Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy Research Articles

Lung Inflammatory Genes in Cystic Fibrosis and Their Relevance to Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapies.

Cystic fibrosis (CF) is a monogenic syndrome determined by over 2000 mutations in the CF Transmembrane Conductance Regulator (CFTR) gene harbored on chromosome 7. In people with CF (PWCF), lung disease is the major determinant of morbidity and mortality and is characterized by a clinical phenotype which differs in the presence of equal mutational assets, indicating that genetic and environmental modifiers play an important role in this variability. Airway inflammation determines the pathophysiology of CF lung disease (CFLD) both at its onset and progression. In this narrative review, we aim to depict the inflammatory process in CF lung, with a particular emphasis on those genetic polymorphisms that could modify the clinical outcome of the respiratory disease in PWCF. The natural history of CF has been changed since the introduction of CFTR modulator therapies in the clinical arena. However, also in this case, there is a patient-to-patient variable response. We provide an overview on inflammatory/immunity gene variants that affect CFLD severity and an appraisal of the effects of CFTR modulator therapies on the inflammatory process in lung disease and how this knowledge may advance the optimization of the management of PWCF.

Effects of modulator therapies on endocrine complications in adults with cystic fibrosis: a narrative review.

Cystic fibrosis is a monogenic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which transports chloride ions in secretory organs. Modulator therapies are small molecules that correct CFTR dysfunction and can lead to a wide range of benefits for both pulmonary and extrapulmonary complications of cystic fibrosis. With advancements in airway, antimicrobial and nutritional therapies and now introduction of modulator therapies, most people living with cystic fibrosis in Australia are now adults. For adults with cystic fibrosis, endocrine manifestations such as cystic fibrosis-related diabetes, metabolic bone disease, and reproductive health are becoming increasingly important, and emerging evidence on the endocrine effects of CFTR modulator therapies is promising and is shifting paradigms in our understanding and management of these conditions. The management of cystic fibrosis-related diabetes will likely need to pivot for high responders to modulator therapy with dietary adaptions and potential use of medications traditionally reserved for adults with type 2 diabetes, but evidence to support changing clinical care needs is currently lacking. Increased attention to diabetes-related complications screening will also be required. Increased exercise capacity due to improved lung function, nutrition and potentially direct modulator effect may have a positive impact on cystic fibrosis-related bone disease, but supporting evidence to date is limited. Fertility can improve in women with cystic fibrosis taking modulator therapy. This has important implications for pregnancy and lactation, but evidence is lacking to guide pre-conception and antenatal management. Provision of multidisciplinary clinical care remains ever-important to ensure the emergence of endocrine and metabolic complications are optimised in adults with cystic fibrosis.

A-340 CFTR Modulator Therapy Increases Serum/Plasma Concentrations of Vitamin a in People with Cystic Fibrosis

Abstract Introduction Pancreatic insufficiency (PI) is common in people with Cystic Fibrosis (PwCF), contributing to malabsorption of fat and fat-soluble vitamins. Thus, PI PwCF are prescribed pancreatic enzyme replacement therapy (PERT) and supplementation with fat-soluble vitamins. The circulating vitamin levels are monitored to guide dietary therapy. Currently, there are multiple cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies available that have shown significant improvements in pulmonary function, anthropometric parameters, and life expectancy in PwCF, but the effects on serum/plasma fat-soluble vitamin levels remain unknown. The goal of this study was to determine how modulator therapy affects serum/plasma vitamin A and E levels in individuals with CF. Methods The analysis included 1139 serum/plasma samples from 157 children and adolescents with CF: 74 males, 83 females, between the ages of 2–17 years. Most individuals were homozygous or compound heterozygous for the F508del variant (n = 81 and n = 72, respectively). 141 individuals (90%) were diagnosed with PI (fecal elastase <200 μg/g stool). 76 individuals (48%) received different CFTR modulator therapies for at least 1 month. Vitamin A (retinol and retinyl palmitate) and Vitamin E (α-tocopherol and γ-tocopherol) were measured using a high-performance liquid chromatography assay. Data analyses were performed in Prism software (La Jolla, CA), and statistical significance was defined as P < 0.05. The study was approved by the IRB. Results Overall, vitamin deficiency was rarely observed in PwCF prescribed PERT and vitamin supplements; <3% of them had low concentrations of Vitamin A and/or E. The proportion of individuals with Vitamin A and/or E above the reference range was larger; 10.9% and 30.8% for Vitamin A and E, respectively, most likely reflecting supplementation. There was no correlation of plasma vitamin A or E results with sex, weight-for-age, height-for-age, or BMI-for-age. However, pancreatic status affected vitamin levels in individuals not taking modulators: samples from PI PwCF (n = 367) had significantly lower Vitamin A and E than those from PS PwCF (n = 71). In contrast, we have observed higher concentrations of Vitamin A retinol in individuals on modulators: 0.49 ± 0.13 mg/L on modulators vs 0.43 ± 0.12 mg/L without modulators. Pairwise analysis of samples from 76 individuals before and after modulator therapy confirmed this finding, showing an average 16% increase in serum/plasma retinol concentration (P < 0.0001). No changes in retinol were observed between different measurements in PwCF who were not taking modulators (n = 82). Vitamin E levels were not impacted by modulator therapy. Conclusions Advances in clinical care improved fat-soluble vitamin status in people with CF. However, even when supplemented and on PERT, PI PwCF not on modulators tend to have lower fat-soluble vitamin concentrations than PS PwCF. CFTR modulator therapy increases serum/plasma concentrations of vitamin A. Thus, individuals receiving modulators and vitamin supplementation should be monitored to avoid Vitamin A toxicity. This is especially true for PS PwCF who already have higher baseline vitamin levels.

Changes in fecal elastase-1 following initiation of CFTR modulator therapy in pediatric patients with cystic fibrosis

BackgroundImprovement in exocrine pancreatic function in persons with CF (pwCF) on cystic fibrosis transmembrane conductance regulator (CFTR) modulators has been documented in clinical trials using fecal pancreatic elastase-1 (FE-1). Our group endeavored to evaluate real-world data on FE-1 in children on CFTR modulator therapy at three pediatric cystic fibrosis (CF) centers. MethodsPediatric pwCF were offered FE-1 testing if they were on pancreatic enzyme replacement therapy (PERT) and on CFTR modulator therapy according to their center's guideline. FE-1 data were collected retrospectively. The primary outcome was absolute change in FE-1. Results70 pwCF were included for analysis. 53 had baseline and post-modulator FE-1 values. There was a significant increase in FE-1 from median 25 mcg/g (IQR 25–60) at baseline to 57 mcg/g (IQR 20–228) post-modulator (p<0.001 by Wilcoxon matched pairs), with an absolute change in FE-1 of median 28 mcg/g (IQR –5–161) and mean 93.5 ± 146.8 mcg/g. Age was negatively correlated with change in FE-1 (Spearman r=-0.48, p<0.001). 15 pwCF (21%) had post-modulator FE-1 values ≥200 mcg/g, consistent with pancreatic sufficiency (PS). The PS group was significant for younger age at initiation of first CFTR modulator and a higher baseline FE-1. ConclusionsMost pwCF experienced an increase in FE-1 while receiving CFTR modulator treatment and a small percentage demonstrated values reflective of PS. These data suggest that PS may be attained in those that initiated modulator therapy at a younger age or had a higher baseline FE-1. FE-1 testing is suggested for children on any CFTR modulator therapy.

Inflammatory Activity of Epithelial Stem Cell Variants from Cystic Fibrosis Lungs Is Not Resolved by CFTR Modulators.

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to improvements in body mass index and lung function. Although it is anticipated that early childhood treatment with CFTR modulators will significantly delay or even prevent the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in patients with CF with established lung disease despite modulator therapy, underscoring the need to identify and ultimately target the sources of this inflammation in CF lungs. Objectives: To determine whether CF lungs, like chronic obstructive pulmonary disease (COPD) lungs, harbor potentially pathogenic stem cell "variants" distinct from the normal p63/Krt5 lung stem cells devoted to alveolar fates, to identify specific variants that might contribute to the inflammatory state of CF lungs, and to assess the impact of CFTR genetic complementation or CFTR modulators on the inflammatory variants identified herein. Methods: Stem cell cloning technology developed to resolve pathogenic stem cell heterogeneity in COPD and idiopathic pulmonary fibrosis lungs was applied to end-stage lungs of patients with CF (three homozygous CFTR:F508D, one CFTR F508D/L1254X; FEV1, 14-30%) undergoing therapeutic lung transplantation. Single-cell-derived clones corresponding to the six stem cell clusters resolved by single-cell RNA sequencing of these libraries were assessed by RNA sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants after CFTR gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies. Measurements and Main Results: End-stage CF lungs display a stem cell heterogeneity marked by five predominant variants in addition to the normal lung stem cell, of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophilic inflammation in xenografts in immunodeficient mice. The proinflammatory functions of these three variants were unallayed by genetic or pharmacological restoration of CFTR activity. Conclusions: The emergence of three proinflammatory stem cell variants in CF lungs may contribute to the persistence of lung inflammation in patients with CF with advanced disease undergoing CFTR modulator therapy.

The modern landscape of fertility, pregnancy, and parenthood in people with cystic fibrosis.

With improved long-term survival and the expanding availability of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies that treat the underlying genetic defect in cystic fibrosis, more people are interested in parenthood. Cystic fibrosis care centers and people with cystic fibrosis need more information to guide decisions related to parenting. Here we present currently available data on fertility, pregnancy, and parenthood in the modern era of cystic fibrosis care. Fertility may be improving in female individuals with cystic fibrosis with the use of CFTR modulator therapies, and there is an associated increase in annual pregnancies. Infertility in male individuals with cystic fibrosis remains approximately 97-98% and is unchanged with CFTR modulators in those already born with cystic fibrosis. As more female individuals with cystic fibrosis experience pregnancy, questions remain about the impact of pregnancy on their health and that of their child. Fortunately, there are multiple routes to becoming a parent; however, more work is needed to understand the impact of pregnancy and parenthood in the context of CF as some previous data suggests potential challenges to the health of parents with cystic fibrosis. We encourage cystic fibrosis care teams to have knowledge and resources available to support the reproductive goals of all individuals with cystic fibrosis.

Lung Transplantation in a New Era in the Field of Cystic Fibrosis.

Lung transplantation for people with cystic fibrosis (PwCF) is a critical therapeutic option, in a disease without a cure to this day, and its overall success in this population is evident. The medical advancements in knowledge, treatment, and clinical care in the field of cystic fibrosis (CF) rapidly expanded and improved over the last several decades, starting from early pathology reports of CF organ involvement in 1938, to the identification of the CF gene in 1989. Lung transplantation for CF has been performed since 1983, and CF now accounts for about 17% of pre-transplantation diagnoses in lung transplantation recipients. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been the latest new therapeutic modality addressing the underlying CF protein defect with the first modulator, ivacaftor, approved in 2012. Fast forward to today, and we now have a growing CF population. More than half of PwCF are now adults, and younger patients face a better life expectancy than they ever did before. Unfortunately, CFTR modulator therapy is not effective in all patients, and efficacy varies among patients; it is not a cure, and CF remains a progressive disease that leads predominantly to respiratory failure. Lung transplantation remains a lifesaving treatment for this disease. Here, we reviewed the current knowledge of lung transplantation in PwCF, the challenges associated with its implementation, and the ongoing changes to the field as we enter a new era in the care of PwCF. Improved life expectancy in PwCF will surely influence the role of transplantation in patient care and may even lead to a change in the demographics of which people benefit most from transplantation.

It Takes Two to Tango! Protein-Protein Interactions behind cAMP-Mediated CFTR Regulation.

Over the last fifteen years, with the approval of the first molecular treatments, a breakthrough era has begun for patients with cystic fibrosis (CF), the rare genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). These molecules, known as CFTR modulators, have led to unprecedented improvements in the lung function and quality of life of most CF patients. However, the efficacy of these drugs is still suboptimal, and the clinical response is highly variable even among individuals bearing the same mutation. Furthermore, not all patients carrying rare CFTR mutations are eligible for CFTR modulator therapies, indicating the need for alternative and/or add-on therapeutic approaches. Because the second messenger 3',5'-cyclic adenosine monophosphate (cAMP) represents the primary trigger for CFTR activation and a major regulator of different steps of the life cycle of the channel, there is growing interest in devising ways to fine-tune the cAMP signaling pathway for therapeutic purposes. This review article summarizes current knowledge regarding the role of cAMP signalosomes, i.e., multiprotein complexes bringing together key enzymes of the cAMP pathway, in the regulation of CFTR function, and discusses how modulating this signaling cascade could be leveraged for therapeutic intervention in CF.

Proliferative activity of antigen-specific CD154+ T cells against bacterial and fungal respiratory pathogens in cystic fibrosis decreases after initiation of highly effective CFTR modulator therapy.

Background: Together with impaired mucociliary clearance, lung disease in cystic fibrosis (CF) is driven by dysregulation of innate and adaptive immunity caused by dysfunctional CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), leading to airway infection and hyperinflamma-tion. The highly effective CFTR modulator therapy (HEMT) elexacaftor/tezacaftor/ivacaftor (ETI) generates substantial improvements in clinical outcomes of people with CF (pwCF) by restoration of CFTR activity. Aberrant immune responses of lymphocytes due to CFTR dysfunction has been described in the past, but not the effects of CFTR restoration by HEMT on these cells. We aimed to examine the effect of ETI on the proliferative activity of antigen-specific CD154 (+) T cells against bacterial and fungal species relevant in CF and on total IgG and IgE as markers of B cell adaptive immunity. Methods: We performed ex vivo analyses of Ki-67 expression in antigen-specific CD154 (+) T cells against Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus fumigatus, Scedosporium apiospermum and Candida albicans from 21 pwCF by cytometric assay based on antigen-reactive T cell enrichment (ARTE), and analysis of total serum IgE and IgG before and after initiation of ETI. Results: Mean Ki-67 expression in antigen-specific CD154 (+) T cells against P. aeruginosa, A. fumigatus, S. apiospermum and C. albicans, but not S. aureus, mean total serum IgG and mean total serum IgE decreased significantly after initiation of ETI. No correlation was found to change in sputum microbiology of the examined pathogens. Mean BMI and FEV1 increased significantly. Conclusion: HEMT is associated with decreased antigen-specific CD154 (+) T cell proliferation activity in our cohort, independent of findings in sputum microbiology of the examined pathogens. Together with the observed clinical improvement and the decrease in total IgE and IgG, this indicates effects due to CFTR restoration on CD154 (+) T cells by ETI and a reduction of B cell activation with subsequent lower immunoglobulin synthesis under HEMT therapy. These results endorse earlier evidence of CFTR dysfunction in T and B cells leading directly to aberrant immune responses with hyperinflammation.

P020 Therapy with elexacaftor/tezacaftor/ivacaftor in a patient with compound heterozygous CFTR mutation and the complex CFTR-allele Phe508del; Leu467Phe

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) was shown to be highly efficacious in patients who have at least one copy of the F508del variant. Cis variants in F508del mutations might influence the response to CFTR modulator therapy. We report the response to ETI in a patient with CF who is heterozygous for the complex Phe508del;Leu467Phe allele.

Characterization of sleep in emerging adults with cystic fibrosis on elexacaftor/tezacaftor/ivacaftor

Characterization of sleep in emerging adults with cystic fibrosis on elexacaftor/tezacaftor/ivacaftor

Inflammation as a Regulator of the Airway Surface Liquid pH in Cystic Fibrosis.

The airway surface liquid (ASL) is a thin sheet of fluid that covers the luminal aspect of the airway epithelium. The ASL is a site of several first-line host defenses, and its composition is a key factor that determines respiratory fitness. Specifically, the acid-base balance of ASL has a major influence on the vital respiratory defense processes of mucociliary clearance and antimicrobial peptide activity against inhaled pathogens. In the inherited disorder cystic fibrosis (CF), loss of cystic fibrosis transmembrane conductance regulator (CFTR) anion channel function reduces HCO3- secretion, lowers the pH of ASL (pHASL), and impairs host defenses. These abnormalities initiate a pathologic process whose hallmarks are chronic infection, inflammation, mucus obstruction, and bronchiectasis. Inflammation is particularly relevant as it develops early in CF and persists despite highly effective CFTR modulator therapy. Recent studies show that inflammation may alter HCO3- and H+ secretion across the airway epithelia and thus regulate pHASL. Moreover, inflammation may enhance the restoration of CFTR channel function in CF epithelia exposed to clinically approved modulators. This review focuses on the complex relationships between acid-base secretion, airway inflammation, pHASL regulation, and therapeutic responses to CFTR modulators. These factors have important implications for defining optimal ways of tackling CF airway inflammation in the post-modulator era.

The Expression of Affective Temperaments in Cystic Fibrosis Patients: Psychopathological Associations and Possible Neurobiological Mechanisms.

The aim of this study was to investigate the association between Cystic Fibrosis (CF) and affective temperaments, considering the relevance of ionic balances in neural excitability, as a possible neurobiological basis for temperamental expression. A cross-sectional study involving 55 adult CF patients was conducted. Sociodemographic, clinical and therapeutic characteristics, temperamental and personality dispositions and depressive and anxiety symptoms were evaluated through standardized semi-structured and structured interviews. The majority of the enrolled CF patients were receiving Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) therapy (72.7%), and most of them had hyperthymic temperament predominance (29.1%). Different TEMPS-A (Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire) dimensions were not associated with the type of CF phenotype-related mutation or with the use of CFTR-modulator therapy. However, a tendency towards irritability was noted in patients not undergoing CFTR modulator therapy (6.7 ± 4.72 vs. 4.7 ± 4.33; p = 0.13). In light of the limitations imposed by the cross-sectional nature of the study, a hyperthymic temperament was found to be protective against current or lifetime psychopathologic events, whereas the other temperaments were associated with positive psychopathological anamnesis. Based on the measurement of temperament profiles and the study of their associations with clinically relevant variables, we argue that subjecting CF patients to such a temperament assessment could prove beneficial in the transition towards integrated and personalized care.

Impact of elexacaftor/tezacaftor/ivacaftor on bacterial cultures from people with cystic fibrosis.

Cystic fibrosis transmembrane conductance regulator (CFTR)modulators have shown beneficial effects on both forced expiratory volume in 1 s(FEV1 ) and frequency of pulmonary exacerbations in people with cystic fibrosis (CF). These positive outcomes may be related to changes in bacterial colonization within the lungs. Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA)is the first triple therapy CFTR modulator approved for use in people with CF6years and older. This study aimed to determine the impact of ELX/TEZ/IVAon the isolation of Pseudomonas aeruginosa (Pa), methicillin-resistant and methicillin-susceptible Staphylococcus aureus (MRSA and MSSA, respectively) in respiratory cultures. A retrospective chart review of the electronic medical record at the University of Iowa was completed for individuals 12 years and older taking ELX/TEZ/IVAfor at least 12 months. The primary outcome was determined by assessing bacterial cultures pre- and postinitiation of ELX/TEZ/IVA.Baseline demographic and clinical characteristics were summarized using mean and standard deviation for continuous outcomes and count and percentage for categorical outcomes. Culture positivity for Pa, MSSA, and MRSA was compared among enrolled subjects between pre- and posttriple combination therapy periods using an exact McNemar's test. One hundred and twenty-four subjects prescribed ELX/TEZ/IVAfor at least 12 months met the requirements for inclusion within our analysis. Culture positivity for Pa, MSSA, and MRSA was approximately 54%, 33%, and 31%, respectively, for the pre-ELX/TEZ/IVAperiod. Prevalence decreased to approximately 30%, 32%, and 24% (-24.2% [p < 0.0001], -0.7% [p = 1.00], and -6.5% [p = 0.0963], respectively) post-ELX/TEZ/IVA.The source of bacterial culture was predominantly sputum (70.2%) in the pre-ELX/TEZ/IVAgroup, whereas a throat source (66.1%) was more common post-ELX/TEZ/IVA. ELX/TEZ/IVAtreatment has an appreciable impact on the detection of common bacterial pathogens in CF respiratory cultures. While previous studies have found a similar effect with single and double CFTR modulator therapies, this is the first single-center study to show the impact of triple therapy, ELX/TEZ/IVA,on bacterial isolation from airway secretions.

EFFECT OF ELEXACAFTOR/TEZACAFTOR/IVACAFTOR ON ANNUAL RATE OF LUNG FUNCTION DECLINE IN PEOPLE WITH CYSTIC FIBROSIS

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 1second (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.

Cystic fibrosis macrophage function and clinical outcomes after elexacaftor/tezacaftor/ivacaftor.

Abnormal macrophage function caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is a critical contributor to chronic airway infections and inflammation in people with cystic fibrosis (PWCF). Elexacaftor/tezacaftor/ivacaftor (ETI) is a new CFTR modulator therapy for PWCF. Host-pathogen and clinical responses to CFTR modulators are poorly described. We sought to determine how ETI impacts macrophage CFTR function, resulting effector functions and relationships to clinical outcome changes. Clinical information and/or biospecimens were obtained at ETI initiation and 3, 6, 9 and 12 months post-ETI in 56 PWCF and compared with non-CF controls. Peripheral blood monocyte-derived macrophages (MDMs) were isolated and functional assays performed. ETI treatment was associated with increased CF MDM CFTR expression, function and localisation to the plasma membrane. CF MDM phagocytosis, intracellular killing of CF pathogens and efferocytosis of apoptotic neutrophils were partially restored by ETI, but inflammatory cytokine production remained unchanged. Clinical outcomes including increased forced expiratory volume in 1 s (+10%) and body mass index (+1.0 kg·m-2) showed fluctuations over time and were highly individualised. Significant correlations between post-ETI MDM CFTR function and sweat chloride levels were observed. However, MDM CFTR function correlated with clinical outcomes better than sweat chloride. ETI is associated with unique changes in innate immune function and clinical outcomes.

Long-term effectiveness of dual CFTR modulator treatment of cystic fibrosis.

Although short-term efficacy of lumacaftor/ivacaftor and tezacaftor/ivacaftor is clearly established in clinical trials, data on long-term effectiveness is limited. This registry-based cohort study assessed real-world longitudinal outcomes of F508del-homozygous people with cystic fibrosis (pwCF) ≥12 years, up to 3 years after the introduction of dual cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Annual data (2010-2019) were retrieved from the Dutch Cystic Fibrosis Registry. Longitudinal trends of per cent predicted forced expiratory volume in 1 s (FEV1 % pred) decline, body mass index (BMI), BMI Z-score and intravenous antibiotic treatment duration before and after CFTR modulator initiation were assessed with linear and negative binomial mixed models. We included 401 participants (41.9% female, baseline age 24.5 years (IQR 18.0-31.5 years), baseline mean±sd FEV1 70.5±23.4% pred). FEV1 decline improved from -1.36% pred per year to -0.48% pred per year after modulator initiation (change: 0.88% pred, 95% CI: 0.35-1.39%, p=0.001). This change was even 1.40% pred per year (95% CI: -0.0001-2.82%, p=0.050) higher in participants with baseline FEV1 <40% pred. In adults, annual BMI trend was not altered (change: 0.10 kg·m-2·year-1, 95% CI:-0.01-0.21, p=0.079). Annual BMI Z-score in children reversed from -0.08 per year before modulator treatment to 0.06 per year afterwards (change: 0.14 per year, 95% CI: 0.06-0.22, p<0.001). Intravenous antibiotic treatment duration showed a three-fold reduction in the first year after modulator initiation (incidence rate ratios (IRR): 0.28, 95% CI: 0.19-0.40, p<0.001), but the annual trend did not change in the subsequent years (IRR: 1.19, 95% CI: 0.94-1.50, p=0.153). Long-term effectiveness of dual CFTR modulator therapies on FEV1 decline, BMI and intravenous antibiotic treatment duration is less pronounced in a real-world setting than in clinical trials and varies considerably between pwCF and different baseline FEV1 levels.

Diagnostic agreement among experts assessing adults presenting with possible cystic fibrosis: need for improvement and implications for patient care.

Increasing awareness of milder presentations of cystic fibrosis (CF) and greater interest in non-CF bronchiectasis are likely to lead to more CF screening by respiratory clinicians. As a result, adults who may not strictly fulfil CF diagnostic criteria yet display evidence of abnormal CF transmembrane conductance regulator (CFTR) function are being identified. The degree of agreement on diagnosis and care needs in these cases between CF clinicians remains unknown, and has implications for patient care, including access to CFTR modulator therapies. We surveyed adult CF physicians in Canada, the USA, the UK and Ireland, and presented them with anonymised vignettes of adult patients referred for assessment of possible CF. Diagnostic inter-rater agreement over diagnosis, ease of classifying cases and appropriate follow-up was assessed using Krippendorff's reliability coefficient (α). Agreement over diagnosis (α=0.282), ease of classification (α= -0.01) and recommended follow-up (α=0.054) was weak. Clinician experience (>10 and 5-10 years versus <5 years) and location (UK and Ireland versus Canada) were associated with higher odds of recommending further testing compared with selecting a formal diagnosis (respectively, OR 2.87; p=0.022, OR 3.74; p=0.013 and OR 3.16; p=0.007). A modified standard of care was recommended in 28.7% of cases labelled as CF. 70% of respondents agreed with the statement that "Accurate distinction between CF and CFTR-related disorder has become significantly more pertinent with the advent of highly effective CFTR modulators". Our results demonstrate low diagnostic concordance among CF specialists assessing cases of possible adult CF and highlight an area in need of improvement.

Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis.

The development of preclinical in vitro models has provided significant progress to the studies of cystic fibrosis (CF), a frequently fatal monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Numerous cell lines were generated over the last 30 years and they have been instrumental not only in enhancing the understanding of CF pathological mechanisms but also in developing therapies targeting the underlying defects in CFTR mutations with further validation in patient-derived samples. Furthermore, recent advances toward precision medicine in CF have been made possible by optimizing protocols and establishing novel assays using human bronchial, nasal and rectal tissues, and by progressing from two-dimensional monocultures to more complex three-dimensional culture platforms. These models also enable to potentially predict clinical efficacy and responsiveness to CFTR modulator therapies at an individual level. In parallel, advanced systems, such as induced pluripotent stem cells and organ-on-a-chip, continue to be developed in order to more closely recapitulate human physiology for disease modeling and drug testing. In this review, we have highlighted novel and optimized cell models that are being used in CF research to develop novel CFTR-directed therapies (or alternative therapeutic interventions) and to expand the usage of existing modulator drugs to common and rare CF-causing mutations.

Analyzing the use and impact of elexacaftor/tezacaftor/ivacaftor on total cost of care and other health care resource utilization in a commercially insured population.

BACKGROUND: Cystic fibrosis (CF) is a rare, life-threatening disease that results in severe respiratory, digestive, and metabolic problems. Elexacaftor/tezacaftor/ivacaftor is an oral drug that was approved by the US Food and Drug Administration (FDA) on October 21, 2019, after demonstrating clinical improvements compared with previous CF transmembrane conductance regulator modulators. Use of CF transmembrane conductance regulator modulators has improved CF care, but their high costs exceed commonly used cost-effectiveness thresholds. The Institute for Clinical and Economic Review issued an access and affordability alert warning that these high costs could threaten sustainable access to high-value care. There exists little real-world evidence on the uptake of elexacaftor/tezacaftor/ivacaftor and the impact on total cost of care and other health care resource utilization. This exploratory study analyzed the uptake and total cost-of-care impact of elexacaftor/tezacaftor/ivacaftor using pharmacy and medical claims data in a commercially insured patient population. OBJECTIVE: To analyze the uptake of elexacaftor/tezacaftor/ivacaftor by members who qualified for treatment and to evaluate the differences in total cost of care and health care resource utilization in members who started treatment with elexacaftor/tezacaftor/ivacaftor. METHODS: Uptake and per-member per-month information was obtained from Prime Therapeutics databases using cystic fibrosis transmembrane conductance regulator (CFTR) modulator claims. The total cost-of-care and resource utilization analysis used pharmacy and medical claims from Prime Therapeutics and Blue Cross NC across approximately 1.34 million commercially insured members over 20 months. Members with CF were identified by 2 or more International Classification of Diseases, Tenth Revision codes (E84.xx) in any field at least 30 days apart or by a CFTR modulator claim. Only continuously enrolled members with CF with an elexacaftor/tezacaftor/ivacaftor pharmacy claim were included. The date of the first claim served as the index date. RESULTS: At 12 months after FDA approval, 77 (68%) Blue Cross NC members with CF were using elexacaftor/tezacaftor/ivacaftor. Of these, 33 had switched from a different CFTR modulator and 44 were naive to CFTR modulator therapy. Pharmacy and medical claims for 51 continuously enrolled members that initiated elexacaftor/tezacaftor/ivacaftor were analyzed. The average total cost of care increased by 52% (P < 0.00001). Hospitalizations decreased from an average of 7.7 (± 7.2) to 3.9 (± 5.5) (P < 0.00001). The sum and average number of Pseudomonas aeruginosa infections were numerically lower, but the results did not meet statistical significance. Use of other supportive medications was numerically lower, but no statistically significant differences were observed. CONCLUSIONS: The uptake of elexacaftor/tezacaftor/ivacaftor was rapid, and the total cost of care increased despite reductions in hospitalizations and nonpharmacy costs. Differences in use of other CF-related medications appeared to be minimally affected. DISCLOSURES: Dr Smith and Dr Borchardt have no financial conflicts of interest to report. Both authors are employed at BCBSNC at the time of writing. The project had no outside funding or sponsorship. The majority of the work and data analysis was completed as part of the requirements of the PGY1 Managed Care Pharmacy Residency program at BCBSNC during the 2020-2021 cycle year. This research does not meet the definition of human subject research as defined by the US Department of Health and Human Services at 45 C.F.R. § 46.102(f). According to definitions in section (e)(1), our research did not require either (i) information or biospecimens through intervention or interaction with any individuals or (ii) obtained, used, studied, analyzed, or generated private information or identifiable biospecimens. Therefore, institutional review board approval or a valid exemption is not required.