear infection (table 2). 12 (23.1%) children had serious adverse events, none of which was considered related or possibly related to study drug by investigators. Two serious adverse events occurred in more than one child, infective pulmonary exacerbation of CF (n=6) and constipation (n=2) (supplementary table S2). One (1.9%) child had a life-threatening adverse event of near drowning, which was not considered related to study drug.
TABLE 2.
Summary of adverse events
| Participants | Events per 100 person-years# | |
|---|---|---|
| Participants | 52 | |
| Average exposure, weeks | 85.3 | |
| Total adverse events | 532 | |
| Participants with any adverse events | 52 (100.0) | 575.6 |
| Adverse events by relationship | ||
| Not related | 22 (42.3) | 283.5 |
| Unlikely to be related | 15 (28.8) | 248.9 |
| Possibly related | 15 (28.8) | 43.3 |
| Related | 0 | 0 |
| Adverse events by maximum severity | ||
| Mild | 17 (32.7) | 439.3 |
| Moderate | 29 (55.8) | 125.5 |
| Severe | 5 (9.6) | 9.7 |
| Life-threatening | 1 (1.9) | 1.1 |
| Adverse events leading to treatment interruption ¶ | 6 (11.5) | 9.7 |
| Adverse events leading to treatment discontinuation | 1 (1.9) | 2.2 |
| Serious adverse events | 12 (23.1) | 28.1 |
| Related adverse events | 15 (28.8) | 43.3 |
| Related serious adverse events | 0 | 0 |
| Adverse events leading to death | 0 | 0 |
| Adverse events occurring in >10% + | ||
| Cough | 25 (48.1) | 72.5 |
| Infective pulmonary exacerbation | 18 (34.6) | 48.7 |
| Upper respiratory tract infection | 16 (30.8) | 36.8 |
| Constipation | 15 (28.8) | 23.8 |
| Pyrexia | 15 (28.8) | 26.0 |
| Rhinorrhoea | 15 (28.8) | 33.5 |
| Vomiting | 14 (26.9) | 24.9 |
| COVID-19 | 13 (25.0) | 15.1 |
| Ear infection | 12 (23.1) | 19.5 |
| Nasal congestion | 9 (17.3) | 10.8 |
| ALT increased | 8 (15.4) | 10.8 |
| Pseudomonas test positive | 7 (13.5) | 7.6 |
| AST increased | 6 (11.5) | 6.5 |
| Diarrhoea | 6 (11.5) | 7.6 |
| Rash | 6 (11.5) | 6.5 |
Data are presented as N or n (%). ALT: alanine aminotransferase; AST: aspartate aminotransferase. #: number of events per 100 person-years=number of events/(total exposure in days/(336×100)); a participant with 336 days of exposure is counted as 1 participant-year; ¶: six children interrupted study drug due to adverse events (three children due to elevated transaminases, one child due to lower respiratory tract viral infection, one child due to gastroenteritis, and one child due to atopic dermatitis); +: events were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 26.0.
Alanine and/or aspartate aminotransferase (ALT/AST) levels more than three times the upper limit of normal (ULN) occurred in nine (17.3%) children, more than five times ULN in five (9.6%) children, and more than eight times ULN in three (5.8%) children (supplementary table S3). No children had bilirubin levels more than two times the ULN. Eight (15.4%) children had an investigator-reported adverse event of elevated transaminases, none of which was categorised as serious. Overall, three (23.1%) out of the 13 children who entered the study as LUM/IVA-naïve interrupted study drug due to adverse events of increased ALT/AST; no children who rolled-over from parent study 809-122 interrupted due to increased aminotransferases. One (1.9%) child discontinued LUM/IVA due to a treatment-emergent adverse event of increased ALT/AST. On day 343 of this study, the child had adverse events of elevated ALT (6.3×ULN) and elevated AST (3.6×ULN) in the context of fever and cough. 2 days later, ALT levels were 10.3×ULN and the study drug was interrupted. Although a suspected potential alternative aetiology of adenovirus was proposed for the transaminase elevations, a decision was made to not reinitiate study drug. 29 days later, aminotransferase levels were within the normal range and the adverse event resolved. Another child, who interrupted study drug dosing on day 151 of the study due to adverse events of increased ALT/AST, discontinued LUM/IVA after the treatment period of the study (day 339) due to an adverse event of granulomatous liver disease, with some evidence of bile duct and hepatocyte injury, which was considered mild in severity and not related to the study drug.
Because some prior clinical studies found incidence of certain respiratory adverse events to be greater in LUM/IVA treatment groups versus placebo [23], respiratory events were reviewed as an adverse event of special interest. Three (5.8%) children had respiratory-related adverse events, all of which were nonserious and mild in severity and none of which led to treatment interruption or discontinuation (supplementary table S4). Mean±sd time-to-onset for respiratory-related adverse events was 332.0±175.8 days and duration was 19.0±9.9 days. There were no adverse events of cataracts and no other relevant safety findings in the clinical or laboratory assessments.
The overall exposure-adjusted rate of adverse events was numerically lower compared to the parent study 809-122 (575.6 versus 868.4 events per 100 participant years). The exposure-adjusted rates of elevated transaminases adverse events and respiratory events adverse events were also numerically lower than in the parent study 809-122 (17.3 versus 26.3 events per 100 participant years and 3.2 versus 4.4 events per 100 participant years, respectively).
Efficacy
The mean (95% CI) absolute change in sweat chloride concentration from pre-treatment baseline at week 96 was −21.0 (−27.6 to −14.3) mmol·L−1 (figure 3 and table 3), with five (15.6%) children achieving sweat chloride concentrations <60 mmol·L−1. Due to the number of children who rolled-over from the parent study who did not have baseline sweat chloride concentration measurements in this study, a sensitivity analysis was conducted using imputed baseline values from the parent study baseline for these children. In this sensitivity analysis, the mean change in sweat chloride concentration from baseline at week 96 was −26.8 mmol·L−1.
FIGURE 3.
Absolute change in sweat chloride concentration from baseline by study visit. Note that sweat chloride assessments were obtained from only lumacaftor (LUM)/ivacaftor (IVA)-naïve participants at week 4 and 12 visits.
TABLE 3.
Secondary and other efficacy end-points
| Baseline# | Participants | Mean absolute change at week 96 | Participants | |
|---|---|---|---|---|
| Secondary end-point | ||||
| Sweat chloride concentration,¶ mmol·L−1 | 101.6±8.9 | 35 | ‒21.0±14.9 (‒27.6 to ‒14.3) | 22 |
| Other end-points | ||||
| Weight, kg | 12.2±1.6 | 47 | 4.1±0.9 (3.8 to 4.4) | 32 |
| Length, cm | 85.6±3.8 | 47 | 15.6±1.9 (14.8 to 16.3) | 31 |
| BMI, kg·m−2 | 16.59±1.50 | 47 | ‒0.65±1.05 (‒1.04 to −0.27) | 31 |
| Weight-for-age z-score | 0.27±0.91 | 47 | −0.06±0.52 (‒0.25 to 0.13) | 32 |
| Length-for-age z-score | ‒0.23±0.93 | 47 | 0.14±0.54 (‒0.05 to 0.34) | 31 |
| Weight-for-length z-score | 0.52±1.02 | 47 | −0.10±0.74 (‒0.38 to 0.17) | 31 |
| BMI-for-age z-score | 0.58±1.04 | 47 | −0.19±0.79 (‒0.48 to 0.10) | 31 |
| Fecal elastase-1 concentration, µg·g−1 (normal range ≥200 µg·g−1) | 13.8±25.6 | 29 | 102.0±165.5 (22.3 to 181.8) | 19 |
| Serum IRT concentration, µg·L−1 (normal range 115‒350 µg·L−1) | 625.5±460.4 | 41 | ‒255.4±268.2 (‒380.9 to ‒129.8) | 20 |
| Fecal calprotectin concentration, µg·g−1 (normal range 0–162.9 µg·g−1) | 216.45±480.03 | 28 | ‒107.19±384.0 (‒298.15 to 83.76) | 18 |
Data are presented as mean±sd, n or (95% CI). BMI: body mass index; IRT: immunoreactive trypsinogen. #: baseline was defined as the most recent nonmissing measurement (scheduled or unscheduled) collection on or before administration of the first dose of study drug; ¶: baseline for sweat chloride concentration was defined as either the most recent nonmissing measurement (scheduled or unscheduled) collected on or before the first dose of lumacaftor (LUM)/ivacaftor (IVA), following a 2-week washout period, for children who rolled-over from study 809-122 or the average of values at screening and the pre-treatment measurement on day 1 of this study for LUM/IVA-naïve participants.
At baseline and end of this study, weight, length, BMI and associated z-scores were within the normal range. Changes from baseline at week 96 in weight-for-length, weight-for-age, and length-for-age z-scores were all close to zero with 95% confidence intervals that overlapped zero (figure 4 and table 3). All children with available measurements had fecal elastase-1 concentrations <200 µg·g−1 at baseline (mean±sd 13.8±25.6 µg·g−1; median 7.5 µg·g−1, range 7.5 to 143.0 µg·g−1; n=29). Notably, there were 22 children who rolled-over from parent study 809-122 who had fecal elastase-1 concentrations at week 24 of the parent study and also at baseline in the current study following the 2-week washout period. For these 22 children, mean±sd fecal elastase-1 concentration at the end of study 809-122 (week 24) was 59.0±88.9 µg·g−1 versus 13.7±28.9 µg·g−1 at baseline in the current study. The mean±sd absolute change in fecal elastase-1 concentration from baseline at week 96 was 102.0±165.5 µg·g−1 (95% CI 22.3 to 181.8 µg·g−1; median +30.5 µg·g−1, range 0.0 to 492.5 µg·g−1; n=19) (figure 5a and table 3 and supplementary table S5). Among the 19 children who contributed both baseline and week 96 fecal elastase measurements, four (21.1%) had fecal elastase-1 concentrations ≥200 µg·g−1 at week 96 (figure 5b). For the overall group of 31 children who provided a fecal elastase measurement at their last study visit, nine (29.0%) had a fecal elastase-1 concentrations ≥200 µg·g−1 (figure 5b), the threshold for exocrine pancreatic sufficiency. The mean±sd absolute change from baseline at week 96 in fecal calprotectin concentration was −107.19±384.0 µg·g−1 (95% CI −298.15 to 83.76 µg·g−1, median −12.5 µg·g−1, range −1626.0 to 121.0 µg·g−1; n=18) (figure 5c and table 3 and supplementary table S5) and in serum immunoreactive trypsinogen concentration was −255.4±268.2 µg·L−1 (95% CI −380.9 to −129.8 µg·L−1, median ‒151.6 µg·L−1, range −731.9 to −4.3 µg·L−1; n=20) (figure 5d and table 3 and supplementary table S5). Lipase levels, which were elevated at baseline, decreased over the 96-week treatment period (mean±sd change −53.26±113.20 U·L−1). Total amylase concentration was normal at baseline and remained stable through the 96-week treatment period (mean±sd change −1.8±28.5 U·L−1).
FIGURE 4.
Absolute changes in growth parameters from baseline by study visit. a) Mean absolute change from baseline in body mass index (BMI)-for-age z-score; b) mean absolute change from baseline in weight-for-age z-score; c) mean absolute change from baseline in length-for-age z-score; d) mean absolute change from baseline in weight-for-length z-score. Data are presented as mean (95% CI). Note that assessments of growth parameters were only obtained from lumacaftor (LUM)/ivacaftor (IVA)-naïve participants at week 4, 8 and 16 visits.
FIGURE 5.
Changes in markers of pancreatic function and intestinal inflammation by study visit. a) Mean fecal elastase-1 concentration; b) individual changes in fecal elastease-1 concentration by study visit; c) mean fecal calprotectin levels; d) mean serum immunoreactive trypsinogen (IRT) concentrations. Data are presented as mean (95% CI) (a, c and d).
Discussion
This phase 3 open-label study assessed long-term safety and efficacy of LUM/IVA in children with the F/F genotype who initiated LUM/IVA between the ages of 12 and <24 months. Over 96 weeks, LUM/IVA treatment remained generally safe and well-tolerated. Rapid and sustained decreases in mean sweat chloride concentration were observed, suggesting improved CFTR function. Growth parameters remained normal and increases in mean fecal elastase-1 concentrations from baseline suggest some children had improvements in pancreatic function and inflammation. These results suggest early LUM/IVA initiation can impact CF disease trajectory, leading to durable improvements in CFTR function with reductions in pancreatic inflammation in some children and the potential to preserve, or even restore, exocrine pancreatic function.
While all children had one or more adverse events, most were mild or moderate in severity and consistent with common manifestations of CF and/or early childhood illnesses and with those reported in parent study 809-122 [23]. The number of children who discontinued or interrupted LUM/IVA treatment due to adverse events was low and there were no serious adverse events assessed as being related to study drug. The majority of children who discontinued this study either transitioned to commercial drug or declined further dosing not due to an adverse event, including some who self-discontinued to qualify for an ELX/TEZ/IVA clinical trial. Most transaminase elevations were mild or moderate in severity and transient, although three children interrupted study drug due to transaminase adverse events. All hepatic adverse events that led to treatment interruption and discontinuation occurred in children who were previously LUM/IVA-naïve. One child discontinued the study drug due to a treatment-emergent adverse event of increased ALT/AST; however, study investigators proposed an alternative aetiology of adenovirus infection for the child's liver function test increases. A second child was diagnosed with granulomatous liver disease from a liver biopsy after interrupting study drug for an adverse event of increased ALT/AST. Investigators considered that this was likely due to underlying CF liver disease. The child eventually discontinued LUM/IVA after the end of the study period. Overall, safety results are consistent with the parent study 809-122 and studies in older children, adolescents and adults, supporting the use of LUM/IVA in the younger paediatric cohort with appropriate monitoring of liver function.
Sweat chloride concentration is an indicator of CFTR function [10, 24, 25]. While it has been shown that there is individual variation in sweat chloride concentration decreases with CFTR modulator use (reflecting improved CFTR function) and the impact of these individual decreases on specific clinical outcomes is still being investigated, in clinical studies, larger decreases in sweat chloride concentration are associated with better clinical outcomes at the population level [26]. At pre-treatment baseline, all children in this study had sweat chloride concentrations >60 mmol·L−1 (range 87.0 to 130.0 mmol·L−1), the concentration at which a clinical diagnosis of CF is likely. At week 96, mean sweat chloride concentration decreased by 21.0 mmol·L−1 from pre-treatment baseline and by 26.8 mmol·L−1 when imputed values from the parent baseline were used for those children missing measurements at start of extension study. This decrease in sweat chloride concentration, indicating sustained improvement in CFTR function, was generally consistent with the mean change from baseline reported in the parent study (−29.1 mmol·L−1) in this age group [23] and similar to studies of LUM/IVA in children aged 6 years through 11 years (−20.8 mmol·L−1 and −24.8 mmol·L−1) [27, 28]. This result demonstrates the clinical benefit of LUM/IVA treatment on CFTR function in children aged ≥12 months.
Changes in growth parameters and markers of pancreatic function and intestinal inflammation were exploratory end-points. During this 2-year study, children taking LUM/IVA maintained normal weight and length/height, suggesting normal nutritional development patterns. At baseline, all children in the study were pancreatic-insufficient (fecal elastase-1 concentrations <200 μg·g−1). Mean fecal elastase-1 concentration increased from baseline at week 96, with nine out of 31 children having fecal elastase measurements ≥200 μg·g−1 at their last study visit. Although this study was not designed or powered to study the nutritional significance of an improved fecal elastase in this cohort (e.g. change in pancreatic enzyme dose or growth parameters), this finding of improved fecal elastase-1 and stable growth during CFTR modulator treatment is consistent with prior reports. Interestingly, the increase in mean fecal elastase-1 concentration at week 96 in this study was greater than that previously reported in the 24-week parent study 809-122, suggesting the possibility of additional improvements with extended LUM/IVA treatment. Additional support for this idea comes from a two-part phase 2 study of LUM/IVA in children aged 2–5 years, in which children who received LUM/IVA in both parts (96 weeks treatment) had a mean increase from baseline in fecal elastase-1 concentration of 81.9 µg·g−1 versus a mean increase of 47.5 µg·g−1 in those children who received placebo in first part and LUM/IVA in the second part (48 weeks treatment) [29, 30]. Further supporting a mechanism of decreased pancreatic inflammation with LUM/IVA treatment, mean±sd lipase concentrations decreased by 53.26±113.20 U·L−1. These results suggest that some young children with CF may experience a pancreatic benefit from early modulator intervention. Because study sites were not instructed to specifically document changes in pancreatic enzyme dosing, we are unable to provide data on how these changes in fecal elastase-1 values were used or the clinical impact. Future studies informed by these findings will be needed to fully understand the clinical significance of these improvements and their potential impacts on the use of pancreatic enzyme replacement therapy. Finally, it is notable that data from the washout period between end of parent study 809-122 and start of the extension suggests that, as has been seen with sweat chloride concentration, this potential pancreatic benefit appears to diminish when CFTR modulator therapy is discontinued, even for 2 weeks.
Limitations of the study include the small sample size and the open-label design that lacked a comparator group, thus limiting the ability to extrapolate safety and efficacy comparisons. However, safety and efficacy results were generally consistent with the parent study 809-122 and other studies of LUM/IVA in children with CF. In addition, parts of this study overlapped with the COVID-19 pandemic, during which social isolation and hygiene procedures may have reduced rates of CF pulmonary exacerbations and hospitalisations in the general CF population [31]. The number of children who identified in racially and ethnically minoritised groups was low. This finding could be due to the F508del allele being less common in these populations and with known barriers for minoritised groups entering clinical trials, including underemphasised outreach efforts by investigative teams, lack of comfort and information on clinical trials, and time and resource constraints [32, 33]. Finally, participants came from two different pools: those who rolled-over from the parent study and those who enrolled directly into the current long-term safety study. These two groups were not completely comparable as rollover participants were by definition slightly older and not LUM/IVA-naïve, but the small total sample size precluded stratified analyses. In conclusion, exposure to LUM/IVA over 96 weeks was generally safe and well-tolerated by children who initiated treatment between ages 12 and <24 months. Improvements in sweat chloride concentrations were sustained over the 2-year treatment period, demonstrating the durable efficacy of LUM/IVA treatment in this young paediatric cohort similar to that experienced by older populations.
Acknowledgements
The authors thank the patients and their families for participating in this trial and the study investigators and coordinators for their contributions to the study. Medical writing and editorial support were provided by Nathan Blow, and graphical assistance was provided by Patrick Coughlin, under the guidance of the authors. N. Blow and P. Coughlin are employees of Vertex Pharmaceuticals (Boston, MA, USA), and may own stock or stock options in the company.
Footnotes
Provenance: Submitted article, peer reviewed.
This clinical trial is prospectively registered with ClinicalTrials.gov as NCT04235140.
Author contributions: The study sponsor (Vertex Pharmaceuticals Incorporated) designed the protocol in collaboration with the academic authors. Site investigators collected the data, which were analysed by the sponsor. All authors had full access to the study data. E.T. Zemanick, P.R. Sosnay and M. Jennings developed the initial draft of the manuscript, with writing assistance from the sponsor. All authors participated in subsequent revisions. All authors approved the final version submitted for publication.
Conflict of interest: E.T. Zemanick has served as a consultant for Vertex Pharmaceuticals, Boehringer Ingelheim and the Cystic Fibrosis Foundation. S.A. McColley has received fees from Vertex Pharmaceuticals, Inc., as an advisor and speaker. R.W. Linnemann reports grants from Vertex Pharmaceuticals and the Cystic Fibrosis Foundation; honoraria from the Cystic Fibrosis Foundation; and consulting fees and travel support from Vertex Pharmaceuticals. J.H. Rayment reports grants to his institution from Vertex Pharmaceuticals, consulting fees from Vertex Pharmaceuticals and Boehringer Ingelheim, and speakers’ fees from Vertex Pharmaceuticals. E. Tullis has received fees from Vertex Pharmaceuticals Inc. as an advisor and speaker. M.A. Mall reports grants from Vertex Pharmaceuticals Incorporated, Boehringer Ingelheim, the German Innovation Fund, German Ministry for Education and Research (BMBF) and German Research Foundation (DFG); travel support from Vertex Pharmaceuticals Incorporated and Boehringer Ingelheim; consulting fees from Abbvie, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Splisense and Vertex Pharmaceuticals Incorporated; is a Fellow of ERS (FERS); and serves on the advisory board for Abbvie, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari and Vertex Pharmaceuticals Incorporated. J.L. Taylor-Cousar has received fees from Vertex to her institution for clinical trial consulting and clinical trial conduct and research funding to her institution from the Cystic Fibrosis Foundation. P.R. Sosnay, N. Ahluwalia, L. Liu and M. Jennings are employees of Vertex Pharmaceuticals Incorporated. M. Rosenfeld reports grants to her institution from Vertex Pharmaceutical and CFF. The other authors have nothing to disclose.
Support statement: This study was funded by Vertex Pharmaceuticals Incorporated, VX19-809-124. Funding information for this article has been deposited with the Open Funder Registry.
Supplementary material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material
00214-2026.SUPPLEMENT
Data availability
Vertex is committed to advancing medical science and improving patient health. This includes the responsible sharing of clinical trial data with qualified researchers. Proposals for the use of these data will be reviewed by a scientific board. Approvals are at the discretion of Vertex and will be dependent on the nature of the request, the merit of the research proposed and the intended use of the data. Please contact CTDS@vrtx.com if you would like to submit a proposal or need more information.
References
- 1.Bell SC, Mall MA, Gutierrez H, et al. The future of cystic fibrosis care: a global perspective. Lancet Respir Med 2020; 8: 65–124. doi: 10.1016/S2213-2600(19)30337-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Elborn JS. Cystic fibrosis. Lancet 2016; 388: 2519–2531. doi: 10.1016/S0140-6736(16)00576-6 [DOI] [PubMed] [Google Scholar]
- 3.Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245: 1066–1073. doi: 10.1126/science.2475911 [DOI] [PubMed] [Google Scholar]
- 4.Anderson MP, Gregory RJ, Thompson S, et al. Demonstration that CFTR is a chloride channel by alteration of its anion selectivity. Science 1991; 253: 202–205. doi: 10.1126/science.1712984 [DOI] [PubMed] [Google Scholar]
- 5.Ranganathan SC, Hall GL, Sly PD, et al. Early lung disease in infants and preschool children with cystic fibrosis. What have we learned and what should we do about it? Am J Respir Crit Care Med 2017; 195: 1567–1575. doi: 10.1164/rccm.201606-1107CI [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.VanDevanter DR, Kahle JS, O'Sullivan AK, et al. Cystic fibrosis in young children: a review of disease manifestation, progression, and response to early treatment. J Cyst Fibros 2016; 15: 147–157. doi: 10.1016/j.jcf.2015.09.008 [DOI] [PubMed] [Google Scholar]
- 7.Walkowiak J, Sands D, Nowakowska A, et al. Early decline of pancreatic function in cystic fibrosis patients with class 1 or 2 CFTR mutations. J Pediatr Gastroenterol Nutr 2005; 40: 199–201. doi: 10.1002/j.1536-4801.2005.tb00964.x [DOI] [PubMed] [Google Scholar]
- 8.Leung DH, Heltshe SL, Borowitz D, et al. Effects of diagnosis by newborn screening for cystic fibrosis on weight and length in the first year of life. JAMA Pediatr 2017; 171: 546–554. doi: 10.1001/jamapediatrics.2017.0206 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Farrell PM, Kosorok MR, Rock MJ, et al. Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Pediatrics 2001; 107: 1–13. doi: 10.1542/peds.107.1.1 [DOI] [PubMed] [Google Scholar]
- 10.Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: consensus guidelines from the cystic fibrosis foundation. J Pediatr 2017; 181S: S4–S15. doi: 10.1016/j.jpeds.2016.09.064 [DOI] [PubMed] [Google Scholar]
- 11.Rosenfeld M, Ostrenga J, Cromwell EA, et al. Real-world associations of US cystic fibrosis newborn screening programs with nutritional and pulmonary outcomes. JAMA Pediatr 2022; 176: 990–999. doi: 10.1001/jamapediatrics.2022.2674 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Lopes-Pacheco M. CFTR modulators: the changing face of cystic fibrosis in the era of precision medicine. Front Pharmacol 2020; 10: 1662. doi: 10.3389/fphar.2019.01662 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Mall MA, Burgel PR, Castellani C, et al. Cystic fibrosis. Nat Rev Dis Primers 2024; 10: 53. doi: 10.1038/s41572-024-00538-6 [DOI] [PubMed] [Google Scholar]
- 14.Habib AR, Kajbafzadeh M, Desai S, et al. A systematic review of the clinical efficacy and safety of CFTR modulators in cystic fibrosis. Sci Rep 2019; 9: 7234. doi: 10.1038/s41598-019-43652-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Van Goor F, Hadida S, Grootenhuis PD, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA 2009; 106: 18825–18830. doi: 10.1073/pnas.0904709106 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Keating D, Marigowda G, Burr L, et al. VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 2018; 379: 1612–1620. doi: 10.1056/NEJMoa1807120 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Van Goor F, Hadida S, Grootenhuis PD, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci USA 2011; 108: 18843–18848. doi: 10.1073/pnas.1105787108 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet 2019; 394: 1940–1948. doi: 10.1016/S0140-6736(19)32597-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 2019; 381: 1809–1819. doi: 10.1056/NEJMoa1908639 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Zemanick ET, Taylor-Cousar JL, Davies J, et al. A phase 3 open-label study of elexacaftor/tezacaftor/ivacaftor in children 6 through 11 years of age with cystic fibrosis and at least one F508del allele. Am J Respir Crit Care Med 2021; 203: 1522–1532. doi: 10.1164/rccm.202102-0509OC [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Keating C, Yonker LM, Vermeulen F, et al. 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. Lancet Respir Med 2025; 13: 256–271. doi: 10.1016/S2213-2600(24)00411-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Hoppe JE, Kasi AS, Pittman JE, et al. 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. Lancet Respir Med 2025; 13: 244–255. doi: 10.1016/S2213-2600(24)00407-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Rayment JH, Asfour F, Rosenfeld M, et al. A phase 3, open-label study of lumacaftor/ivacaftor in children 1 to less than 2 years of age with cystic fibrosis homozygous for F508del-CFTR. Am J Respir Crit Care Med 2022; 206: 1239–1247. doi: 10.1164/rccm.202204-0734OC [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet 2009; 373: 1891–1904. doi: 10.1016/S0140-6736(09)60327-5 [DOI] [PubMed] [Google Scholar]
- 25.McKone EF, Velentgas P, Swenson AJ, et al. Association of sweat chloride concentration at time of diagnosis and CFTR genotype with mortality and cystic fibrosis phenotype. J Cyst Fibros 2015; 14: 580–586. doi: 10.1016/j.jcf.2015.01.005 [DOI] [PubMed] [Google Scholar]
- 26.Zemanick ET, Ramsey B, Sands D, et al. Sweat chloride reflects CFTR function and correlates with clinical outcomes following CFTR modulator treatment. J Cyst Fibros 2025; 24: 246–254. doi: 10.1016/j.jcf.2024.12.006 [DOI] [PubMed] [Google Scholar]
- 27.Milla CE, Ratjen F, Marigowda G, et al. Lumacaftor/ivacaftor in patients aged 6-11 years with cystic fibrosis and homozygous for F508del-CFTR. Am J Respir Crit Care Med 2017; 195: 912–920. doi: 10.1164/rccm.201608-1754OC [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Ratjen F, Hug C, Marigowda G, et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med 2017; 5: 557–567. doi: 10.1016/S2213-2600(17)30215-1 [DOI] [PubMed] [Google Scholar]
- 29.Stahl M, Roehmel J, Eichinger M, et al. Effects of lumacaftor/ivacaftor on cystic fibrosis disease progression in children 2 through 5 years of age homozygous for F508del-CFTR: a phase 2 placebo-controlled clinical trial. Ann Am Thorac Soc 2023; 20: 1144–1155. doi: 10.1513/AnnalsATS.202208-684OC [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Stahl M, Roehmel J, Eichinger M, et al. Long-term impact of lumacaftor/ivacaftor treatment on cystic fibrosis disease progression in children 2–5 years of age homozygous for F508del-CFTR: a phase 2, open-label clinical trial. Ann Am Thorac Soc 2024; 21: 1550–1559. doi: 10.1513/AnnalsATS.202402-201OC [DOI] [PubMed] [Google Scholar]
- 31.Servidio AG, Capata G, Levantino L, et al. COVID-19 lockdown beneficial effects on lung function in a cohort of cystic fibrosis patients. Ital J Pediatr 2021; 47: 12. doi: 10.1186/s13052-021-00970-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.McGarry ME, McColley SA. Cystic fibrosis patients of minority race and ethnicity less likely eligible for CFTR modulators based on CFTR genotype. Pediatr Pulmonol 2021; 56: 1496–1503. doi: 10.1002/ppul.25285 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Clark LT, Watkins L, Piña IL, et al. Increasing diversity in clinical trials: overcoming critical barriers. Curr Probl Cardiol 2019; 44: 148–172. doi: 10.1016/j.cpcardiol.2018.11.002 [DOI] [PubMed] [Google Scholar]
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Data Availability Statement
Vertex is committed to advancing medical science and improving patient health. This includes the responsible sharing of clinical trial data with qualified researchers. Proposals for the use of these data will be reviewed by a scientific board. Approvals are at the discretion of Vertex and will be dependent on the nature of the request, the merit of the research proposed and the intended use of the data. Please contact CTDS@vrtx.com if you would like to submit a proposal or need more information.