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Corresponding author: Tim Lee, Clinical Associate Professor, Head of Studies, Postgraduate Programmes in Child Health, University of Leeds, Leeds Regional Paediatric Cystic Fibrosis Centre, A Floor, Clarendon Wing, Leeds Children's Hospital, Great George Street LS1 3EX, United Kingdom, Tel: +44 113 3927125.
We analyzed the impact of ELX/TEZ/IVA on rate of lung function decline over time.
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On average, there was no lung function loss over the 2-year period with ELX/TEZ/IVA.
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Mean annualized rate of change in ppFEV1 with ELX/TEZ/IVA was +0.39 percentage points.
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Mean annualized rate of change in ppFEV1 in controls was –1.92 percentage points.
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ELX/TEZ/IVA is the first CFTR modulator shown to halt lung function decline.
ABSTRACT
Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) with ≥ 1 F508del-CFTR allele in Phase 3 clinical trials. ELX/TEZ/IVA treatment led to improved lung function, with increases in percent predicted forced expiratory volume in 1 second (ppFEV1) and Cystic Fibrosis Questionnaire-Revised respiratory domain score. Here, we evaluated the impact of ELX/TEZ/IVA on the rate of lung function decline over time by comparing changes in ppFEV1 in participants from the Phase 3 trials with a matched group of people with CF from the US Cystic Fibrosis Foundation Patient Registry not eligible for cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Participants treated with ELX/TEZ/IVA had on average no loss of pulmonary function over a 2-year period (mean annualized rate of change in ppFEV1, +0.39 percentage points [95% CI, −0.06 to 0.85]) compared with a 1.92 percentage point annual decline (95% CI, −2.16 to −1.69) in ppFEV1 in untreated controls. ELX/TEZ/IVA is the first CFTR modulator therapy shown to halt lung function decline over an extended time period.
Progressive lung function decline is a hallmark of cystic fibrosis (CF), with most patients experiencing a decline in percent predicted forced expiratory volume in 1 second (ppFEV1) of 1 to 3 percentage points annually [
]. More rapid decline is associated with more severe CF lung disease and earlier mortality; therefore, preserving lung function is a primary goal of CF clinical care [
Previous studies indicated that patients treated with the CF transmembrane conductance regulator modulators (CFTRm) ivacaftor (IVA), lumacaftor (LUM)/IVA, and tezacaftor (TEZ)/IVA had reduced rates of lung function decline—47.1%, 41.9%, and 61.5%, respectively—compared with CFTRm-untreated controls [
Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study.
Long-term safety and efficacy of tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study.
]. A triple combination regimen of elexacaftor (ELX)/TEZ/IVA was shown to be safe and efficacious in patients aged ≥12 years with CF and heterozygous for F508del-CFTR and a minimal function mutation (F/MF genotypes; Study 445–102) or homozygous for F508del-CFTR (F/F genotype; Study 445–103) [
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.
Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one F508del allele: 144-week interim results from an open-label extension study.
To further characterize the impact of ELX/TEZ/IVA on lung function decline over time, we compared the annualized rate of change in ppFEV1 in patients treated with ELX/TEZ/IVA with a propensity score–matched historical cohort of CFTRm-untreated controls from the US Cystic Fibrosis Foundation Patient Registry (CFFPR).
2. Methods
Patients who received ELX/TEZ/IVA in the phase 3 clinical studies 445–102 (NCT03525444) and 445–103 (NCT03525548) or open-label extension study 445–105 (NCT03525574) and had ≥3 ppFEV1 measurements over ≥6 months were propensity score matched with up to 5 patients from the CFFPR aged ≥12 years with F/MF or F/F genotypes using methods described in previous studies of IVA, LUM/IVA, and TEZ/IVA [
Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study.
Long-term safety and efficacy of tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study.
]. Eligibility criteria were applied to the registry population to mimic the clinical trial eligibility criteria. Patients in the US CFFPR were required to be ≥12 years old, have an F/MF or F/F genotype, have no evidence of CFTRm use during either the baseline year or the analysis period, have ≥3 non-missing FEV1 records spanning ≥6 months through the 2-year follow-up period, and have at least one “stable” encounter in the baseline year with valid nutritional and pulmonary function test data.
Data from 2015 to 2017 were used for F/MF controls to avoid possible ELX/TEZ/IVA use in clinical trials or expanded access programs. Data from 2012 to 2014 were used for F/F controls to avoid LUM/IVA eligibility. Patients treated with ELX/TEZ/IVA with F/MF genotypes were matched with CFTRm-untreated patients with F/MF genotypes; patients with the F/F genotype were matched with CFTRm-untreated patients with the F/F genotype. Two logistic regression models were developed, one for each genotype, which included the same set of candidate variables for propensity score matching known to predict lung function decline and used in prior rate of change analyses [
Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study.
Long-term safety and efficacy of tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study.
] (Table S1 and S2). Backwards stepwise selection was implemented with a statistical significance threshold of 0.20 to identify predictor variables of ELX/TEZ/IVA exposure (ELX/TEZ/IVA patient vs CFFPR control). The two final models with variables identified from backwards stepwise selection were used to generate propensity scores for each patient. A match was identified if patients belonged to the same age and ppFEV1 category and were within 0.5 standard deviations (SD) of the logit propensity score caliper.
The annualized mean rate of change in ppFEV1 was estimated with a mixed model using all available ppFEV1 measures through up to 120 weeks, excluding measures during the first 21 days of ELX/TEZ/IVA to avoid inclusion of acute lung function improvement. The primary analysis included all matched patients with F/F or F/MF genotypes; subgroup analyses by genotype were also conducted. Estimation and significance testing were conducted using a mixed model, with random intercepts and slopes for each patient-within-match group and unstructured covariance. The model included fixed effects for treatment group (ELX/TEZ/IVA or control), time, and a treatment-group-by-time interaction.
3. Results
3.1 Participant population
A total of 468 patients treated with ELX/TEZ/IVA (n = 367 F/MF; n = 101 F/F) were matched with 1714 CFTRm-untreated controls (n = 1242 F/MF; n = 472 F/F). ELX/TEZ/IVA and CFTRm-untreated control groups were well balanced across baseline characteristics after matching; baseline mean ppFEV1 was 61.05 percentage points (SD, 15.69) in the ELX/TEZ/IVA group and 62.60 percentage points (SD, 9.61) in the control group (Table 1).
Table 1Demographic and Clinical Characteristics at Baseline.
Characteristic
ELX/TEZ/IVA (N = 468)
Control (NW = 468; N = 1714)
Age, mean ± SD, years
26.41 ± 10.66
25.77 ± 5.65
Age ≥18 years, n (%)
342 (73.1)
342 (73.1)
Female, n (%)
232 (49.6)
231 (49.4)
Race, n (%)
White
436 (93.2)
439 (93.7)
Black
4 (0.9)
8 (1.7)
Other
28 (6.0)
22 (4.6)
Ethnicity, n (%)
Hispanic
20 (4.3)
23 (4.9)
Not Hispanic
426 (91.0)
427 (91.2)
Not reported
22 (4.7)
18 (3.9)
CF-related diabetes, n (%)
158 (33.8)
154 (32.9)
Height-for-age z-score, mean ± SD
−0.44 ± 0.97
−0.49 ± 0.53
Weight-for-age z-score, mean ± SD
−0.37 ± 0.96
−0.40 ± 0.57
BMI-for-age z-score, mean ± SD
−0.24 ± 0.92
−0.24 ± 0.53
BMI, mean ± SD, kg/m2
21.57 ± 3.17
21.65 ± 1.92
Percent predicted FEV1, mean ± SD
61.05 ± 15.69
62.60 ± 9.61
Percent predicted FEV1 group, n (%)
<40
49 (10.5)
49 (10.5)
40–70
267 (57.1)
267 (57.1)
>70
152 (32.5)
152 (32.5)
Percent predicted FEV1 decile, mean ± SD
6.57 ± 2.12
6.67 ± 1.16
Percent predicted FVC, mean ± SD
76.51 ± 14.35
77.83 ± 9.26
Percent predicted FEF25–75, mean ± SD
37.67 ± 20.66
39.47 ± 11.83
Percent predicted FEV1/FVC ratio, mean ± SD
78.88 ± 11.01
79.66 ± 6.61
Tobramycin solution for inhalation, n (%)
92 (19.7)
138 (29.4)
Colistin, n (%)
23 (4.9)
26 (5.5)
Aztreonam, n (%)
83 (17.7)
103 (22.0)
Dornase alfa, n (%)
400 (85.5)
407 (87.0)
Acetylcysteine, n (%)
6 (1.3)
8 (1.6)
Oral corticosteroid, n (%)
17 (3.6)
18 (3.9)
Inhaled corticosteroid, n (%)
194 (41.5)
165 (35.2)
Leukotriene modifiers, n (%)
90 (19.2)
105 (22.4)
Hypertonic saline, n (%)
338 (72.2)
342 (73.0)
Azithromycin, n (%)
259 (55.3)
266 (56.8)
MRSA, n (%)
109 (23.3)
136 (29.0)
MSSA, n (%)
152 (32.5)
186 (39.8)
Hemophilus influenzae, n (%)
50 (10.7)
56 (12.0)
Pseudomonas aeruginosa, n (%)
334 (71.4)
326 (69.7)
Alcaligenes, n (%)
53 (11.3)
60 (12.8)
Stenotrophomonas, n (%)
92 (19.7)
99 (21.1)
Aspergillus, n (%)
174 (37.2)
157 (33.6)
Nontuberculosis mycobacterium, n (%)
5 (1.1)
9 (1.9)
BMI: body mass index; CF: cystic fibrosis; ELX/TEZ/IVA: elexacaftor/tezacaftor/ivacaftor; FEF25–75: forced expiratory flow at 25% and 75% of pulmonary volume; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; MRSA: methicillin-resistant Staphylococcus aureus; MSSA: methicillin-susceptible Staphylococcus aureus; NW: weighted sample size of the control group using the inverse of the number of controls in each matched set to account for one-to-many matching used in the analysis; SD, standard deviation. A match was identified if patients belonged to the same age and ppFEV1 category and were within 0.5 SD of the logit propensity score caliper. Match quality was assessed by calculating the weighted effect sizes of all candidate variables separately as well as by identifying any statistically significant differences; a weighted effect size of <0.20 was deemed acceptable.
Patients treated with ELX/TEZ/IVA had a mean annualized rate of change in ppFEV1 of +0.39 percentage points (95% CI, −0.06 to 0.85) compared with −1.92 percentage points (95% CI, −2.16 to −1.69) in matched controls (mean difference, 2.32 percentage points; P<0.001) (Fig 1a). The between-group difference in ppFEV1 was 16.91 percentage points (95% CI, 15.56 to 18.27; P<0.001) at year 2.
Fig 1Estimation of the annualized slope for ppFEV1 in (A) all patients with F/MF and F/F genotypes, (B) patients with F/MF genotypes, and (C) patients with the F/F genotype. Start of analysis was defined as >21 days after ELX/TEZ/IVA initiation to remove the acute lung function improvement due to ELX/TEZ/IVA from the calculation of rate of ppFEV1 change. Patients were matched on demographic and clinical characteristics at baseline. Estimation and significance testing were conducted using a mixed model, with random intercepts and slopes for each patient-within-match group and unstructured covariance. The model included fixed effects for treatment group (ELX/TEZ/IVA or control), time, and a treatment-group-by-time interaction. Patients with the F/F genotype treated with ELX/TEZ/IVA had a 4-week run-in period with TEZ/IVA prior to baseline; patients were matched on the baseline ppFEV1, which reflects the acute benefits of TEZ/IVA. Reduction in the rate of lung function decline is calculated as the percent difference between the ELX/TEZ/IVA-treated and matched control slopes. Because patients treated with ELX/TEZ/IVA had on average no decrease in ppFEV1 over the 2-year period, the reduction in rate of decline is calculated as >100% (120.3%; 95% CI, 96.8%−144.4%). ELX: elexacaftor; F/F: homozygous for the F508del-CFTR mutation; F/MF: heterozygous for F508del-CFTR and a minimal function mutation; IVA: ivacaftor; ppFEV1: percent predicted forced expiratory volume in 1 second; TEZ: tezacaftor.
Fig 1Estimation of the annualized slope for ppFEV1 in (A) all patients with F/MF and F/F genotypes, (B) patients with F/MF genotypes, and (C) patients with the F/F genotype. Start of analysis was defined as >21 days after ELX/TEZ/IVA initiation to remove the acute lung function improvement due to ELX/TEZ/IVA from the calculation of rate of ppFEV1 change. Patients were matched on demographic and clinical characteristics at baseline. Estimation and significance testing were conducted using a mixed model, with random intercepts and slopes for each patient-within-match group and unstructured covariance. The model included fixed effects for treatment group (ELX/TEZ/IVA or control), time, and a treatment-group-by-time interaction. Patients with the F/F genotype treated with ELX/TEZ/IVA had a 4-week run-in period with TEZ/IVA prior to baseline; patients were matched on the baseline ppFEV1, which reflects the acute benefits of TEZ/IVA. Reduction in the rate of lung function decline is calculated as the percent difference between the ELX/TEZ/IVA-treated and matched control slopes. Because patients treated with ELX/TEZ/IVA had on average no decrease in ppFEV1 over the 2-year period, the reduction in rate of decline is calculated as >100% (120.3%; 95% CI, 96.8%−144.4%). ELX: elexacaftor; F/F: homozygous for the F508del-CFTR mutation; F/MF: heterozygous for F508del-CFTR and a minimal function mutation; IVA: ivacaftor; ppFEV1: percent predicted forced expiratory volume in 1 second; TEZ: tezacaftor.
For the F/MF subgroup, the estimated annualized rate of change in ppFEV1 was +0.32 percentage points (95% CI, −0.19 to 0.82) with ELX/TEZ/IVA compared with −1.85 percentage points (95% CI, −2.13 to −1.58) in CFTRm-untreated controls (mean difference, 2.17 percentage points; P<0.001) (Fig 1b). Similarly, for the F/F subgroup, the estimated annualized rate of change in ppFEV1 was +0.74 percentage points (95% CI, −0.28 to 1.75) with ELX/TEZ/IVA compared with −2.08 percentage points (95% CI, −2.54 to −1.63) in CFTRm-untreated controls (mean difference, 2.82 percentage points; P<0.001) (Fig 1c).
4. Discussion and conclusions
We analyzed rates of lung function decline in patients with F/F and F/MF genotypes treated with ELX/TEZ/IVA in the pivotal clinical trials compared with CFTRm-untreated matched controls from the CFFPR. While previous studies demonstrated that CFTRm can slow rates of lung function decline [
Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study.
Long-term safety and efficacy of tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study.
], patients treated with ELX/TEZ/IVA had on average no loss of pulmonary function over a 2-year period (mean annualized rate of change in ppFEV1, +0.39 percentage points) compared with a 1.92 percentage point annual decline in ppFEV1 in CFTRm-untreated controls. Subgroup analyses showed that both genotype groups had on average no loss of ppFEV1 over the 2-year period.
This study has several limitations. The use of noncontemporaneous controls may introduce temporal bias due to changes in clinical care. Although propensity score matching was used to reduce bias by balancing the risk factors for lung function decline between groups, a sensitivity analysis was conducted to evaluate any remaining bias related to the use of noncontemporaneous controls. In this analysis, patients with the F/F genotype treated with ELX/TEZ/IVA were matched with the more recent cohort of patients with F/MF genotypes (2015–2017); results were consistent with the F/F–specific analysis, suggesting limited impact of noncontemporaneous controls (data not shown). Patients with the F/F genotype in the ELX/TEZ/IVA trial may have been exposed to CFTRm prior to enrollment and during a 4-week run-in with TEZ/IVA; therefore, baseline characteristics used for matching (e.g., ppFEV1) may reflect benefits of CFTRm treatment. Matching on factors known to predict future lung function decline was expected to address differences in treatment history; however, this assumption could not be tested. Data on education and insurance were not collected in clinical trials and therefore were not included in the propensity score model. Twenty-one patients with F/MF genotypes treated with ELX/TEZ/IVA could not be matched with CFTRm-untreated controls. While these patients were generally younger with more severe disease burden, sensitivity analyses confirmed that their exclusion had no material impact on results. Finally, portions of the open-label extension study that provided data for the current analysis occurred during the COVID-19 global pandemic, when social distancing and mask use likely led to a decline in pulmonary exacerbations [
]; the impact on the estimated rate of change in ppFEV1 in the present analysis is unknown.
ELX/TEZ/IVA is the first CF therapy shown to halt lung function decline over an extended follow-up period of 2 years, suggesting that ELX/TEZ/IVA treatment has a significant impact on the progression and trajectory of CF lung disease.
Funding
This work was supported by Vertex Pharmaceuticals Incorporated.
Conflicts of interest statement
All authors received nonfinancial assistance (assistance with manuscript preparation) from ArticulateScience, LLC, which was funded by Vertex Pharmaceuticals Incorporated. Additional disclosures are as follows: TL reports participation on a data safety monitoring board for AlgiPharma outside the submitted word and is a member of the steering committee and protocol review committee for the European Cystic Fibrosis Society (ECFS) Clinical Trial Network. GSS reports grants to his institution for clinical trials, consulting fees, and payment or honoraria for a webinar from Vertex Pharmaceuticals. JA has nothing further to disclose. SJM is a former employee and consultant of ICON plc. ICON plc received payments from Vertex Pharmaceuticals related to the submitted work and received payments, grants, and travel support from various other pharmaceutical, biotechnology, and device companies outside the submitted work. JMG, MTJ, YY, LJM, and KVB are employees of Vertex Pharmaceuticals and may own stock or stock options in that company. RWL reports consulting fees from Vertex Pharmaceuticals; grants to her institution from Vertex Pharmaceuticals and the US Cystic Fibrosis Foundation; and uncompensated participation on advisory boards for Vertex Pharmaceuticals.
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 [email protected] if you would like to submit a proposal or need more information. The US Cystic Fibrosis Foundation Patient Registry collects and manages its own data and maintains processes for researchers to request summarized data (https://www.cff.org/researchers/patient-registry-data-requests).
CRediT authorship contribution statement
Tim Lee: Investigation, Writing – original draft, Writing – review & editing, Visualization, Supervision. Gregory S. Sawicki: Conceptualization, Writing – review & editing, Visualization. Josje Altenburg: Conceptualization, Writing – original draft, Writing – review & editing, Visualization. Stefanie J. Millar: Conceptualization, Methodology, Software, Validation, Formal analysis, Resources, Data curation, Writing – review & editing. Jessica Morlando Geiger: Methodology, Resources, Writing – original draft, Writing – review & editing, Supervision, Project administration. Mark T. Jennings: Conceptualization, Methodology, Investigation, Writing – review & editing, Supervision, Project administration. Yiyue Lou: Conceptualization, Methodology, Writing – review & editing. Lisa J. McGarry: Conceptualization, Methodology, Writing – review & editing, Visualization, Supervision, Project administration. Kate Van Brunt: Conceptualization, Methodology, Writing – review & editing, Visualization, Supervision, Project administration. Rachel W. Linnemann: Conceptualization, Methodology, Investigation, Writing – review & editing.
Acknowledgments
We thank the patients and their families for participating in the 445–102, 445–103, and 445–105 trials; all site trial investigators and coordinators for their support of the trial sites; the Cystic Fibrosis Foundation for the use of CFFPR data to conduct this study; the patients, care providers, and clinic coordinators at CF centers throughout the United States for their contributions to the CFFPR; Nathan Blow, PhD, of Vertex Pharmaceuticals, who may own stock or stock options in the company, for providing medical writing support under the guidance of the authors; and ArticulateScience, LLC for providing editorial assistance under the guidance of the authors with support from Vertex Pharmaceuticals.
Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study.
Long-term safety and efficacy of tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study.
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.
Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one F508del allele: 144-week interim results from an open-label extension study.
Data from this study were presented at the following meeting: 45th Annual European Cystic Fibrosis Conference (ECFS), 8–11 June 2022, Rotterdam, the Netherlands
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