Abstract
Rationale
Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and effective in people with cystic fibrosis (CF) aged ⩾6 years with at least one F508del-CFTR allele but has not been studied in younger children.
Objectives
To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of ELX/TEZ/IVA in children with CF aged 2–5 years.
Methods
In this phase 3, open-label, two-part study (parts A and B), children weighing <14 kg (on Day 1) received ELX 80 mg once daily (qd), TEZ 40 mg qd, and IVA 60 mg each morning and 59.5 mg each evening; children weighing ⩾14 kg received ELX 100 mg qd, TEZ 50 mg qd, and IVA 75 mg every 12 hours.
Measurements and Main Results
The primary endpoints for part A (15-d treatment period) were pharmacokinetics and safety and tolerability. For part B (24-wk treatment period), the primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics and absolute changes from baseline in sweat chloride concentration and lung clearance index2.5 (LCI2.5, defined as the number of lung turnovers required to reduce the end tidal N2 concentration to 2.5% of its starting value) through Week 24. Analysis of pharmacokinetic data from 18 children enrolled in part A confirmed the appropriateness of the part B dosing regimen. In part B, 75 children (F508del/minimal function genotypes, n = 52; F508del/F508del genotype, n = 23) were enrolled and dosed. Seventy-four children (98.7%) had adverse events, which were all mild (62.7%) or moderate (36.0%) in severity. The most common adverse events were cough, fever, and rhinorrhea. Decreases in sweat chloride concentration (−57.9 mmol/L; 95% confidence interval [CI], −61.3 to −54.6; n = 69) and LCI2.5 (−0.83 U; 95% CI, −1.01 to −0.66; n = 50) were observed from baseline through Week 24. Mean body mass index was within the normal range at baseline and remained stable at Week 24.
Conclusions
In this open-label study in children 2–5 years of age, ELX/TEZ/IVA treatment was generally safe and well tolerated, with a safety profile consistent with that observed in older age groups, and led to clinically meaningful reductions in sweat chloride concentration and LCI2.5.
Clinical trial registered with www.clinicaltrials.gov (NCT04537793).
Keywords: preschool children, CF, ELX, TEZ, IVA
At a Glance Commentary
Scientific Knowledge on the Subject
Previous studies have shown that the triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is safe and efficacious in people with cystic fibrosis (CF) who are 6 years of age or older and have at least one F508del allele. Clinical manifestations of CF can appear in infancy, making early treatment intervention critical to changing the trajectory of CF disease progression.
What This Study Adds to the Field
This two-part, open-label study was designed to assess the safety, pharmacokinetics, pharmacodynamics, and efficacy of ELX/TEZ/IVA treatment in children 2–5 years of age with at least one F508del allele. ELX/TEZ/IVA was generally safe and well tolerated, with a safety profile consistent with that previously reported in older children, adolescents, and adults. ELX/TEZ/IVA treatment led to clinically meaningful improvements in CFTR function and lung function and was associated with stable nutritional status over a 24-week treatment period. These results support the use of ELX/TEZ/IVA in children with CF who are as young as 2 years of age.
Cystic fibrosis (CF) is an autosomal-recessive disorder caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR) gene that leads to decreased quantity and function of CFTR protein at epithelial surfaces (1). The clinical manifestations of CF appear early in life and include pancreatic insufficiency and lung disease caused by mucus accumulation in the airways (2). More than 85% of infants with CF have pancreatic insufficiency at birth as a result of in utero pancreatic damage, and most develop small-airway dysfunction within the first 6 months of life (3–5). Early intervention with CFTR modulator therapies offers the potential to significantly improve the trajectory of CF lung disease (6).
CFTR modulators are small-molecule therapies that target the underlying cause of CF (7, 8). The first modulator approved for the treatment of people with CF was the potentiator ivacaftor (IVA) (9), which enhances the gating activity of the CFTR protein. IVA has been shown to be safe and effective in people with CF as young as 4 months of age with CFTR gating mutations (10, 11). Correctors such as tezacaftor (TEZ) and elexacaftor (ELX) enhance the processing and trafficking of CFTR proteins to the cell surface (12, 13). A triple combination of the correctors ELX and TEZ and the potentiator IVA (ELX/TEZ/IVA) was shown to markedly improve lung function, CFTR function, and respiratory symptoms in adults and children aged ⩾6 years and homozygous for F508del (F/F genotype) or heterozygous for F508del and a minimal function mutation (F/MF genotypes) (14–18). These results established that ELX/TEZ/IVA treatment is beneficial to people with CF who have at least one F508del allele.
In clinical trials in children aged 6–11 years with F/F or F/MF genotypes, ELX/TEZ/IVA treatment led to clinically meaningful improvements in lung function as measured by lung clearance index2.5 (LCI2.5, defined as the number of lung turnovers required to reduce the end tidal N2 concentration to 2.5% of its starting value) and percent predicted FEV1, respiratory symptoms as measured by the Cystic Fibrosis Questionnaire–Revised respiratory domain score, CFTR function as measured by sweat chloride concentration, and improved growth parameters over a 24-week treatment period (14, 18). These results, which were similar to those seen in the pivotal trials of ELX/TEZ/IVA in people with CF aged ⩾12 years (15, 16), demonstrated that ELX/TEZ/IVA treatment has the ability to improve early airway disease in younger patients. Because early diagnosis of CF is possible through prenatal testing and newborn screening, and many clinical manifestations of CF are present in infancy, it is important to assess the potential of treating children with CF with ELX/TEZ/IVA early in life to potentially slow or avoid irreversible organ damage.
Here, we report results from a phase 3, open-label study designed to assess the safety, pharmacokinetics, pharmacodynamics, and efficacy of ELX/TEZ/IVA in children with CF aged 2–5 years, the youngest population of patients to be treated with ELX/TEZ/IVA to date. Some of the results of this study have previously been reported in the form of an abstract (19).
Methods
Patients, Trial Design, and Oversight
Study VX20-445-111 (ClinicalTrials.gov ID NCT04537793) was a phase 3, open-label, two-part (part A and part B), multicenter, international study of ELX/TEZ/IVA that enrolled children 2–5 years of age with CF. Part A enrolled children with F/MF or F/F genotypes; part B enrolled children who had at least one F508del mutation or an ELX/TEZ/IVA-responsive CFTR mutation. A list of qualifying minimal function mutations (Table E1 in the online supplement) and other eligibility criteria are provided in the online supplement.
Part A of the study assessed pharmacokinetics, safety, and tolerability over a 15-day treatment period to confirm the ELX/TEZ/IVA dose to be used in part B. The ELX/TEZ/IVA dose evaluated in part A (ELX 100 mg once daily [qd], TEZ 50 mg qd, and IVA 75 mg every 12 h) in children weighing ⩾14 kg was the same dose studied in lower-weight children aged 6 to <12 years and was based on population pharmacokinetic modeling. Part B of the study assessed safety, pharmacokinetics, pharmacodynamics, and efficacy over a 24-week treatment period (Figure E1). In part B, children weighing <14 kg (on Day 1) received ELX 80 mg qd, TEZ 40 mg qd, and IVA 60 mg in the morning and 59.5 mg in the evening, whereas children weighing ⩾14 kg (on Day 1) received ELX 100 mg qd, TEZ 50 mg qd, and IVA 75 mg every 12 hours (half the adult dose).
The trial was designed by Vertex Pharmaceuticals in collaboration with the authors. For each enrolled child, informed consent was provided by a parent or legal guardian in accordance with local requirements. The clinical trial protocol and informed consent forms were approved by independent ethics committees at each region or site as required by local regulations. 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 VX20-445-111 Study Group. Authors had full access to the trial data after the final database lock, critically edited the manuscript, and approved it for submission. The 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. Confidentiality agreements were in place between the sponsor and each investigative site during the trial.
Because parts of this trial were conducted during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, a global protocol addendum was implemented so participants could continue in the study while minimizing the risk of exposure through travel. Implemented measures included shipment of study drug to the participant’s home, remote monitoring/source verification, and remote consent. These measures were enabled based on country and local regulations and site-level considerations.
Outcome Measures
The primary endpoints of part A were pharmacokinetic parameters of ELX, TEZ, IVA, and their respective metabolites (M23-ELX, M1-TEZ, and M1-IVA) and safety and tolerability. The primary endpoint of part B was safety and tolerability as assessed by adverse events (AEs), clinical laboratory values, electrocardiograms, vital signs, pulse oximetry, and physical examinations. Ophthalmologic examinations were conducted at the screening visit and Week 24. Secondary endpoints were pharmacokinetic parameters and absolute change from baseline through Week 24 in sweat chloride concentration and LCI2.5. Nitrogen multiple breath washout testing was performed with an Exhalyzer-D (Eco Medics) using Spiroware version 3.1.6. Assessments of LCI2.5 were conducted in children ⩾3 years of age at screening. Other endpoints included absolute change from baseline at Week 24 in body mass index (BMI) and BMI-for-age z-score; height and height-for-age z-score; weight and weight-for-age z-score; fecal elastase-1, fecal calprotectin, and serum immunoreactive trypsinogen concentrations; and number of pulmonary exacerbations through Week 24. Additional details on outcome measures, including a definition of pulmonary exacerbations, are provided in the online supplement.
Statistical Analysis
Because this was an open-label trial and all participants received ELX/TEZ/IVA, randomization was not required. Safety analyses included all participants who received at least one dose of ELX/TEZ/IVA. Safety analyses included in-person and in-home assessments. Analysis of safety data was descriptive.
Efficacy and pharmacodynamic analyses included all enrolled participants who received at least one dose of study drug. Absolute change from baseline in sweat chloride concentration was analyzed using a mixed-effects model for repeated measures. The model included absolute change from baseline in sweat chloride concentration as the dependent variable and visit as the fixed effect, with baseline sweat chloride value and CFTR genotype group as covariates. Absolute change from baseline in LCI2.5 was analyzed with a similar mixed-effects model for repeated measures using baseline LCI2.5 as the covariate instead of sweat chloride concentration. Data from all postbaseline visits (Weeks 4, 12, and 24) were included in the model. An unstructured covariance structure was used to model within-patient variance. Analysis of other efficacy endpoints was descriptive. Additional details of the statistical analyses, including management of missing data, are provided in the online supplement.
Results
Population
Part A was conducted at seven sites in the United States between November 19, 2020, and March 5, 2021. Eighteen children were enrolled and received at least one dose of ELX/TEZ/IVA. All children completed the 15-day treatment period. Demographic and baseline clinical characteristics for part A are provided in Table E2.
Part B was conducted at 22 sites in North America, Europe, and Australia between July 19, 2021, and June 3, 2022. Overall, 75 children were enrolled and received at least one dose of ELX/TEZ/IVA (Figure 1). The mean (SD) age at baseline was 4.1 (1.1) years; genotype-targeted enrollment led to 30.7% of the children having the F/F genotype and 69.3% having F/MF genotypes. Part B cohort baseline demographic and clinical characteristics are reported in Tables 1 and E3. One child (1.3%) discontinued the study because of an AE of abnormal behavior.
Figure 1.
Patient disposition diagram for part B of the study. AE = adverse event.
Table 1.
Demographic and Clinical Characteristics at Baseline in Part B of the Study
| Characteristic | ELX/TEZ/IVA (N = 75) |
|---|---|
| Sex, n (%) | |
| Male | 34 (45.3) |
| Female | 41 (54.7) |
| Age at baseline, yr | 4.1 ± 1.1 |
| Age group at screening visit, n (%) | |
| ⩾2 to <3 yr | 11 (14.7) |
| ⩾3 to <4 yr | 27 (36.0) |
| ⩾4 to <5 yr | 22 (29.3) |
| ⩾5 to <6 yr | 15 (20.0) |
| Ethnicity, n (%) | |
| Hispanic or Latino | 6 (8.0) |
| Not Hispanic or Latino | 63 (84.0) |
| Not collected per local regulations | 6 (8.0) |
| Race, n (%)* | |
| White | 68 (90.7) |
| Black or African American | 2 (2.7) |
| Not collected per local regulations | 6 (8.0) |
| CFTR genotype group, n (%) | |
| F/F | 23 (30.7) |
| F/MF | 52 (69.3) |
| Sweat chloride concentration, mmol/L | 100.7 ± 11.2 |
| LCI2.5 | 8.41 ± 1.48 |
| Weight group, n (%) | |
| <14 kg | 16 (21.3) |
| ⩾14 kg | 59 (78.7) |
| BMI, kg/m2 | 15.79 ± 1.06 |
| BMI-for-age z-score | 0.09 ± 0.85 |
| Fecal elastase-1 concentration, μg/g | 28.1 ± 65.7 |
Definition of abbreviations: BMI = body mass index; CFTR = cystic fibrosis transmembrane conductance regulator; ELX/TEZ/IVA = elexacaftor/tezacaftor/ivacaftor; F/F = homozygous for the F508del-CFTR mutation; F/MF = heterozygous for the F508del-CFTR mutation and a minimal function CFTR mutation; LCI2.5 = lung clearance index2.5.
Data presented as mean ± standard deviation where applicable.
If a participant reported multiple races, the participant was counted for each race reported.
Safety and Pharmacokinetics
Safety results for part A are reported in the online supplement (Table E4). In part B, 74 children (98.7%) had at least one AE during the 24-week treatment period, all of which were mild (62.7%) or moderate (36.0%) in severity and generally consistent with common CF disease manifestations or childhood infections (Tables 2 and 3). The most commonly reported AEs were cough (61.3%), pyrexia (34.7%), rhinorrhea (33.3%), and vomiting (28.0%). Two children (2.7%) had serious AEs. One child who was 3.6 years of age had a serious AE of abnormal behavior that led to study drug discontinuation. The child had a history of behavioral and developmental issues and developed hyperactivity, aggression, increased urinary urgency, and enuresis, which resolved after ELX/TEZ/IVA discontinuation. The investigator did not consider the child’s behavioral changes to be outside of what is typically seen in children in this age group but assessed the events as possibly related to ELX/TEZ/IVA. Another child had a serious AE of pulmonary exacerbation considered not related to ELX/TEZ/IVA, which resolved without a change in study drug dosing. Five children (6.7%) interrupted treatment as a result of AEs (rash [n = 2], anal and urinary incontinence [n = 1; discontinued treatment as described above], increased liver function tests [n = 1], and aggression [n = 1]). No children had AEs of cataract; one child (1.3%) had a nonserious AE of lenticular opacities that was mild in severity and did not lead to a change in study drug dose.
Table 2.
Summary of Adverse Events in Part B of the Study
| ELX/TEZ/IVA (N = 75) | |
|---|---|
| Participants with AEs | 74 (98.7) |
| AEs by maximum severity | |
| Mild | 47 (62.7) |
| Moderate | 27 (36.0) |
| Severe | 0 |
| Life-threatening | 0 |
| AEs by strongest relationship | |
| Not related | 15 (20.0) |
| Unlikely related | 27 (36.0) |
| Possibly related | 32 (42.7) |
| Related | 0 |
| Serious AEs | 2 (2.7) |
| Related serious AEs | 1 (1.3) |
| AEs leading to discontinuation | 1 (1.3)* |
| AEs leading to interruption | 5 (6.7) |
Definition of abbreviations: AE = adverse event; ELX/TEZ/IVA = elexacaftor/tezacaftor/ivacaftor.
Data presented as number of patients (%).
One child had an AE of abnormal behavior, which resolved after ELX/TEZ/IVA discontinuation.
Table 3.
Most Common Adverse Events (⩾10%) in Part B of the Study
| ELX/TEZ/IVA (N = 75) | |
|---|---|
| Participants with AEs* | 74 (98.7) |
| Cough | 46 (61.3) |
| Pyrexia | 26 (34.7) |
| Rhinorrhea | 25 (33.3) |
| Vomiting | 21 (28.0) |
| COVID-19 | 14 (18.7) |
| Nasal congestion | 13 (17.3) |
| Rash | 12 (16.0) |
| Upper respiratory tract infection | 11 (14.7) |
| Decreased appetite | 9 (12.0) |
| Alanine aminotransferase increased | 8 (10.7) |
| Infective pulmonary exacerbation of cystic fibrosis | 8 (10.7) |
Definition of abbreviations: AE = adverse event; COVID-19 = coronavirus disease 2019; ELX/TEZ/IVA = elexacaftor/tezacaftor/ivacaftor.
Data presented as number of patients (%).
When summarizing the number and percentage of children, a child with multiple occurrences of the same AE or a continuing AE was counted once.
On the basis of previous clinical trial experience with ELX/TEZ/IVA (14–16, 20), data related to aminotransferases, rash events, creatine kinase, and blood pressure from part B were reviewed. Increased levels of alanine aminotransferase and/or aspartate aminotransferase greater than three times, five times, and eight times the upper limit of normal occurred in six children (8.0%), two children (2.7%), and one child (1.3%), respectively (Table E5). No children had alanine aminotransferase and/or aspartate aminotransferase levels greater than three times the upper limit of normal concurrent with total bilirubin level greater than two times the upper limit of normal. Among the nine children with increased aminotransferase levels on laboratory examinations, eight (10.7%) had AEs of increased aminotransferase levels, none of which were serious or led to treatment discontinuation (see Table E5). One child (1.3%) interrupted ELX/TEZ/IVA at study Day 32 because of an AE of increased aminotransferase levels, which was mild in severity, nonserious, and not considered to be related to ELX/TEZ/IVA. The child completed the study and subsequently was enrolled in the open-label extension study.
Fifteen children (20.0%) had rash events (Table E6). Rash events comprise a group AE term that includes rash and other rash-related terms (e.g., rash erythematous, rash maculopapular, rash papular, and urticaria). No rash events were serious or led to treatment discontinuation (see Table E6). Two children (2.7%) interrupted study drug because of rash events, and both resumed ELX/TEZ/IVA without recurrence. Overall, there was a higher percentage of male participants (11 of 34; 32.4%) with rash events compared with female participants (4 of 41; 9.8%) (see Table E6). No children had creatine kinase levels greater than five times the upper limit of normal (Table E7). One child (1.3%) had an AE of increased creatine kinase levels, which was not serious and did not lead to treatment interruption or discontinuation. The mean change from baseline at Week 24 in systolic blood pressure was −0.1 (11.2) mm Hg, and that in diastolic blood pressure was 0.2 (10.9) mm Hg (Table E8). No children had AEs related to blood pressure. There were no other relevant safety findings or clinical assessments.
Analysis of the pharmacokinetic data from part A confirmed the appropriateness of the dosing regimen that was used in part B (Figure E2). The plot of the area under the curve versus time in part B confirmed that the exposures of ELX, TEZ, and IVA were within the exposure ranges previously shown to be safe and efficacious in adolescents and adults and that M23-ELX and M1-TEZ exposures were generally within the range of previous clinical experience (Figure 2). These population pharmacokinetic modeling results support the current dosing regimens and the 14-kg weight cutoff for dose transition.
Figure 2.
Pharmacokinetic exposure simulations. In each box plot, the median is represented by the horizontal line and the interquartile range by the box. Whisker marks indicate the largest and smallest within 1.5× the interquartile range. The gray area represents the 5th percentile (bottom border) and 95th percentile (top border), the green line represents the 50th percentile of the adult area under the curve values, and the red line represents the no observable adverse events level. AUC = area under the curve; ELX = elexacaftor; IVA = ivacaftor; M1 = metabolite 1; M23 = metabolite 23; NOAEL = no observable adverse events level; q12h = once every 12 hours; qd = once daily; TEZ = tezacaftor. *Children received ivacaftor 60 mg in the morning and ivacaftor 59.5 mg in the evening.
Efficacy
Treatment with ELX/TEZ/IVA led to a mean absolute change in sweat chloride concentration from study baseline through Week 24 of −57.9 mmol/L (95% CI, −61.3 to −54.6) (Table 4) that was observed by Week 4 and sustained through Week 24 (Figure 3A). Rapid and sustained decreases in LCI2.5 were also observed with ELX/TEZ/IVA treatment, with a mean absolute change from baseline through Week 24 of −0.83 U (95% CI, −1.01 to −0.66) (Figure 3B and Tables 4 and E9).
Table 4.
Secondary and Other Efficacy Endpoints in Part B of the Study
| Endpoint | ELX/TEZ/IVA (N = 75) |
|---|---|
| Secondary endpoints | |
| Absolute change in SwCl concentration from baseline through Week 24, mmol/L | −57.9 (−61.3 to −54.6)* |
| Absolute change in LCI2.5 from baseline through Week 24† | −0.83 (−1.01 to −0.66)‡ |
| Other endpoints | |
| Observed rate of PEx per year (48 wk) | 0.32 |
| Absolute change in BMI from baseline at Week 24, kg/m2 | 0.03 (−0.10 to 0.17)§ |
| Absolute change in BMI-for-age z-score from baseline at Week 24 | 0.10 (0.0 to 0.20)ǁ |
| Mean absolute change in fecal elastase-1 from baseline at Week 24 ± SD, μg/g | 39.5 ± 89.2¶ |
Definition of abbreviations: BMI = body mass index; ELX/TEZ/IVA = elexacaftor/tezacaftor/ivacaftor; LCI2.5 = lung clearance index2.5; PEx = pulmonary exacerbation; SwCl = sweat chloride.
Values presented as least-squares mean (95% confidence interval) where applicable. Baseline was defined as the most recent nonmissing measurement before the first dose of study drug in the treatment period in part B.
n = 69.
LCI was assessed only in participants aged ⩾3 yr.
n = 50.
n = 75.
n = 75.
n = 54.
Figure 3.
Secondary efficacy results by visit in part B. (A) Mean (SE) change from baseline in sweat chloride concentration is shown for each visit. (B) Mean (SE) change from baseline in LCI2.5 is shown for each visit. LCI2.5 = lung clearance index2.5; LS = least squares.
The mean absolute change in BMI, which was within the normal range at baseline (Table 1), was 0.03 kg/m2 (95% CI, −0.10 to 0.17) at Week 24. From baseline to Week 24, the mean absolute change in BMI-for-age z-score was 0.10 (95% CI, 0.00 to 0.20), change in weight-for-age z-score was 0.02 (95%, −0.04 to 0.09), and change in height-for-age z-score was −0.06 (95% CI, −0.11 to 0.00) (Figures 4A–4C and Table 4). There were 12 pulmonary exacerbations in 12 children (16.0%) during the 24-week treatment period, for a mean rate of 0.32 pulmonary exacerbations per year (Tables 4 and E10). The mean (SD) absolute change in fecal elastase-1 concentration was 39.5 (89.2) μg/g from baseline to Week 24 (Tables 4 and E11). Six children had a fecal elastase-1 concentration >200 μg/g at Week 24, compared with two children at baseline (Figure 4D). The mean (SD) absolute changes from baseline to Week 24 in immunoreactive trypsinogen and fecal calprotectin concentrations were −166.6 (285.0) μg/L and −289.66 (719.72) mg/kg, respectively.
Figure 4.
Changes in growth parameters and fecal elastase-1 concentrations by visit in part B of the study. Mean (SE) absolute change from baseline in the growth parameters (A) BMI-for-age z-score, (B) weight-for-age z-score, and (C) height-for-age z-score for each study visit. (D) Spaghetti plot showing individual changes from baseline in fecal elastase-1 concentration at each visit. Blue lines indicate children with at least one fecal elastase-1 measurement >200 µg/g at a study visit. BMI = body mass index; LS = least squares.
An analysis of absolute change in sweat chloride concentration from baseline through Week 24 by genotype group and a post hoc analysis of change in LCI2.5 from baseline through Week 24 by genotype group showed that children with the F/F genotype had greater reductions in sweat chloride concentration than those with F/MF genotypes (−70.0 mmol/L [95% CI, −75.4 to −64.5] and −52.6 mmol/L [95% CI, −56.9 to −48.4], respectively), whereas both genotype groups had similar changes in LCI2.5 (−0.89 U [95% CI, −1.15 to −0.63] and −0.82 U [95% CI, −1.06 to −0.57], respectively) (see Figures E3 and E4 and Table E9). The proportions of children with sweat chloride concentrations <60 mmol/L (threshold for a definitive diagnosis of CF) and <30 mmol/L (concentration below which a diagnosis of CF is unlikely) at Week 24 were also assessed. At baseline, the mean (SD) sweat chloride concentration was 100.7 (11.2) mmol/L, and only one of 71 children (1.4%; F/MF genotype) had a sweat chloride concentration <60 mmol/L. Through Week 24, all children with the F/F genotype (22 of 22) and 85.1% of children with F/MF genotypes (40 of 47) had sweat chloride concentrations <60 mmol/L, with 63.6% of children with the F/F genotype (14 of 22) and 12.8% of children with F/MF genotypes (6 of 47) having sweat chloride concentrations <30 mmol/L (Figure 5 and Tables E9 and E12).
Figure 5.
Sweat chloride responder analysis by genotype group. The percentage of children in each genotype group (F/F and F/MF) with sweat chloride concentrations <60 mmol/L and <30 mmol/L at Week 24 is shown. Percentages were calculated by dividing the number of children with sweat chloride concentrations below the indicated threshold at Week 24 by the total number of children with evaluable data. Children with missing data were considered to be missing at random and were not counted in the denominator. F/F = homozygous for the F508del–cystic fibrosis transmembrane conductance regulator (CFTR) mutation; F/MF = heterozygous for the F508del-CFTR mutation and a minimal-function CFTR mutation.
Discussion
In this study, the safety, pharmacokinetics, pharmacodynamics, and efficacy of ELX/TEZ/IVA were evaluated in children aged 2–5 years with CF and F/F or F/MF genotypes. Treatment with ELX/TEZ/IVA was generally safe and well tolerated in this age range, with a safety profile consistent with the established profile in older children, adolescents, and adults. Pharmacokinetic data showed that the exposures of ELX, TEZ, and IVA in these children were comparable to those in adult patients, confirming the dosing regimen and the 14-kg cutoff for dose transition in this age group. ELX/TEZ/IVA treatment led to improvements in CFTR function (as measured by changes in sweat chloride concentration) and lung function (as measured by LCI2.5), and was associated with stable BMI, a low rate of pulmonary exacerbations, and trends toward improved pancreatic function over the 24-week treatment period.
Overall, children in this study had low rates of serious AEs, treatment interruptions, and discontinuations. All AEs were mild or moderate in severity and generally consistent with typical manifestations of CF disease at this age or common childhood infections. The incidence of increased liver aminotransferase levels was consistent with the incidence observed in older children and adolescents and adults taking ELX/TEZ/IVA (14–16). Increased aminotransferase levels resulted in interruption of study drug in one participant but did not require treatment discontinuation in any participants. Rash events were observed more frequently in male (32.4%) than female (9.8%) participants, in contrast with studies in adults in which higher percentages of female than male participants had rash events (15, 16). The majority of rash events (12 of 15) were considered unrelated or unlikely to be related to ELX/TEZ/IVA and/or were confounded by concurrent viral symptoms. Overall, data related to rash events and increased aminotransferase levels were consistent with the known safety profile of ELX/TEZ/IVA, and there were no relevant safety findings in other clinical or laboratory assessments. There was a single treatment discontinuation due to a serious AE of abnormal behavior in a child with a previous history of behavioral issues, which the investigator considered to be possibly related to ELX/TEZ/IVA. The AE resolved 4 days after treatment discontinuation. Another child had a nonserious AE of aggression that led to treatment interruption; the AE resolved, and there was no recurrence of the event following study drug resumption. Although ELX/TEZ/IVA treatment could have played a role in these events, behavioral changes, including aggression, are common in this age group, with previous studies reporting between 3% and 7% of children and adolescents displaying signs of aggression (21), and may have been more common in preschool-aged children during the SARS-CoV-2 pandemic because of quarantines and restrictions on social interactions (22). In summary, treatment with ELX/TEZ/IVA was generally safe and well tolerated, with a safety profile consistent with the established profile in older children and adults.
Treatment with ELX/TEZ/IVA led to rapid and robust decreases in sweat chloride concentration, a direct indicator of systemic CFTR function (23). The mean (SD) sweat chloride concentration decreased from 100.7 (11.2) mmol/L at baseline to 42.7 (20.2) mmol/L at Week 24. Overall, at Week 24, almost 90% of children in this study had sweat chloride concentrations <60 mmol/L, the threshold for a definitive diagnosis of CF (7). Similar to studies in children aged 6–11 years, in this study children with the F/F genotype, on average, had greater decreases in sweat chloride concentrations than children with F/MF genotypes, which was most likely the result of a greater abundance of F508del-CFTR protein for modulation by ELX/TEZ/IVA (14). However, in this study, a greater proportion of children with the F/F genotype exhibited a sweat chloride concentration <30 mmol/L (63.6%) than did children aged 6–11 years (42.9%) or adolescents and adults (23%) with the F/F genotype in other studies (14, 24). Taken together, these results demonstrate that ELX/TEZ/IVA treatment improves CFTR function in children aged 2–5 years. These results also suggest that earlier treatment with ELX/TEZ/IVA might lead to greater improvements in CFTR function, although additional studies are needed to better understand this finding.
Declining lung function is common as CF disease progresses, with impaired lung function often evident early in life (25). LCI2.5 is a sensitive measure of ventilation inhomogeneity, with increases in LCI2.5 indicative of worsening of lung function. In a natural-history study of preschool-age children with CF not treated with CFTR modulators, most had abnormal LCI2.5, and there was longitudinal progression, with an average annual increase of 0.4 U/yr (26). In the present study, the mean (SD) LCI2.5 at baseline was 8.41 (1.48) U, indicating that most children had baseline distal airway pathology. ELX/TEZ/IVA treatment for 24 weeks led to a decrease in LCI2.5 (−0.83 U) from baseline, demonstrating improvements in lung function in these children during the treatment period. The rate of pulmonary exacerbations was low (0.32 per person per 48 wk) in this study, but the interpretation of this result is difficult because the study largely took place during the SARS-CoV-2 pandemic, during which masking and social-distancing measures may have contributed to decreased pulmonary exacerbation rates (27). A previous study from 2013 reported that the average rate of pulmonary exacerbations in children younger than 5 years of age with CF not treated with CFTR modulators was 3.66 exacerbations per person-year (28). These results suggest that early initiation of ELX/TEZ/IVA improves lung function in children with CF who are as young as 3 years of age.
In most children with F/F or F/MF genotypes, exocrine pancreatic insufficiency leads to macronutrient malabsorption and can impair growth (29). In the present study, growth parameters, which were normal at baseline, remained stable at Week 24 even though most children had pancreatic insufficiency (fecal elastase-1 concentration <200 μg/g) at baseline. Markers of pancreatic function and intestinal inflammation showed trends toward improvement in some children during the 24-week treatment period, suggesting that ELX/TEZ/IVA treatment might have the potential to improve pancreatic function in children who already have documented exocrine pancreatic insufficiency. Although trends toward improved exocrine pancreatic function have been reported in trials of IVA in children 2–5 years of age with CFTR gating mutations (30, 31), longer-term studies and studies in younger children will be required to understand the extent to which ELX/TEZ/IVA can halt or potentially stabilize or reverse early exocrine pancreatic damage due to CF.
This study had some limitations. First, the study lacked a comparator group, which limits the ability to interpret the safety and efficacy results. However, the safety profile and the improvements in CFTR function and lung function seen in this study in children aged 2–5 years are consistent with those that have been reported in randomized controlled trials in children aged 6–11 years and in adolescents and adults (15, 16, 18). Second, as previously noted, parts of this study did take place during the SARS-CoV-2 pandemic, likely contributing to decreased pulmonary exacerbation rates (27).
In conclusion, ELX/TEZ/IVA treatment in children aged 2–5 years was generally safe and well tolerated, led to improvements in CFTR function and lung function, and was associated with stable nutritional status over a 24-week treatment period. These results show that ELX/TEZ/IVA has a favorable safety profile and provides clinically meaningful benefits to people with CF who are as young as 2 years of age.
Acknowledgments
Acknowledgment
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, Ph.D., an employee of Vertex Pharmaceuticals, Inc., who may own stock or stock options in the company, under the guidance of the authors. Editorial assistance was provided by ArticulateScience, LLC, and funded by Vertex Pharmaceuticals, Inc.
Footnotes
Supported by Vertex Pharmaceuticals (VX20-445-111).
Author Contributions: The study sponsor (Vertex Pharmaceuticals Incorporated) designed the protocol in collaboration with the academic authors. Site investigators collected the data, which were analyzed by the sponsor. All authors had full access to the study data. J.L.G., F.R., and M.R. 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.
Data sharing 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.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Originally Published in Press as DOI: 10.1164/rccm.202301-0084OC on March 15, 2023
Author disclosures are available with the text of this article at www.atsjournals.org.
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