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Person-level simulation model of CFTR modulator impact on long-term health outcomes.
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Projected survival for people with CF treated with ELX/TEZ/IVA was 71.6 years.
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Projected survival was 82.5 years when ELX/TEZ/IVA was initiated at age 12–17 years.
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ELX/TEZ/IVA reduced disease severity, pulmonary exacerbations, and lung transplants.
Abstract
Background
A series of phase 3 clinical trials have demonstrated that elexacaftor plus tezacaftor plus ivacaftor (ELX/TEZ/IVA) is safe and efficacious in people with cystic fibrosis (pwCF) aged ≥12 years with ≥1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The impact of this treatment on lifetime clinical outcomes and survival, however, has yet to be assessed.
Methods
We used a person-level microsimulation model to estimate the survival and lifetime clinical benefits of ELX/TEZ/IVA treatment versus other CFTR modulator combinations (tezacaftor plus ivacaftor [TEZ/IVA] or lumacaftor plus ivacaftor [LUM/IVA]) or best supportive care (BSC) alone in pwCF aged ≥12 years who are homozygous for F508del-CFTR. Disease progression inputs were derived from published literature; clinical efficacy inputs were derived from an indirect treatment comparison conducted using relevant phase 3 clinical trial data and extrapolations of clinical data.
Results
The median projected survival for pwCF homozygous for F508del-CFTR treated with ELX/TEZ/IVA was 71.6 years. This was an increase of 23.2 years versus TEZ/IVA, 26.2 years versus LUM/IVA, and 33.5 years versus BSC alone. Treatment with ELX/TEZ/IVA also reduced disease severity as well as the number of pulmonary exacerbations and lung transplants. In a scenario analysis, the median projected survival for pwCF initiating ELX/TEZ/IVA between the ages of 12 and 17 years was 82.5 years, an increase of 45.4 years compared with BSC alone.
Conclusions
The results from our model suggest ELX/TEZ/IVA treatment may substantially increase survival for pwCF, with early initiation potentially allowing pwCF to achieve near-normal life expectancy.
]. CF is a chronic, multisystemic disease that is associated with severe symptom burden, frequent complications and hospitalizations, and premature mortality [
Existing treatments for CF are broadly classified as either supportive care, in which CF-related symptoms and complications (e.g., physical airway clearance therapy, bronchodilators, inhaled mucolytics, and antibiotics) are managed, or CFTR modulator therapy, in which small molecules target the underlying cause of the disease [
]. CFTR modulators represent a major advance in the treatment of CF by providing significant improvements in pulmonary and extrapulmonary outcomes, and modifying the course of disease by slowing progression and improving survival relative to supportive care alone [
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.
Real-world outcomes among patients with cystic fibrosis treated with lumacaftor/ivacaftor (LUM/IVA) in 2017: an interim analysis of data from the US CF Foundation Patient Registry (CFFPR).
]. Current CFTR modulators include potentiators, such as ivacaftor (IVA), that enhance channel gating, and correctors, such as lumacaftor (LUM), tezacaftor (TEZ), and elexacaftor (ELX), that improve CFTR protein processing and trafficking [
]. The CFTR dual modulator combinations LUM plus IVA (LUM/IVA) and TEZ plus IVA (TEZ/IVA) have been shown to be safe and effective in treating pwCF homozygous for the F508del-CFTR genotype (i.e., with two F508del-CFTR alleles), which is the most common form of CFTR mutation among pwCF.
More recently, a triple-combination regimen of ELX plus TEZ plus IVA (ELX/TEZ/IVA) was shown to be highly efficacious and safe in pwCF with at least one F508del allele, which includes the population homozygous for F508del-CFTR [
Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.
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.
]. Across several phase 3 clinical trials, ELX/TEZ/IVA has demonstrated meaningful and unprecedented clinical benefits for pwCF, including significant improvements in lung function, respiratory symptoms, nutritional status, and health-related quality of life, as well as substantial reductions in the frequency of pulmonary exacerbations (PEx) [
Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.
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.
]. These clinical benefits have exceeded those reported with other CFTR modulator combinations, including TEZ/IVA, for pwCF homozygous for F508del-CFTR [
Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.
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.
]. Notably, a recent open-label study concluded that the rapid, robust, and clinically meaningful improvements in lung function achieved with ELX/TEZ/IVA were maintained for up to 2 years of continued use [
Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one F508del allele: 96-week interim results from an open-label extension study.
Poster 681 presented at the 35th Annual North American Cystic Fibrosis Conference (Virtual), November 2–5. 2021
Due to its relatively recent regulatory approval and availability, the impact of ELX/TEZ/IVA on the lifetime survival of pwCF has not yet been evaluated. Here, we developed an individual person-level microsimulation model to estimate the effects of ELX/TEZ/IVA plus current best supportive care (BSC) versus other CFTR modulators (TEZ/IVA, LUM/IVA) plus BSC and BSC alone on survival and other relevant clinical outcomes in pwCF aged ≥12 years homozygous for F508del-CFTR.
2. Methods
2.1 Model overview
A person-level microsimulation model was developed to estimate the lifetime clinical outcomes and survival of pwCF aged ≥12 years and homozygous for F508del-CFTR in the UK. The modeled interventions included ELX/TEZ/IVA, TEZ/IVA, and LUM/IVA, each in combination with BSC, as well as BSC alone. The model framework and underlying survival calculation approach were aligned with those of a previously published model used to predict the long-term clinical outcomes of pwCF in the US treated with LUM/IVA [
Validation of modeled 5-year survival outcomes among patients with cystic fibrosis (CF) treated with the CF transmembrane conductance regulator modulator (CFTRM) ivacaftor using US CF Foundation Patient Registry (USCFFPR) data.
]. After calibration, 5-year mortality projections from the model closely approximated mortality observed in the study, confirming the model's ability to make accurate long-term projections of CF population survival and the impact of CFTR modulator therapies.
The model used in the current study tracked both disease progression and CFTR modulator treatment benefits for simulated individuals over a lifetime horizon (Fig. 1). Four cohorts of 2000 simulated pwCF were generated and assigned treatment with either ELX/TEZ/IVA, TEZ/IVA, LUM/IVA, or BSC alone. All cohorts used the same set of 2000 simulated individuals, ensuring any differences in modeled outcomes between cohorts were attributable to the treatment received rather than differences in baseline characteristics.
Fig. 1Simulation model structure.
Abbreviations: BSC = best supportive care; ELX/TEZ/IVA = elexacaftor plus tezacaftor plus ivacaftor; LUM/IVA = lumacaftor plus ivacaftor; TEZ/IVA = tezacaftor plus ivacaftor.
A baseline survival probability was assigned to each simulated individual based on age-specific mortality derived from the 2008 UK Cystic Fibrosis Registry, which represents the survival of a CFTR modulator-naive CF population in the UK. Over the individual's modeled lifetime, their survival probability was continuously updated using a Cox proportional hazards model that links survival in pwCF to demographics and clinical characteristics including age, sex, percent predicted forced expiratory volume in 1 second (ppFEV1), annual number of PEx requiring hospitalization and/or treatment with intravenous antibiotics, weight-for-age z-score (WFAZ), and CF-related diabetes (CFRD) [
]. This allowed survival to be influenced by clinical characteristics as they evolved over time. (See Supplementary Fig. S1 and Table S1 for additional details on the model mortality calculations.) Survival differences between the treatment cohorts were driven by differences in ppFEV1, annual number of PEx, and WFAZ, as CFTR modulator treatment has been shown to impact on these three characteristics based on the available clinical evidence. Treatment efficacy inputs for these three characteristics were derived from the relevant CFTR modulator clinical trials, the longer-term open-label extension studies, and extrapolations of clinical data.
2.2 Model inputs
2.2.1 Baseline characteristics
Baseline clinical characteristics were derived from individual person-level baseline data collected from phase 3 clinical trials of CFTR modulators conducted in pwCF aged ≥12 years who were homozygous for F508del-CFTR and naive to CFTR modulator treatment at baseline (Table S2) [
]. Each individual was randomly assigned a CFRD status (diabetic/non-diabetic) based on the age-specific prevalence reported in the 2019 UK Cystic Fibrosis Registry [
Based on extensive evidence documenting disease progression in pwCF, the model estimated the lifetime decline in lung function, occurrence of PEx and lung transplantation, and development of CFRD in the absence of CFTR modulation for each simulated individual over time. Age-specific estimates of annual ppFEV1 decline were based on rates observed in a retrospective cohort study of pwCF homozygous for F508del-CFTR [
]. The model predicted the occurrence of PEx based on age and ppFEV1 using a published mathematic relationship in which the annual rate of PEx was found to increase with lower ppFEV1 [
Consistent with clinical guidelines and observed transplantation rates among pwCF in the UK, the model assumed 24.5% of simulated individuals whose ppFEV1 dropped below 30 would receive a lung transplant [
The American Society for Transplant Physicians (ASTP)/American Thoracic Society (ATS)/European Respiratory Society (ERS)/International Society for Heart and Lung Transplantation (ISHLT) International guidelines for the selection of lung transplant candidates.
]. The risk for developing CFRD was conservatively assumed to be equal for individuals receiving a CFTR modulator and those receiving BSC alone, although several long-term studies have shown reductions in the incidence of diabetes with CFTR modulator use [
Real-world outcomes among patients with cystic fibrosis treated with lumacaftor/ivacaftor (LUM/IVA) in 2017: an interim analysis of data from the US CF Foundation Patient Registry (CFFPR).
The microsimulation model required placebo-adjusted estimates of clinical efficacy for CFTR modulators because the assignment of baseline survival probability was based on a CFTR modulator-naive population. In the absence of a placebo control group in the clinical trials of ELX/TEZ/IVA conducted in pwCF homozygous for F508del-CFTR, an indirect treatment comparison was conducted to estimate placebo-adjusted efficacy to inform model inputs. A detailed description of the methodology, including an illustration of the network used to conduct the analysis, and the associated results are provided in the Supplementary Materials (Fig. S2 and Table S3).
Simulated individuals receiving a CFTR modulator were assumed to experience an acute increase in ppFEV1 and WFAZ over the first 24 weeks of the model simulation, to reflect the improvements observed in phase 3 clinical trials [
Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.
]. Model inputs were based on statistically significant placebo-adjusted estimates of change from baseline derived from the indirect treatment comparison (Table 1) [
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 elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.
The American Society for Transplant Physicians (ASTP)/American Thoracic Society (ATS)/European Respiratory Society (ERS)/International Society for Heart and Lung Transplantation (ISHLT) International guidelines for the selection of lung transplant candidates.
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.
The American Society for Transplant Physicians (ASTP)/American Thoracic Society (ATS)/European Respiratory Society (ERS)/International Society for Heart and Lung Transplantation (ISHLT) International guidelines for the selection of lung transplant candidates.
Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.
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.
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.
Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.
Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.
In the model, the annual decline in lung function was set to begin after week 24. For simulated individuals treated with a CFTR modulator, a percent reduction was applied to the rates of decline in ppFEV1 observed among untreated individuals in order to capture the effect of CFTR modulators on long-term disease progression. The treatment effects for LUM/IVA and TEZ/IVA (42.0% and 61.5% reduction in the rate of ppFEV1 decline, respectively) were based on published analyses comparing pwCF treated in clinical studies for up to 120 weeks with untreated matched control participants [
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.
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.
]. In a similar matched analysis, pwCF treated with ELX/TEZ/IVA demonstrated no loss of lung function on average over a 2-year treatment period, in contrast to declines observed in untreated matched control participants (i.e., 100% reduction in the rate of ppFEV1 decline) [
]. To conservatively allow for some lung function decline over time, a 90% reduction in the rate of ppFEV1 decline was applied to simulated individuals treated with ELX/TEZ/IVA.
Simulated individuals treated with a CFTR modulator were also assumed to experience a reduction in the rate of PEx based on the treatment effect observed in the relevant clinical trials and open-label extension studies (Table 1). Because the active-controlled clinical trials of ELX/TEZ/IVA in pwCF homozygous for F508del-CFTR did not include PEx as an efficacy endpoint, the treatment effect for the model was derived from the pivotal trial of ELX/TEZ/IVA in pwCF with a single F508del-CFTR allele [
Rates of CFTR modulator discontinuation for the first 24 weeks of the model simulation were based on attrition reported in the relevant phase 3 clinical trials (Table 1) [
Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.
]. Upon discontinuation, simulated individuals were assumed to receive no further benefit of CFTR modulator treatment and to experience the same disease progression (e.g., ppFEV1 decline, rate of PEx) as those receiving BSC alone (i.e., no reductions applied).
2.3 Model analyses
2.3.1 Base case analysis
The model input parameters used in the base case analysis are described in Table 1. Model outputs included median predicted survival, mean residual life-years (years alive in the simulation), proportion of life-years spent at varying levels of disease severity, mean change from baseline in ppFEV1, total number and annual rate of PEx, and the proportion of simulated individuals who receive a lung transplant and mean time to transplantation among those transplanted. Outputs were generated for each treatment cohort. Probabilistic sensitivity analyses were used to generate 95% credible intervals (Bayesian 95% confidence intervals [CIs]) on the point estimates of incremental median predicted survival (Supplementary Table S4). See Supplementary Materials for methods and other results of the sensitivity analyses (Figs. S3–S8).
2.3.2 Scenario analyses
Three scenario analyses were performed to investigate the impact of key model assumptions on survival outcomes: 1) using age-specific cohorts (i.e., simulated individuals entering the model at the ages of 12–17, 18–25, and ≥25 years); 2) varying the long-term impact of ELX/TEZ/IVA on lung function decline from 80% to 100%; 3) using a 10-year model time horizon.
3. Results
3.1 Base case analysis
The projected survival curves for pwCF aged ≥12 years who are homozygous for F508del-CFTR and are treated with ELX/TEZ/IVA, TEZ/IVA, LUM/IVA, or BSC alone are shown in Fig. 2. The median projected survival for the cohort of individuals treated with BSC alone was 38.1 years (95% CI: 36.3, 40.6), approximately 45 years less than the life expectancy for the general UK population (approximately 83 years) [
]. The median projected survival for the cohort treated with ELX/TEZ/IVA was 71.6 years (95% CI: 58.9, 77.2); this was an increase of 33.5 years (95% CI: 20.8, 39.5) versus BSC alone, 26.2 years (95% CI: 12.9, 32.9) versus LUM/IVA, and 23.2 years (95% CI: 9.3, 30.4) versus TEZ/IVA.
Fig. 2Projected survival for pwCF homozygous for F508del-CFTR who receive ELX/TEZ/IVA, TEZ/IVA, LUM/IVA, or BSC alone (base case analysis).
Abbreviations: BSC = best supportive care; CFTR = cystic fibrosis transmembrane conductance regulator; ELX/TEZ/IVA = elexacaftor plus tezacaftor plus ivacaftor; LUM/IVA = lumacaftor plus ivacaftor; pwCF = people with cystic fibrosis; TEZ/IVA = tezacaftor plus ivacaftor.
. Curves for BSC alone and CFTR modulators were estimated by applying the Kaplan–Meier product limit formula to the simulation results (see Supplementary Materials).
In addition to increasing overall survival, treatment with ELX/TEZ/IVA was associated with substantial improvements in other key clinical outcomes (Table 2). The model predicted that individuals homozygous for F508del-CFTR receiving ELX/TEZ/IVA would spend more of their lifetime with higher lung function versus those receiving BSC alone (50.5% of life-years spent with mild disease vs only 7.0% for those treated with BSC alone) and substantially less time with severe lung disease (0.8% of life-years vs 46.8% for BSC alone). Despite additional years of survival, the model predicted individuals homozygous for F508del-CFTR receiving ELX/TEZ/IVA would have 13 fewer PEx over a lifetime compared with individuals receiving BSC alone. The model also predicted that treatment with ELX/TEZ/IVA would substantially decrease the need for lung transplantation, with 0.1% of the ELX/TEZ/IVA cohort receiving a lung transplant versus 9.6% of the BSC-alone cohort, and double the time to the procedure among those transplanted (24.5 vs 12.0 years, respectively).
Table 2Projected lifetime clinical outcomes for pwCF treated with ELX/TEZ/IVA, TEZ/IVA, LUM/IVA, or BSC alone (base case analysis).
ELX/TEZ/IVA
TEZ/IVA
LUM/IVA
BSC
Median age of death, years (95% CI)
71.6 (58.9, 77.2)
48.5 (44.0, 54.2)
45.4 (42.6, 50.2)
38.1 (36.3, 40.6)
Mean age of death, years
67.4
49.8
46.3
38.9
Mean residual life-years
43.0
25.9
22.5
15.6
Proportion of life-years spent with ppFEV1, %
≥70%
50.5
13.7
10.0
7.0
≥40% to <70%
48.7
61.0
54.2
46.2
<40%
0.8
25.4
35.9
46.8
Mean change in ppFEV1, %
+5.7
−15.7
−21.2
−25.2
Total number of PEx
6.4
14.7
12.2
19.1
Annual rate of PEx, per person-year
0.15
0.59
0.57
1.35
Proportion undergoing lung transplant, %
0.1
5.3
8.0
9.6
Mean time to lung transplant among those transplanted, years
24.5
26.4
22.9
12.0
Abbreviations: BSC = best supportive care; CI = confidence interval; ELX/TEZ/IVA = elexacaftor plus tezacaftor plus ivacaftor; LUM/IVA = lumacaftor plus ivacaftor; PEx = pulmonary exacerbations; ppFEV1 = percent predicted forced expiratory volume in 1 second; pwCF = people with cystic fibrosis; TEZ/IVA = tezacaftor plus ivacaftor.
The model predicted that the clinical improvements provided by ELX/TEZ/IVA would also be substantially greater than those provided by TEZ/IVA and LUM/IVA (Table 2). ELX/TEZ/IVA was predicted to increase the proportion of life spent with mild lung disease (ppFEV1 ≥70%) more than threefold compared with the other CFTR modulator treatment options (3.7 times vs TEZ/IVA; 5.1 times vs LUM/IVA), and to reduce the annual rate of PEx by nearly 75%.
3.2 Scenarios analyses
Results from the age-specific baseline cohort scenarios indicated that initiating treatment with a CFTR modulator at younger ages would lead to greater survival benefits (Fig. 3). For all CFTR modulator combinations, the greatest survival benefit versus BSC alone was achieved when initiating treatment aged 12–17 years (mean age: 14.9 years), the youngest cohort studied here. Median projected survival for the cohort of individuals homozygous for F508del-CFTR initiating ELX/TEZ/IVA treatment aged 12–17 years was 82.5 years, which was a 45.4-year increase compared with the cohort treated with BSC alone. The median predicted survival increment with ELX/TEZ/IVA versus BSC alone was 40.2 years in the cohort initiating treatment aged 18–24 years and 21.0 years in those initiating treatment aged ≥25 years. Similar improvements were seen with ELX/TEZ/IVA versus TEZ/IVA and LUM/IVA (Fig. 3).
Fig. 3Median predicted survival with ELX/TEZ/IVA, TEZ/IVA, and LUM/IVA versus BSC alone, by age of treatment initiation.
Abbreviations: BSC = best supportive care; ELX/TEZ/IVA = elexacaftor plus tezacaftor plus ivacaftor; LUM/IVA = lumacaftor plus ivacaftor; TEZ/IVA = tezacaftor plus ivacaftor
Increasing the reduction in the rate of lung function decline with ELX/TEZ/IVA to 100% (indicating preserved lung function for the duration of the model horizon) increased the median projected survival for the cohort to 75.4 years, a 26.9-year increase over TEZ/IVA, 30.0-year increase over LUM/IVA, and 37.2-year increase over BSC alone (Figs. S3–S5). Decreasing the ELX/TEZ/IVA reduction in rate of decline to 80% still resulted in very meaningful survival benefits, with an 18.6-year increase in median survival versus TEZ/IVA, a 21.7-year increase versus LUM/IVA, and a 28.9-year increase versus BSC alone (Figs. S3–S5).
The scenario utilizing a shorter model horizon demonstrated the substantial clinical benefits achieved within the first 10 years of initiating CFTR modulator treatment (Table S5). After 10 years of treatment, a greater proportion of individuals in the ELX/TEZ/IVA cohort were alive (87%) compared with the TEZ/IVA (77%), LUM/IVA (75%), and BSC (64%) cohorts. The projected mean change in ppFEV1 from model baseline to 10 years was also substantially higher among those treated with ELX/TEZ/IVA (12.2 points higher than baseline) compared with BSC alone (13.9 points lower than baseline) and the other treatment cohorts (2.2 and 5.9 points lower than baseline with TEZ/IVA and LUM/IVA, respectively).
4. Discussion
The magnitude of improvements in clinical and patient-reported outcomes achieved with ELX/TEZ/IVA have established ELX/TEZ/IVA as a new benchmark for CFTR modulator therapy and the current standard of care for treating pwCF with at least one F508del-CFTR allele. Because lung function has been identified as a key predictor of long-term survival [
Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.
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.
] suggest that ELX/TEZ/IVA treatment may provide a lifetime therapeutic benefit for pwCF. We, therefore, set out to estimate the potential lifetime clinical benefits for pwCF aged ≥12 years and homozygous for F508del-CFTR treated with ELX/TEZ/IVA, as well as the incremental survival benefit over treatment with TEZ/IVA, LUM/IVA, or BSC alone. To do so, we used an adapted version of a well-established, validated, person-level simulation model that translates improvements in ppFEV1, PEx rate, and nutritional status observed with the use of CFTR modulators to long-term health outcomes.
The results of our simulation model illustrate the substantial long-term benefits that pwCF homozygous for F508del-CFTR may experience over a lifetime when treated with ELX/TEZ/IVA, including improved survival and reduced disease progression and severity. The median projected survival for pwCF homozygous for F508del-CFTR treated with ELX/TEZ/IVA was 71.6 years, which is a three-decade increase compared with survival in the absence of CFTR modulator treatment and more than two decades longer than with other available CFTR modulators. These estimates support the potential transformative effects on the health and well-being of pwCF provided by ELX/TEZ/IVA. Furthermore, ELX/TEZ/IVA is expected to decrease healthcare resource utilization based on the projected reductions in the rate of PEx requiring intravenous antibiotics and/or hospitalization and lung transplantation. Early real-world studies of ELX/TEZ/IVA have shown improvements in lung function that have been substantial enough to influence the status of individual patients in terms of lung transplant planning [
]. A number of planned and ongoing real-world studies have the potential to provide further evidence of the impact of ELX/TEZ/IVA on clinical and economic outcomes in the clinical practice setting.
The age-specific scenario analysis further demonstrates the potential survival benefit of ELX/TEZ/IVA treatment, as well as highlighting the importance of early treatment initiation. In the youngest simulated cohort (those aged 12–17 years), who have a higher ppFEV1 at baseline than older cohorts, the acute improvement in ppFEV1 paired with the long-term reduction in ppFEV1 decline provided by ELX/TEZ/IVA led to preserved lung function over the lifetime horizon, which translates into a maximized survival benefit. The median projected survival for this cohort was 82.5 years, which is more than double the survival in the cohort treated with BSC alone, approximately three decades longer than in the other CFTR modulator-treated cohorts, and nearly equivalent to the life expectancy of the general UK population [
]. These results contribute to accumulating evidence that early intervention in pwCF is associated with better outcomes later in life. The advent of newborn CF screening, which results in earlier initiation of effective treatment for asymptomatic pwCF, has been shown to prevent CF-related deaths in early childhood and lead to substantial and prolonged clinical benefits, including a reduced mortality risk [
]. Furthermore, access to routine care from multidisciplinary CF care teams in infants with CF has been suggested to be the reason for improved health benefits at older ages, including improved lung structure and function, growth, and survival [
]. The results of our simulation analysis further demonstrate that early intervention in a progressive disease such as CF is critical to minimizing functional loss and maximizing survival benefits. Further analyses are needed to quantify the potential additional benefit of ELX/TEZ/IVA therapy when initiated in pwCF aged 6–11 years who have at least one F508del-CFTR mutation, an age group for which ELX/TEZ/IVA therapy recently received regulatory approval.
The scenario evaluating a 10-year model horizon demonstrates the substantial near-term benefits that ELX/TEZ/IVA treatment may provide. In addition to increasing the proportion of pwCF homozygous for F508del-CFTR remaining alive at 10 years, there were considerable reductions in healthcare resource utilization over this time period, including substantially fewer hospitalizations and intravenous antibiotics required to treat PEx and a complete elimination of the need for lung transplantation. A Canadian modeling study published in 2021 also evaluated the potential impact of ELX/TEZ/IVA over a 10-year time horizon [
]. Compared with that study, our model generally produced a greater impact of ELX/TEZ/IVA on mortality (15% reduction in deaths in the Canadian study vs 64% estimated here) and other clinical outcomes. The magnitude of the difference is not unexpected given the Canadian analysis included all pwCF, including those who were not eligible for and did not receive ELX/TEZ/IVA treatment during the study period, and also assumed a substantially lower impact of ELX/TEZ/IVA on lung function decline over time (50% reduction), as the longer-term data on ELX/TEZ/IVA used in the current study were not available at the time of their analysis. Nonetheless, despite different methodologies, patient populations, and model input values, both analyses suggest immense benefits of ELX/TEZ/IVA treatment.
A limitation of our model structure is the use of a Cox proportional hazards equation, which was developed in a CFTR modulator-naive population to estimate the impact of clinical characteristics on survival, and not the impact of treatment, as attempted here [
]. However, the previous model validation demonstrates that changes in clinical outcomes as a result of CFTR modulator treatment can be combined with the Cox proportional hazard equation to generate plausible clinical predictions that match real-world survival benefits [
Validation of modeled 5-year survival outcomes among patients with cystic fibrosis (CF) treated with the CF transmembrane conductance regulator modulator (CFTRM) ivacaftor using US CF Foundation Patient Registry (USCFFPR) data.
]. While the aforementioned validation study encourages confidence in model projections, we further note that the available data for validation included only 5 years of follow-up in a US population of pwCF treated with a single CFTR modulator. Further validation and refinement of the model may be warranted as longer-term real-world data for additional CFTR modulators and broader populations become available.
Additionally, the simulation model can only evaluate variables selected for inclusion in the Cox proportional hazards equation [
], were not identified as predictors of survival in the Cox proportional hazards equation and are, therefore, not accounted for in this study. Other inherent limitations of using predictive models include the use of inputs from multiple data sources and extrapolation of observations from clinical trials over longer periods of time and to real-world populations. The modeled survival benefits were generated for a cohort of clinical trial participants; however, because the characteristics of pwCF homozygous for F508del-CFTR in the UK Cystic Fibrosis Registry are similar to those for trial participants used for the base-case model population, survival benefits of similar magnitude would be expected for both populations. When UK-specific data were not available, inputs were derived from studies conducted using the US Cystic Fibrosis Foundation Patient Registry (e.g., rate of lung function decline [
]); the extent to which differences in underlying disease progression differ across countries and, therefore, influence model projections, is unknown. However, sensitivity analyses that varied all key model inputs demonstrate the robustness of this model's survival predictions to plausible changes in inputs (Supplementary Materials). The model assumed that the CFTR modulator treatment effects observed over 2–3 years in clinical settings would apply over the lifetime model horizon. In particular, the estimated reduction in the rate of lung function decline with use of ELX/TEZ/IVA, a key driver of model outcomes, was based on within-group estimates of change in ppFEV1 from a single-arm open-label extension study, which lacked control participants [
Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one F508del allele: 96-week interim results from an open-label extension study.
Poster 681 presented at the 35th Annual North American Cystic Fibrosis Conference (Virtual), November 2–5. 2021
]. Analyses may need to be revised as longer-term data become available.
An additional limitation is that the model does not account for the potential future effects of aging in a CF population. Much of current CF research, including the evidence underpinning this model, is focused on pediatric and adolescent CF populations. As life expectancy continues to increase, pwCF may be at increased risk for other diseases, particularly those prevalent in older populations (e.g., cancer, cardiovascular disease) [
]. Incorporating increased disease risk for older pwCF into the simulation model could potentially decrease the life expectancy projections reported herein. As further real-world data on the impacts of aging in a CF population become available, refinement and calibration of the model should be conducted.
5. Conclusion
Our analysis predicts that treating pwCF homozygous for F508del-CFTR with ELX/TEZ/IVA will likely lead to substantial increases in survival compared with all other available treatment options. In addition to extending life, treatment with ELX/TEZ/IVA is projected to limit the amount of time pwCF homozygous for F508del-CFTR spend with moderate and severe disease and reduce healthcare resource utilization, including hospitalizations and lung transplants. Furthermore, our model predicts that early intervention with ELX/TEZ/IVA may allow pwCF to achieve near-normal life expectancy. Results highlight the need for early treatment.
Funding
This work was supported by Vertex Pharmaceuticals Incorporated.
CRediT authorship contribution statement
Andrea Lopez: Conceptualization, Methodology, Formal analysis, Writing – original draft, Writing – review & editing. Conor Daly: Conceptualization, Data curation, Validation, Writing – original draft, Writing – review & editing. Gabriela Vega-Hernandez: Conceptualization, Writing – review & editing. Gordon MacGregor: Conceptualization, Writing – review & editing. Jaime L. Rubin: Conceptualization, Writing – review & editing.
Declaration of Competing Interest
Andrea Lopez, Conor Daly, Gabriela Vega-Hernandez, and Jaime L. Ru- bin are employees of Vertex Pharmaceuticals and might own stock or stock options in the company. Gordon MacGre- gor has no conflicts of interest to declare.
Acknowledgments
Editorial coordination and support were provided by Nathan Blow, under the guidance of the authors. Nathan Blow is an employee of Vertex Pharmaceuticals Incorporated and might own stock or stock options in the company. Project management support was provided by Alice Newman, PhD, and editing support was provided by Adam Paton, BA, of Complete HealthVizion, IPG Health Medical Communications, funded by Vertex Pharmaceuticals Incorporated.
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.
Real-world outcomes among patients with cystic fibrosis treated with lumacaftor/ivacaftor (LUM/IVA) in 2017: an interim analysis of data from the US CF Foundation Patient Registry (CFFPR).
Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.
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: 96-week interim results from an open-label extension study.
Poster 681 presented at the 35th Annual North American Cystic Fibrosis Conference (Virtual), November 2–5. 2021
Validation of modeled 5-year survival outcomes among patients with cystic fibrosis (CF) treated with the CF transmembrane conductance regulator modulator (CFTRM) ivacaftor using US CF Foundation Patient Registry (USCFFPR) data.
The American Society for Transplant Physicians (ASTP)/American Thoracic Society (ATS)/European Respiratory Society (ERS)/International Society for Heart and Lung Transplantation (ISHLT)
International guidelines for the selection of lung transplant candidates.
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.
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