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

Ivacaftor (IVA) has been shown to change the trajectory of cystic fibrosis (CF) disease progression by slowing the rate of lung function decline in clinical studies. Long-term real-world data help to confirm the durability of this response. This non-interventional, longitudinal study used data from the US CF Foundation Patient Registry to describe the annualized rate of change in lung function in people with CF receiving IVA. The IVA-treated cohort included people with CF aged ≥ 6years who had ≥ 1 CF transmembrane conductance regulator (CFTR)-gating mutation and initiated IVA between 31 January 2012 and 31 December 2018. An age-matched comparator cohort included people with CF heterozygous for the F508del-CFTR mutation and a minimal function mutation (R117H excluded) and had not received CFTR modulator therapy. Baseline characteristics were balanced using standardized mortality ratio (SMR) weights computed from estimated propensity scores. The annualized rate of change in percent predicted forced expiratory volume in 1s (ppFEV1) was estimated over 5years and used to calculate the relative annualized rate of change in lung function in the IVA-treated versus comparator cohorts. In the 5-year follow-up period, 548 people were in the IVA-treated and 541 in the comparator cohorts after SMR weighting. The annualized rate of change in ppFEV1 over 5years was -1.23 (95% CI -1.45, -1.03) and -2.03 (-2.16, -1.90) percentage points in the IVA-treated and comparator cohorts, respectively. There was a 39% reduction (95% CI: 28, 50) in the rate of lung function decline in the IVA-treated versus comparator cohort over 5years. Findings were generally consistent with those of shorter follow-up periods. IVA showed a durable clinical benefit by slowing the rate of lung function decline over 5years. Results support a sustained and consistent impact of IVA on lung function trajectory in people with CF. Word count: 300 (limit: 300 words).

ObjectivePatients with cystic fibrosis (CF) and mutations associated with residual CFTR chloride transport have improved survival rates compared with those homozygous for the F508del-CFTR mutation. Since little is known about...

The field of personalized medicine, based on genetic information, represents a tremendous but largely unfulfilled opportunity for a future generation of therapies [1]. While better clinical outcomes have been realized using predictive biomarkers in some forms of cancer [2], the influence of genetic information on the treatment of most other human diseases has been limited. However, in the case of the inherited genetic disease cystic fibrosis (CF), pre-emptive possibilities have recently been uncovered. In particular, an investigational drug known as VX-770, has demonstrated great promise in clinical trials in patients with a specific cystic fibrosis transmembrane conductance regulator (CFTR) allele selected for clinical investigation based on data from in vitro studies [3,4]. This article highlights some of the opportunities and challenges associated with developing novel genotype-directed therapies for CF.

IntroductionCystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Approximately 5% of people with CF have residual function (RF) CFTR mutations that result in partially retained CFTR activity. Published literature on disease trajectory among those with RF mutations is limited. In this retrospective study, we characterized lung function decline across different age groups in CFTR modulator-untreated people with CF heterozygous for F508del and an RF mutation (F/RF).MethodsRate of decline in percent predicted forced expiratory volume in 1 s (ppFEV1) was analyzed using data from the US CF Foundation Patient Registry (2006–2014) in F/RF (all), F/RF (excluding R117H), and F508del homozygous (F/F) cohorts. Annual rates of ppFEV1 decline were estimated over 2-year periods based on calendar year. Subgroup analyses by age [6–12 (children), 13–17 (adolescents), 18–24 (young adults), and ≥ 25 years (adults)] were performed.ResultsThe estimated annualized rate of ppFEV1 decline was − 0.70 percentage points per year (95% CI −1.09, −0.30) in the F/RF (all) cohort (N = 1242) versus −1.91 percentage points per year (95% CI −2.01, −1.80) in the F/F cohort (N = 11,916) [difference, 1.29 percentage points per year (95% CI 0.88, 1.70); P < 0.001]. In the F/RF (all) cohort, all age groups demonstrated lung function decline ranging from −0.30 to −1.38. In the F/RF (excluding R117H) cohort, the rate of decline was −1.05 percentage points per year (95% CI −1.51, −0.60) [difference versus F/F cohort, 0.95 percentage points per year (95% CI 0.48, 1.41; P < 0.001); not statistically significant in children and young adults].ConclusionProgressive lung function decline was observed in people with F/RF genotypes across all assessed age groups, reinforcing the importance of early intervention and clinical monitoring to preserve lung function in all people with CF.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41030-022-00202-y.

Rationale: Studies estimating the rate of lung function decline in cystic fibrosis have been inconsistent regarding the methods used. How the methodology used impacts the validity of the results and comparability between studies is unknown. Objectives: The Cystic Fibrosis Foundation established a work group whose tasks were to examine the impact of differing approaches to estimating the rate of decline in lung function and to provide analysis guidelines. Methods: We used a natural history cohort of 35,252 individuals with cystic fibrosis aged ⩾6 years in the Cystic Fibrosis Foundation Patient Registry (CFFPR), 2003-2016. Modeling strategies using linear and nonlinear forms of marginal and mixed-effects models, which have previously quantified the rate of forced expiratory volume in 1 second (FEV1) decline (percent predicted per year), were evaluated under clinically relevant scenarios of available lung function data. Scenarios varied by sample size (overall CFFPR, medium-sized cohort of 3,000 subjects, and small-sized cohort of 150), data collection/reporting frequency (encounter, quarterly, and annual), inclusion of FEV1 during pulmonary exacerbation, and follow-up length (<2 yr, 2-5 yr, entire duration). Results: Rate of FEV1 decline estimates (percent predicted per year) differed between linear marginal and mixed-effects models; overall cohort estimates (95% confidence interval) were 1.26 (1.24-1.29) and 1.40 (1.38-1.42), respectively. Marginal models consistently estimated less rapid lung function decline than mixed-effects models across scenarios, except for short-term follow-up (both were ∼1.4). Rate of decline estimates from nonlinear models diverged by age 30. Among mixed-effects models, nonlinear and stochastic terms fit best, except for short-term follow-up (<2 yr). Overall CFFPR analysis from a joint longitudinal-survival model implied that an increase in rate of decline of 1% predicted per year in FEV1 was associated with a 1.52-fold (52%) increase in the hazard of death/lung transplant, but the results exhibited immortal cohort bias. Conclusions: Differences were as high as 0.5% predicted per year between rate of decline estimates, but we found estimates were robust to lung function data availability scenarios, except short-term follow-up and older age ranges. Inconsistencies among previous study results may be attributable to inherent differences in study design, inclusion criteria, or covariate adjustment. Results-based decision points reported herein will support researchers in selecting a strategy to model lung function decline most reflective of nuanced, study-specific goals.

In clinical trials, patients with cystic fibrosis and a G551D mutation who received ivacaftor experienced improvements in pulmonary and nutritional outcomes. However, whether these improvements reflect a change in disease trajectory cannot be determined without longer-term analyses with an appropriate comparator population. To examine, over a 3-year period, whether ivacaftor therapy affects pulmonary function and nutritional measures in patients with CF with a G551D mutation compared with patients with CF who are homozygous for the F508del mutation. A propensity score was used to match patients with CF greater than or equal to 6 years of age who have a G551D mutation and received ivacaftor in clinical trials for up to 144 weeks with data from patients in the U.S. Cystic Fibrosis Foundation Patient Registry who are homozygous for the F508del mutation. Matching was based on variables including age, sex, weight for age, height for age, body mass index for age, % predicted FEV1, and chronic therapies (dornase alfa, inhaled antibiotics, inhaled and oral corticosteroids). By calculating the annual estimated rate of decline in lung function for G551D patients receiving ivacaftor and comparing it with the rate of decline in lung function for matched F508del control patients, we show that the rate of lung function decline in G551D ivacaftor-treated patients was slower by nearly half. Moreover, treatment with ivacaftor is shown to improve body mass index and weight-for-age z scores for G551D patients over the 3-year analysis period. These findings suggest that ivacaftor is a disease-modifying therapy for the treatment of cystic fibrosis.

Cystic fibrosis (CF) is a disease affecting over 10,000 people in the UK. It has no cure, but there are many treatments to help improve health. Randomised controlled trials are the gold standard for establishing treatment efficacy, but most trials for CF treatments have no more than one year of follow-up. In practice treatments are commonly used for many years, and it is therefore important to evaluate their long-term effectiveness. The UK CF Registry collects annual data on almost all people with CF in the UK. The overall aim of this work is to investigate how data from such registries can be harnessed to provide insights into the effects of long-term treatment use. My research illustrates the potential of registry data by investigating two CF treatments: DNase and ivacaftor. DNase is a common CF treatment and generally, once started, it continues to be used indefinitely. Despite this, no studies have investigated its long-term effects. Estimating these effects using registry data is difficult due to time-dependent confounding. I investigate five methods that can account for this: sequential conditional mean models, inverse probability weighting of marginal structural models (MSM), history-adjusted MSM, gcomputation formula and g-estimation of structural nested models. The performance of these methods is assessed through simulation studies, where it is shown that all methods perform similarly under correct model specification, suggesting that more than one method could be applied to assess consistency of results. My analysis of the UK CF Registry data suggests that DNase provides a step-change improvement in lung function only in individuals with ppFEV1 < 70% (e.g. for a person starting DNase with ppFEV1 of 20%, the one-year treatment effect was a 1.6% absolute difference in ppFEV1, 95% CI 0.4, 2.8). However, the slope of lung function decline over five years remained unchanged. Ivacaftor was introduced in the UK in 2012, but it is only available to people with a gating mutation. In this subgroup, it appears to be so beneficial that almost all eligible people are now receiving it. In this situation, it is difficult to estimate the treatment effect, because there are no eligible people not receiving treatment. Two possible comparator groups were identified: 1) those currently receiving ivacaftor, but using their data from years prior to its introduction, 2) those ineligible to receive ivacaftor due to their genotype. This work shows how analyses using negative controls can be used to assess the comparability of the different groups, and how differences between groups not due to treatment can be mitigated. Our analysis suggests that these two groups are comparable to people who are currently receiving ivacaftor, and the results of the analysis show that ivacaftor not only provides an initial step-change improvement in lung function (5.9% absolute difference in ppFEV1, 95% CI 4.7, 7.1), but also decrease the rate of lung function decline (0.5% absolute decrease in ppFEV1 decline per year, 95% CI 0.02, 1.0).

Early Aggressive Intervention in Cystic Fibrosis: Is It Time To Redefine Our “Best Practice” Strategies?

Clinical Characteristics Associated With Lung Function Decline in Individuals With Adult-Diagnosed Cystic Fibrosis: Contemporary Analysis of the Canadian CF Registry

the endoplasmic reticulum (ER) serves as a way station during the biogenesis of nearly every integral membrane and secreted protein synthesized in eukaryotic cells. As such, its primary role is to facilitate the folding of nascent polypeptides. Thus plentiful among the ER resident proteins are 1 )

Fertility in Patients With Cystic Fibrosis

Exophiala dermatitidis is increasingly isolated from cystic fibrosis (CF) respiratory samples. The decision to treat is hampered by limited evidence demonstrating the clinical significance of isolating E. dermatitidis. The objective was to assess the impact of E. dermatitidis isolation on the lung function of CF patients. The rate of lung function decline in the local CF population was calculated using historic lung function data. A control population who had never had E. dermatitidis cultured from the respiratory tract was compared with the E. dermatitidis group, calculating their rate of lung function decline before and after the first isolation of the organism. A total of 1840 lung function measurements were reviewed between the 31 E. dermatitidis group patients and 62 control patients. Their demographics were similar. The control group declined at a rate of −0.824 FEV1%/year. The rate of decline in the E. dermatitidis group prior to infection was −0.337 FEV1%/year (p = 0.2). However, post infection with E. dermatitidis, there was a significant increase in the rate of decline in lung function (−1.824 FEV1%/year, p < 0.01). The results suggest E. dermatitidis has a temporal relationship with accelerated rate of lung function decline. It is not clear if this is a cause or effect, but this accelerated rate of decline indicates a need for further investigation.

Average rate of lung function decline in adults with cystic fibrosis in the United Kingdom: Data from the UK CF registry

Generation of Novel AAV Variants by Directed Evolution for Improved CFTR Delivery to Human Ciliated Airway Epithelium

Lung function decline is delayed but not decreased in patients with cystic fibrosis and the R117H gene mutation