Rationale: A 24-week, phase 3, open-label study showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6–11 years with cystic fibrosis (CF) and one or more F508del-CFTR alleles.
Objectives: To assess long-term safety and efficacy of ELX/TEZ/IVA in children who completed the pivotal 24-week phase 3 trial.
Methods: In this phase 3, two-part (part A and part B), open-label extension study, children aged ⩾6 years with CF heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) or homozygous for F508del (F/F genotype) who completed the 24-week parent study received ELX/TEZ/IVA based on weight. Children weighing <30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours, whereas children weighing ⩾30 kg received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours (adult dose). The 96-week analysis of part A of this extension study is reported here.
Measurements and Main Results: Sixty-four children (F/MF genotypes, n = 36; F/F genotype, n = 28) were enrolled and received one or more doses of ELX/TEZ/IVA. Mean (SD) period of exposure to ELX/TEZ/IVA was 93.9 (11.1) weeks. The primary endpoint was safety and tolerability. Adverse events and serious adverse events were consistent with common manifestations of CF disease. Overall, exposure-adjusted rates of adverse events and serious adverse events (407.74 and 4.72 events per 100 patient-years) were lower than in the parent study (987.04 and 8.68 events per 100 patient-years). One child (1.6%) had an adverse event of aggression that was moderate in severity and resolved after study drug discontinuation. From parent study baseline at Week 96 of this extension study, the mean percent predicted FEV1 increased (11.2 [95% confidence interval (CI), 8.3 to 14.2] percentage points), sweat chloride concentration decreased (−62.3 [95% CI, −65.9 to −58.8] mmol/L), Cystic Fibrosis Questionnaire-Revised respiratory domain score increased (13.3 [95% CI, 11.4 to 15.1] points), and lung clearance index 2.5 decreased (−2.00 [95% CI, −2.45 to −1.55] units). Increases in growth parameters were also observed. The estimated pulmonary exacerbation rate per 48 weeks was 0.04. The annualized rate of change in percent predicted FEV1 was 0.51 (95% CI, −0.73 to 1.75) percentage points per year.
Conclusions: ELX/TEZ/IVA continued to be generally safe and well tolerated in children aged ⩾6 years through an additional 96 weeks of treatment. Improvements in lung function, respiratory symptoms, and CFTR function observed in the parent study were maintained. These results demonstrate the favorable long-term safety profile and durable clinical benefits of ELX/TEZ/IVA in this pediatric population.
Clinical trial registered with www.clinicaltrials.gov (NCT04183790).
Previously, a 24-week, phase 3 study showed that the triple-combination CFTR (cystic fibrosis transmembrane conductance regulator) modulator regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6–11 years with cystic fibrosis and at least one F508del allele.
This two-part, open-label extension study was designed to assess the long-term safety and efficacy of ELX/TEZ/IVA in children aged ⩾6 years who completed the previous 24-week pivotal trial. Treatment with ELX/TEZ/IVA continued to be generally safe and well tolerated, and the clinically meaningful improvements in lung function, respiratory symptoms, and CFTR function that were observed over the 24-week treatment period in the parent study were maintained through an additional 96 weeks of treatment in this extension study. These results support the favorable long-term safety profile and durable efficacy of ELX/TEZ/IVA in this pediatric population.
Cystic fibrosis (CF) is an autosomal recessive disorder that results from mutations in the CFTR (CF transmembrane conductance regulator) gene (1). Clinical manifestations of CF appear early, with pancreatic insufficiency, growth impairment, and progressive lung disease usually evident within the first few years of life (2–4). Given this, early treatment intervention is crucial in altering the course of CF disease.
The advancement of small-molecule CFTR modulator therapies over the past decade has profoundly changed the CF treatment landscape (5). Potentiators, such as ivacaftor (IVA), augment the gating of mutant CFTR proteins, whereas correctors, such as tezacaftor (TEZ) and elexacaftor (ELX), remedy defects in CFTR protein processing and trafficking associated with CFTR misfolding mutations such as F508del, the most common CFTR mutation, present on at least one allele in up to 90% of patients with CF in many parts of the world (6–10). A triple-combination CFTR modulator regimen of ELX/TEZ/IVA has been shown to be safe and efficacious in people with CF aged ⩾6 years who have at least one F508del allele (11–16). Pivotal clinical trials in patients aged ⩾12 years who were homozygous for F508del (F/F genotype; 4-wk study) (12) or heterozygous for F508del and a minimal function mutation (F/MF genotypes; 24-wk study) (13) showed ELX/TEZ/IVA treatment led to robust and clinically meaningful improvements in lung function, CFTR function, and respiratory symptoms that exceeded the improvements previously seen with the dual CFTR modulator regimen TEZ/IVA in patients with the F/F genotype and suggest that a single F508del allele is sufficient for response to ELX/TEZ/IVA. A subsequent 24-week pivotal clinical trial of ELX/TEZ/IVA in children aged 6–11 years who had either F/F or F/MF genotypes showed the safety and efficacy seen in children were consistent with that reported in adolescents and adults (14). Taken together, these findings have established ELX/TEZ/IVA as the standard of care in countries where it has been approved for treating patients aged ⩾6 years with CF who have one or more F508del allele or at least one ELX/TEZ/IVA-responsive allele.
As ELX/TEZ/IVA has the potential to be a lifelong therapy for patients with CF, it is important to understand the long-term impact of ELX/TEZ/IVA treatment, especially when therapy is initiated at younger ages. Recent interim analyses from an ongoing extension study in adolescents and adults aged ⩾12 years have shown that after >2 years of treatment, ELX/TEZ/IVA continues to be safe and effective (17). Here, we describe results from an analysis of 96-week duration from part A of a long-term, open-label extension study of ELX/TEZ/IVA treatment in children aged ⩾6 years.
Study VX19-445-107 (study 445-107, NCT04183790) is a phase 3, two-part, multicenter, open-label extension study that enrolled children aged ⩾6 years with CF and either F/F or F/MF genotypes who completed the ELX/TEZ/IVA treatment period in the parent study (VX18-445-106 [study 445-106 part B]). A list of qualifying minimal function mutations and other eligibility criteria is provided in Table E1 in the online supplement.
Part A of the 445-107 extension study (reported here) assessed safety, tolerability, efficacy, and pharmacodynamics over a 96-week treatment period (Figure E1). Part B of the study will assess a further 96-week treatment period. Dosing in part A was based on weight: children weighing <30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours, whereas children weighing ⩾30 kg received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours (adult dose).
The trial was designed by Vertex Pharmaceuticals (Boston, MA) in collaboration with the authors. For each enrolled child, informed consent was provided by a parent or legal guardian; assent was obtained in accordance with local requirements. 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 VX19-445-107 Study Group. Authors had full access to trial data after database lock, critically reviewed 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. Confidentiality agreements were in place between the sponsor and each investigative site during the trial. The clinical trial protocol and informed consent forms were approved by independent ethics committees for each region or site, as required by local regulations.
As parts of this trial took place during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, a global protocol addendum was implemented that provided participants with the opportunity to continue participation in the study while ensuring safety by minimizing the risk of exposure through travel. Implemented measures, as permitted by country and local regulation, enabled remote consent, remote monitoring visits, in-home assessments, and shipment of study drugs to participants’ homes.
The primary endpoint of part A was safety and tolerability as assessed by adverse events (AEs), clinical laboratory values, ECGs, vital signs, pulse oximetry, and ophthalmologic examinations. Secondary endpoints included absolute change from parent study baseline at Week 96 in percent predicted FEV1 (ppFEV1), sweat chloride concentration, Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, lung clearance index 2.5 (LCI2.5), body mass index (BMI) and BMI-for-age z-score, height and height-for-age z-score, weight and weight-for-age z-score, and number of pulmonary exacerbations. Other endpoints included absolute change from parent study baseline at Week 96 in fecal elastase-1 concentration and serum levels of immunoreactive trypsinogen. According to the study protocol, individual LCI2.5 results were determined using the EcoMedics Exhalyzer-D multiple-breath washout device with Spiroware Version 3.1.6. Of note, this version of the Spiroware software was updated to correct for cross-sensitivity issues in the device’s oxygen and carbon dioxide sensors that can overestimate the nitrogen concentration (18). The impact of this update was assessed in a recent study, which showed that although the corrected algorithm resulted in lower LCI2.5 values, the interpretation or significance of any observed treatment effects did not change (19).
Safety and efficacy analyses included all children who received at least one dose of ELX/TEZ/IVA in part A. Safety analyses were based on data collected up to Week 96 in part A and could include both local or in-home and at-clinic assessments. Analysis of safety data was descriptive, and there was no statistical testing.
Absolute changes from parent study baseline in ppFEV1, sweat chloride concentration, CFQ-R respiratory domain score, LCI2.5, and nutritional parameters were analyzed using a mixed-effects model for repeated measures. Post hoc analyses for the proportion of children achieving sweat chloride concentrations <60 mmol/L and <30 mmol/L as well as an analysis of the annualized rate of change in ppFEV1 were conducted. Additional details of the statistical analyses, including management of missing data, are provided in the online supplement.
Part A of the 445-107 trial was conducted at 21 sites in the United States, Australia, Canada, United Kingdom, and Ireland between February 17, 2020, and May 24, 2022. Overall, 64 children were enrolled and received at least one dose of ELX/TEZ/IVA (Figure 1). Three children (4.7%) discontinued treatment: one child had an AE of aggression that the investigator considered to be moderate in severity and unlikely related to ELX/TEZ/IVA; one child refused further dosing (not due to an AE); and one child started commercially available ELX/TEZ/IVA. Consistent with the parent study, baseline demographics and clinical characteristics remained similar between children with F/F and F/MF genotypes (Tables 1 and E2).
|Parameter||Parent Study 445-106 Part B|
(N = 66)
|OLE Study 445-107 Part A|
(N = 64)*
|Female, n (%)||39 (59.1)||39 (60.9)|
|Age at baseline, yr, mean (SD)||9.3 (1.9)||9.3 (1.8)|
|Race, n (%)†|
|White||58 (87.9)||56 (87.5)|
|Black or African American||0||0|
|Asian||1 (1.5)||1 (1.6)|
|American Indian or Alaska Native||0||0|
|Not collected per local regulations||8 (12.1)||8 (12.5)|
|Ethnicity, n (%)|
|Hispanic or Latino||0||0|
|Not Hispanic or Latino||58 (87.9)||56 (87.5)|
|Not collected per local regulations||8 (12.1)||8 (12.5)|
|Weight <30 kg at baseline, n (%)||36 (54.5)||35 (54.7)|
|CFTR genotype group, n (%)|
|F/F||29 (43.9)||28 (43.8)|
|F/MF||37 (56.1)||36 (56.3)|
|ppFEV1, percentage points, mean (SD)||88.8 (17.7)||88.3 (17.6)|
|Sweat chloride concentration, mmol/L, mean (SD)||102.2 (9.1)||102.2 (9.2)|
|CFQ-R respiratory domain score, points, mean (SD)||80.3 (15.2)||79.8 (15.2)|
|LCI2.5, mean (SD)||9.77 (2.68)||9.87 (2.68)|
|BMI, kg/m2, mean (SD)||16.39 (1.69)||16.32 (1.66)|
|BMI z-score, mean (SD)||−0.16 (0.74)||−0.19 (0.73)|
|Weight, kg, mean (SD)||30.0 (7.7)||29.9 (7.7)|
|Weight z-score, mean (SD)||−0.22 (0.76)||−0.24 (0.76)|
|Height, cm, mean (SD)||134.1 (12.3)||134.0 (12.3)|
|Height z-score, mean (SD)||−0.11 (0.98)||−0.11 (0.99)|
Overall, 63 children (98.4%) had at least one AE during this 96-week open-label extension study, which for most children were mild (46.9%) or moderate (48.4%) in severity and generally consistent with common CF disease manifestations or childhood infections (Tables 2 and 3). The overall exposure-adjusted rates of AEs and serious AEs in this 96-week extension study (407.74 and 4.72 events per 100 patient-years, respectively) were lower than in the parent study (987.04 and 8.68 events per 100 patient-years) (Table 3). The most commonly reported AEs were cough (37.5%), headache (28.1%), rhinorrhea (25.0%), nasal congestion (21.9%), pyrexia (21.9%), and upper respiratory tract infection (20.3%). Four children (6.3%) had serious AEs. One child had a serious AE of idiopathic intracranial hypertension (with ophthalmologic examination showing papilledema) that started on Day 1 and was considered possibly related to ELX/TEZ/IVA. The child, who had vitamin A concentrations in the normal range, was treated with acetazolamide and interrupted study drug on Day 62 and then resumed treatment on Day 112. An ophthalmologic examination conducted at Week 96 showed 20/20 visual acuity and no abnormalities, and at the data cut, the child remains on ELX/TEZ/IVA and acetazolamide with no evidence of idiopathic intracranial hypertension. The remaining three children had serious AEs of constipation (n = 1), pyrexia (n = 1), and constipation, anaphylactic reaction, and hematuria traumatic (n = 1) that were considered not related to study drug, and that all had resolved. The anaphylactic reaction was due to an allergy to peanuts. As described above, one child had an AE of aggression that was considered moderate in severity, unlikely to be related to ELX/TEZ/IVA, and that resolved after ELX/TEZ/IVA discontinuation.
|Patients, n (%)||Parent Study 445-106 Part B ELX/TEZ/IVA (N = 66)||OLE Study 445-107 Part A ELX/TEZ/IVA (N = 64)|
|Any AE||65 (98.5)||63 (98.4)|
|AEs by maximum relatedness|
|Not related||16 (24.2)||21 (32.8)|
|Unlikely related||16 (24.2)||19 (29.7)|
|Possibly related||29 (43.9)||23 (35.9)|
|AEs by maximum severity|
|Mild||36 (54.5)||30 (46.9)|
|Moderate||28 (42.4)||31 (48.4)|
|Severe||1 (1.5)||2 (3.1)|
|Serious AEs||1 (1.5)||4 (6.3)|
|AE leading to death||0||0|
|AE leading to discontinuation||1 (1.5)||1 (1.6)|
|AE leading to interruption||1 (1.5)||3 (4.7)|
|Preferred Terms||Parent Study 445-106 Part B|
(N = 66)
|OLE Study 445-107 Part A|
(N = 64)
|n (%)||Events per 100 Patient-Years||n (%)||Events per 100 Patient-Years|
|Patients with AEs||65 (98.5)||987.04||63 (98.4)||407.74|
|Cough||28 (42.4)||121.57||24 (37.5)||31.49|
|Headache||16 (24.2)||55.00||18 (28.1)||21.25|
|Rhinorrhea||8 (12.1)||26.05||16 (25.0)||15.74|
|Nasal congestion||10 (15.2)||40.52||14 (21.9)||15.74|
|Pyrexia||14 (21.2)||55.00||14 (21.9)||18.89|
|Upper respiratory tract infection||11 (16.7)||40.52||13 (20.3)||14.96|
|Abdominal pain||8 (12.1)||26.05||12 (18.8)||10.23|
|Oropharyngeal pain||12 (18.2)||40.52||12 (18.8)||11.81|
|Vomiting||7 (10.6)||28.95||12 (18.8)||14.96|
|Constipation||4 (6.1)||11.58||10 (15.6)||12.59|
|Nasopharyngitis*||1 (1.5)||2.89||8 (12.5)||12.59|
|Productive cough||5 (7.6)||14.47||8 (12.5)||7.87|
|Diarrhea||7 (10.6)||23.16||7 (10.9)||7.08|
|Alanine aminotransferase increased||7 (10.6)||26.05||6 (9.4)||6.30|
|Viral upper respiratory tract infection||8 (12.1)||23.16||4 (6.3)||5.51|
|Influenza||7 (10.6)||23.16||1 (1.6)||0.79|
|Rash||8 (12.1)||28.95||1 (1.6)||0.79|
On the basis of previous clinical trial experience with ELX/TEZ/IVA (11–14), data related to aminotransferases, rash events, creatine kinase, and blood pressure were reviewed. Elevated concentrations of alanine aminotransferase and/or aspartate aminotransferase greater than three times, greater than five times, and greater than eight times the upper limit of normal occurred in four children (6.3%), one child (1.6%), and no children, respectively (Table E3). There were no children who had alanine aminotransferase and/or aspartate aminotransferase concentrations greater than three times the upper limit of normal concurrent with total bilirubin greater than two times the upper limit of normal. Six children (9.4%) had AEs of elevated transaminases, none of which were serious or led to treatment interruption or discontinuation (Table E3). The exposure-adjusted rate of AEs of elevated transaminases was lower in the part A extension study than in the 445-106 parent study (11.02 and 31.84 events per 100 patient-years, respectively). Three children (4.7%) had AEs related to rash events, none of which were serious or led to treatment interruption or discontinuation (Table E4). The exposure-adjusted rate of rash events was lower in the extension study (4.72 events per 100 patient-years) than in the parent study (60.79 events per 100 patient-years). There were no children who had creatine kinase concentrations greater than five times the upper limit of normal (Table E5). Three children (4.7%) had AEs of increased creatine kinase, which were not serious and did not lead to treatment interruption or discontinuation. The mean change from parent study baseline in systolic blood pressure was 1.7 (10.3) mm Hg and in diastolic blood pressure was 1.5 (11.3) mm Hg at Week 96 (Table E6). One child had a nonserious AE of hypertension, which was moderate in severity, considered possibly related to ELX/TEZ/IVA, and led to study drug interruption. The AE resolved without treatment, the child resumed ELX/TEZ/IVA, and the hypertension did not recur. There were no other relevant safety findings or clinical assessments.
Continued treatment with ELX/TEZ/IVA during this 96-week extension study led to maintenance of the improvements in key clinical outcomes seen in the 24-week parent pivotal study. In terms of secondary endpoints, the mean absolute change from parent study baseline at Week 96 in ppFEV1 was 11.2 percentage points (95% confidence interval [CI], 8.3 to 14.2), in sweat chloride concentration was −62.3 mmol/L (95% CI, −65.9 to −58.8), and in CFQ-R respiratory domain score was 13.3 points (95% CI, 11.4 to 15.1) (Table 4; Figures 2A–2C and E2). Increases in BMI and BMI-for-age z-score (1.92 [95% CI, 1.50 to 2.35] and 0.24 [95% CI, 0.11 to 0.37], respectively) as well as improvements in LCI2.5 (−2.00 units [95% CI, −2.45 to −1.55]) were also seen from parent study baseline at Week 96 (Table 4; Figures 2D and 3A). Increases in weight-for-age z-score and height-for-age z-score were also observed (Table 4; Figures 3B and 3C). Overall, there were five children (7.6%) who experienced a total of seven pulmonary exacerbations during the parent study and this 96-week extension study for an estimated rate of pulmonary exacerbations per year of 0.04 (Table E7). The post hoc analysis of annualized rate of change in ppFEV1 was 0.51 percentage points per year (95% CI, −0.73 to 1.75). In terms of other endpoints, mean (SD) fecal elastase-1 concentration was 9.8 (12.7) μg/g (range, 7.5 to 98.0 μg/g) at parent study baseline and 20.2 (42.6) μg/g (range, 7.5 to 240.0 μg/g) at Week 96. One child with a fecal elastase-1 concentration <200 μg/g at baseline, indicative of pancreatic insufficiency, had a concentration >200 μg/g at Week 96. Mean (SD) serum immunoreactive trypsinogen concentration was 84.0 (178.9) μg/L (range, 7.0 to 1,200.0 μg/L) at parent study baseline and 59.3 (132.9) μg/L (range, 7.0 to 855.8 μg/L) at Week 96.
|Absolute Change from Parent Study Baseline*||Through Week 24 of Parent Study 445-106 Part B|
(N = 66)
|At Week 96 of OLE Study 445-107 Part A|
(N = 64)
|ppFEV1, percentage points†||10.2 (7.9 to 12.6); n = 59||11.2 (8.3 to 14.2); n = 45|
|Sweat chloride concentration, mmol/L||−60.9 (−63.7 to −58.2); n = 60||−62.3 (−65.9 to −58.8); n = 56|
|CFQ-R respiratory domain score, points†||7.0 (4.7 to 9.2); n = 65||13.3 (11.4 to 15.1); n = 59|
|LCI2.5, units||−1.71 (−2.11 to −1.30); n = 50||−2.00 (−2.45 to −1.55); n = 35|
|BMI-for-age z-score||0.37 (0.26 to 0.48)‡; n = 33||0.24 (0.11 to 0.37); n = 60|
|Weight-for-age z-score||0.25 (0.16 to 0.33)‡; n = 33||0.23 (0.10 to 0.35); n = 60|
|Height-for-age z-score||−0.05 (−0.12 to 0.01)‡; n = 33||0.06 (−0.03 to 0.16); n = 60|
Subgroup analyses by genotype for absolute change in ppFEV1 and sweat chloride concentration from parent study baseline at Week 96 showed children with the F/F and F/MF genotypes had similar changes in ppFEV1 (11.4 percentage points [95% CI, 7.2 to 15.5] and 11.0 percentage points [95% CI, 6.8 to 15.2], respectively), whereas children with the F/F genotype had greater reductions in sweat chloride concentration than those with F/MF genotypes (−70.2 mmol/L [95% CI, −75.1 to −65.4] and −56.5 mmol/L [95% CI, −62.4 to −50.6], respectively) (Table E8). The mean (SD) sweat chloride concentration at Week 96 for children with the F/F genotype was 31.1 (11.5) mmol/L and for children with the F/MF genotype was 45.6 (13.7) mmol/L (overall population mean sweat chloride concentration was 39.2 [14.6] mmol/L).
To further examine changes in sweat chloride concentration with ELX/TEZ/IVA treatment in this pediatric population, a post hoc analysis was performed to look at the proportion of children who had mean post-treatment sweat chloride concentrations of <60 mmol/L (threshold for a definitive diagnosis of CF) and <30 mmol/L (concentration observed in a population of asymptomatic carriers of a single CFTR mutation). At parent study baseline, there were no children with sweat chloride concentrations <60 mmol/L. At Week 96 of this open-label extension study, all children with the F/F genotype (26/26) and 84.8% of children with F/MF genotypes (28/33) had sweat chloride concentrations <60 mmol/L, whereas 38.5% of children with F/F and 9.1% of children with F/MF genotypes had sweat chloride concentrations <30 mmol/L (Figure 4; Table E9).
The long-term safety and efficacy of ELX/TEZ/IVA in children aged ⩾6 years is being evaluated in this two-part, open-label extension study. Here, we report results from part A, a 96-week study in children who took part in the pivotal 24-week 445-106 trial (14). Treatment with ELX/TEZ/IVA remained generally safe and well tolerated in this pediatric population, with most children having AEs that were mild or moderate in severity and consistent with CF disease manifestations. The improvements in lung function, respiratory symptoms, and CFTR function seen in the parent study were maintained through an additional 96 weeks of ELX/TEZ/IVA treatment.
During this 2-year extension study, the most commonly experienced AEs (cough, headache, rhinorrhea, nasal congestion, pyrexia, and upper respiratory tract infection) were consistent with underlying CF. Overall, the exposure-adjusted rates for both AEs and serious AEs were lower in this extension study than in the parent study. The only discontinuation due to an AE was for a child with no medical history of behavioral changes who had an AE of aggression that was moderate in severity and nonserious. The AE, which resolved after study drug discontinuation, was considered by the investigator as unlikely to be related to ELX/TEZ/IVA and consistent with the child’s age. Aggressive behavior is known to occur in children in this age group, with a reported 3–7% of children and adolescents manifesting signs of aggression (20). In addition, neurobehavioral AEs, including aggression, have been more common in school-aged children during the SARS-CoV-2 pandemic, likely due to restrictions on social interactions and quarantines (21). There were no other AEs of aggression in the study. One child had a serious AE of idiopathic intracranial hypertension considered to be possibly related to ELX/TEZ/IVA, which resolved with continued ELX/TEZ/IVA treatment and acetazolamide. This is the only case of idiopathic intracranial hypertension that has occurred within all clinical trials of ELX/TEZ/IVA in more than 2,800 patients with CF treated (>4,600 patient-years). The incidence of idiopathic intracranial hypertension in ELX/TEZ/IVA clinical trials (0.2 per 1,000 patient-years) is well within the expected background incidence in the CF population (1.0 per 1,000 patient-years) (Tables E10 and E11). Overall, the data do not suggest an association between ELX/TEZ/IVA treatment and idiopathic intracranial hypertension. Rash events and aminotransferase elevations were less frequently seen in the extension study than in the parent study; all rash events were mild in severity and there were no serious AEs, treatment interruptions, or treatment discontinuations due to either rash events or aminotransferase elevations. Changes in blood pressure through the 96-week treatment period were variable but generally consistent with changes reported in the 24-week parent study. These results demonstrate a positive long-term safety profile in children aged ⩾6 years that is consistent with the established safety profile of ELX/TEZ/IVA.
Robust improvements in lung function and respiratory symptoms with ELX/TEZ/IVA treatment were previously reported in children aged 6–11 years (14). Improvements in ppFEV1 and LCI2.5 seen in the 24-week pivotal trial were maintained through an additional 96 weeks of treatment. In addition, an annualized rate of change analysis that included data from both the extension study and the parent study showed there was no decline in mean ppFEV1 (annualized rate of change, 0.51 percentage points) over the combined 2.5-year treatment period. The absolute change in CFQ-R respiratory domain score from parent study baseline was higher (13.3 points [95% CI, 11.4–15.1]) at Week 96 than through Week 24 in the parent study (7.0 points [95% CI, 4.7–9.2]), with the difference exceeding the minimal clinically important difference of 4 points (22). This result suggests that children receiving ELX/TEZ/IVA over an extended period continue to experience clinically meaningful improvements in respiratory symptoms. Pulmonary exacerbations lead to loss of lung function, worse quality of life, and shortened survival (23), so reducing the frequency of these events is critical to improved CF care. A retrospective study using U.S. Cystic Fibrosis Foundation Patient Registry data from 2011, before the introduction of CFTR modulators, showed children aged <12 years had a mean pulmonary exacerbation rate of 0.3 (24). For children taking ELX/TEZ/IVA, the rate of pulmonary exacerbations in the combined parent study and extension study period was only 0.04 per 48 weeks. Notably, this rate was also lower than in the parent study period alone (0.12), suggesting further reductions in pulmonary exacerbations are possible with extended ELX/TEZ/IVA use. The sustained improvements in lung function, as measured by ppFEV1 and the annualized rate of change in ppFEV1, together with the continued improvement in CFQ-R respiratory domain score and low rate of pulmonary exacerbations, are consistent with long-term findings in patients with CF aged ⩾12 years treated with ELX/TEZ/IVA for 144 weeks in an open-label extension study. Taken together, these results firmly demonstrate that treatment with ELX/TEZ/IVA not only improves lung function and respiratory symptoms but also has the potential to halt lung function decline in children, adolescents, and adults with CF and at least one F508del allele.
Changes in sweat chloride concentration provide an indicator of systemic CFTR function (25). At Week 96 of this extension study, all children with the F/F genotype and 84.8% of children with F/MF genotypes had sweat chloride concentrations <60 mmol/L, the threshold for a definitive diagnosis of CF (4), with 38.5% of those with F/F genotypes and 9.1% of those with F/MF genotypes having sweat chloride concentrations <30 mmol/L, matching concentrations seen in asymptomatic carriers with a single mutant CFTR allele (26). These findings are consistent with the results seen in the 24-week parent study, strongly suggesting improvements in sweat chloride concentration achieved with ELX/TEZ/IVA treatment are durable. It is notable that, on average, children with the F/F genotype had greater improvements in sweat chloride concentration and a lower mean sweat chloride concentration at Week 96 than those with F/MF genotypes. This supports the idea that people with the F/F genotype have a greater abundance of F508del protein that can be targeted for modulation by ELX/TEZ/IVA. In contrast to the genotype differences observed in the change in sweat chloride concentrations with ELX/TEZ/IVA, differences by genotype were not seen in the changes from baseline in either ppFEV1 or LCI2.5.
Children with CF often experience poor growth and inadequate weight gain due to malnutrition, chronic inflammation, and lung disease (27), and studies have shown normal body weight is associated with better preserved lung function (28). The increases in BMI-for-age z-score and weight-for-age z-score with ELX/TEZ/IVA treatment seen in the parent study were maintained during the 96-week extension study. BMI continued to increase during the extension period, albeit at a slower rate than in the first 24 weeks of the parent study and remained in the normal range. Notably, there was also a slight increase in height-for-age z-score during the extension study. Taken together, these results would suggest that ELX/TEZ/IVA leads to rapid improvements in growth parameters that are then maintained over time. Pancreatic insufficiency, which is seen in approximately 85% of children with CF before the age of 1 year, contributes to the poor growth and weight loss seen in these patients (29). Improvements in pancreatic function have been reported in children with CF aged <5 years taking the CFTR modulator IVA (30, 31). All children in this extension study were pancreatic insufficient at baseline, with fecal elastase-1 concentrations of <200 μg/g. After 96 weeks of ELX/TEZ/IVA treatment, there was a small increase in mean fecal elastase-1 concentration, and there was one child who attained a fecal elastase-1 concentration of ⩾200 μg/g. Future studies of ELX/TEZ/IVA in children aged <5 years will provide greater insight into the potential impact of early ELX/TEZ/IVA treatment on pancreatic disease and injury in children with CF.
There are limitations to the current study. The trial lacked a comparator group, which limited the ability to interpret the safety and efficacy results. However, it is important to note that the safety profile and improvements in lung function and CFTR function seen in the current trial are consistent with what was reported in the 24-week, randomized, placebo-controlled trial of ELX/TEZ/IVA in children of the same age range (15). In addition, the conduct of this study overlapped with the SARS-CoV-2 pandemic. A global protocol addendum was implemented to provide children with the opportunity to continue in the study while minimizing risk. Implemented measures included shipping study drug to the participants’ homes, remote monitoring visits, at-home weight and height assessments, and at-home or in-clinic safety assessments. In general, there was minimal impact of the SARS-CoV-2 pandemic on the conduct of this study. The implementation of social distancing measures and mask use during the pandemic was associated with a reduction in the incidence of pulmonary exacerbations in the CF population (32), which may have partially influenced some of the findings in the current study, including CFQ-R respiratory domain score, which has been shown to be correlated with pulmonary exacerbations (33). Still, it is also important to note that both the pivotal 24-week parent study and this extension study partially overlapped with the pandemic, and a further decline in the rate of pulmonary exacerbations was observed with extended ELX/TEZ/IVA treatment in the extension study.
In the first 96 weeks of this open-label extension study, treatment with ELX/TEZ/IVA was generally safe and well tolerated in children aged ⩾6 years with CF who have at least one F508del allele. The improvements in lung function, respiratory symptoms, CFTR function, and nutritional parameters seen in the 24-week pivotal trial were maintained for an additional 2 years. These results support the long-term safety profile and durable efficacy of ELX/TEZ/IVA in this pediatric population.
The authors thank the patients and their families for participating in this trial; Nathan Blow, Ph.D., of Vertex Pharmaceuticals, who may own stock or options in the company, for providing medical writing and editorial support under the guidance of the authors; and Rosalba Satta, Ph.D., of Complete HealthVizion, IPG Health Medical Communications, for providing project management support and Adam Paton, B.A., of Complete HealthVizion, IPG Health Medical Communications, for providing editing support under the guidance of the authors and with support from the study sponsors.
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Supported by Vertex Pharmaceuticals grant VX19-445-107; and the National Institute for Health Research through a Senior Investigator Award, the Imperial Biomedical Research Centre, and the Brompton Clinical Research Facility (J.C.D.).
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. C.W., T.W., and J.C.D. 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 the health of people with cystic fibrosis. 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 [email protected] 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.202301-0021OC on May 8, 2023