Elexacaftor-tezacaftor-ivacaftor Research Articles

P216 The impact of the COVID-19 pandemic and elexacaftor/tezacaftor/ivacaftor initiation on high-cost medication utilisation in adults living with cystic fibrosis

The COVID-19 pandemic, lockdowns, and availability of elexacaftor/tezacaftor/ivacaftor (ETI) were significant simultaneous events for people living with cystic fibrosis (pwCF) in the UK. In this study, we aimed to assess the impact of these events on other high-cost medication utilisation.

EPS4.10 Obstetric and neonatal outcomes in women with cystic fibrosis (wwCF) and diabetes in pregnancy

Objectives: Pre-conception diabetes and gestational diabetes (GDM) are associated with higher rates of adverse obstetric and neonatal outcomes. GDM has a 16% incidence in the UK and CF-Diabetes (CFD) affects 30–50% of adults. The management and outcomes relating to diabetes in pregnancy are of interest due to increased pregnancies since elexacaftor-tezacaftor-ivacaftor (ETI).

P155 The impact of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on occurrence of bacterial lung infections in cystic fibrosis patients

Lung disease is the main cause of morbidity and mortality in CF. The introduction of CFTR modulators has led to clinical benefits in CF patients. However, the extent to which these therapies reduce susceptibility to chronic lung infections remains to be elucidated. We aimed to evaluate the impact of ETI on CF airway microbiology after one year of treatment.

P162 Elexacaftor/tezacaftor/ivacaftor significantly improves thoracic radiological outcomes in cystic fibrosis

Cystic Fibrosis (CF) care has been revolutionised by the introduction of elexacaftor/tezacaftor/ivacaftor (ETI) therapy. Clinical trials have demonstrated positive effects of ETI on lung function, weight and quality of life, but little is known about how this treatment impacts the structural lung damage seen in established CF.

P245 Real-world elexacaftor/tezacaftor/ivacaftor(ETI) changes prospective sputum collection and microbiological reporting in a single centre pilot cystic fibrosis cohort

Microbiological analysis of patients-with-cystic-fibrosis (PWCF) is aided by spontaneous sputum expectoration at clinic visits.

EPS6.03 Pulmonary pathogen prevalence 12 months after elexacaftor/tezacaftor/ivacaftor introduction: results from the Danish National Cystic Fibrosis Cohort

Objectives: Several pathogens colonize the lungs and cause intermittent or persistent infection in cystic fibrosis (CF). The objective of this study was to assess change in pulmonary pathogen prevalence in clinically relevant subgroups from five years before and until 12 months after elexacaftor/tezacaftor/ivacaftor (ETI) initiation.

P062 The impact of elexacaftor/tezacaftor/ivacaftor on adherence to inhaled medication in adults with cystic fibrosis: a 3-centre study in Greece

Objective: To compare adherence to inhaled medications before and after elexacaftor/tezacaftor/ivacaftor (ETI) initiation

P167 Antibiotic courses in children and adolescents with cystic fibrosis: after only a year of elexacaftor/tezacaftor/ivacaftor, there’s a “before and after”

To describe the evolution of antibiotic administration in a 1-year experience with elexacaftor/tezacaftor/ivacaftor (ETI) in children and adolescents diagnosed with Cystic Fibrosis (pwCF).

P168 Determining the relationship between vitality and C-Reactive protein in those initiating elexacaftor/tezacaftor/ivacaftor

Systemic inflammation is a biomarker of disease activity in people with Cystic Fibrosis (pwCF) as it correlates with health-related quality of life (HRQoL). Elexacaftor/tezacaftor/ivacaftor (ETI) reduces systemic inflammation and increases HRQoL in pwCF, but no prior studies have examined the relationship between these parameters. Vitality is an important aspect of HRQoL and we hypothesized that decreases in systemic inflammation would correlate with improvements in vitality post-ETI.

Elexacaftor-tezacaftor-ivacaftor in patients with cystic fibrosis ineligible for clinical trials: a 24-week observational study.

Introduction: Seminal clinical trials with the triple combination of elexacaftor-tezacaftor-ivacaftor (ETI) demonstrated clinical efficacy in people with cystic fibrosis (pwCF) who carry at least one F508del mutation. However, due to exclusion criteria of these clinical trials, the effect of ETI was not studied in a substantial number of pwCF. Thus, we ran a single center trial to evaluate a clinical efficacy of ETI treatment in adult pwCF who were ineligible for enrollment in registration studies. Methods: PwCF on ETI with prior lumacaftor-ivacaftor therapy, severe airway obstruction, well-preserved lung function, or with airway infection with pathogens at risk of more rapid decline in lung function formed the study group, while all the others on ETI formed the control group. Lung function, nutritional status and sweat chloride concentration were assessed before and after initialization of ETI therapy over a 6-month period. Results: Approximately a half of the ETI-treated pwCF at the adult Prague CF center (49 of 96) were assigned to the study group. Their mean changes in body mass index ( + 1.04kg/m2) and in sweat chloride concentration (-48.4mmol/L) were similar to the control group ( + 1.02kg/m2; -49.7mmol/L), while the mean change in percent predicted forced expiratory volume in 1s (ppFEV1; + 10.3 points) was significantly lower than in the control group ( + 15.8 points) (p = 0.0015). In the subgroup analysis, pwCF with severe airway obstruction (ppFEV1 <40) and pwCF with well-preserved lung function (ppFEV1 >90) showed a less potential for improvement in lung function during the ETI treatment than controls (median change in ppFEV1 + 4.9 points and + 9.5 points, respectively). Conclusion: PwCF not eligible for inclusion in clinical trials demonstrated improvement in lung function and nutritional status following the initiation of treatment with the ETI combination. Moderate increase in ppFEV1 was observed in those with severe airway obstruction or well-preserved lung function.

Positive and negative impacts of elexacaftor/tezacaftor/ivacaftor: Healthcare providers' observations across US centers.

Elexacaftor/tezacaftor/ivacaftor (ETI) has been associated with unprecedented clinical improvements, transforming the management of cystic fibrosis (CF). However, side effects with implications for safety and well-being have been reported, including neuropsychiatric changes. This study aimed to better characterize the emerging positive and negative impacts of ETI. The Cystic Fibrosis Foundation's Mental Health Advisory Committee distributed a 26-item survey to US CF care teams to assess clinician observations of patient-reported experiences with ETI. Survey responses measured the prevalence of these effects in five domains: (1) positive physical and psychological effects, (2) sleep difficulties, (3) cognitive difficulties, (4) worsening mental health, and (5) concerns about the future and finances. Seventy-five healthcare providers responded from a pediatric, adult, and combined centers. Positive physical effects of ETI and increased optimism were reported in the upper quartiles (50%-100%) and rated as having a significant impact on daily functioning. Sleep and cognitive difficulties were reported in 1%-24%, with slight impacts on functioning, and psychological symptoms (e.g., increased stress, depression, anxiety) and new psychiatric medications were reported in 1%-24%, with moderate impacts. Concerns about the future were reported in 1%-24%, with minimal impacts. Across US centers, providers most often observed positive physical effects of ETI. However, a variety of negative side effects were also reported, including sleep disruptions and worsening psychological functioning, which should be systematically monitored by CF teams. These national-level data are a first step in evaluating the prevalence and consequences of these side effects and can directly inform future studies.

P158 Elexacaftor, tezacaftor, ivacaftor (ETI) improves lung function but not rate of decline in a two year observational study of adolescents

ETI became available in the UK in August 2020 to treat people with CF >12 years. We report a real-world efficacy study of respiratory outcomes after ETI in adolescents attending our CF centre.

WS13.06 Regional bronchoscopy sampling indicates that Pseudomonas aeruginosa infections persist throughout the lung after elexacaftor/tezacaftor/ivacaftor (ETI) due to intra-lung bacterial migration

Recent work suggests Pseudomonas aeruginosa (Pa) infections usually persist after ETI, but mechanisms of post-ETI infection are unknown. A leading hypothesis posits that lung segments with mild structural damage will clear infection, while those with severe damage will remain infected. To test this, we performed bronchoscopy in 9 adults with ΔF508 CFTR. CTs identified the 2 most- and 3 least-severely damaged lung segments in each subject. All 5 segments were lavaged before and 1.5 years after ETI. Before ETI, 43/45 segments were Pa-positive. After ETI, average Pa density declined 2.3 log10 CFU/mL. However, 6 subjects remained infected. In these subjects, nearly all high and low-damage segments remained Pa-positive. This finding contradicts the hypothesis that infection persists only in high-damage lung segments.

Q1291H-CFTR molecular dynamics simulations and ex vivo theratyping in nasal epithelial models and clinical response to elexacaftor/tezacaftor/ivacaftor in a Q1291H/F508del patient.

Background: Cystic fibrosis (CF) is caused by a wide spectrum of mutations in the CF transmembrane conductance regulator (CFTR) gene, with some leading to non-classical clinical presentations. We present an integrated in vivo, in silico and in vitro investigation of an individual with CF carrying the rare Q1291H-CFTR allele and the common F508del allele. At age 56years, the participant had obstructive lung disease and bronchiectasis, qualifying for Elexacaftor/Tezacaftor/Ivacaftor (ETI) CFTR modulator treatment due to their F508del allele. Q1291H CFTR incurs a splicing defect, producing both a normally spliced but mutant mRNA isoform and a misspliced isoform with a premature termination codon, causing nonsense mediated decay. The effectiveness of ETI in restoring Q1291H-CFTR is largely unknown. Methods: We collected clinical endpoint measurements, including forced expiratory volume in 1s percent predicted (FEV1pp) and body mass index (BMI), and examined medical history. In silico simulations of the Q1291H-CFTR were compared to Q1291R, G551D, and wild-type (WT)-CFTR. We quantified relative Q1291H CFTR mRNA isoform abundance in patient-derived nasal epithelial cells. Differentiated pseudostratified airway epithelial cell models at air liquid interface were created and ETI treatment impact on CFTR was assessed by electrophysiology assays and Western blot. Results: The participant ceased ETI treatment after 3months due to adverse events and no improvement in FEV1pp or BMI. In silico simulations of Q1291H-CFTR identified impairment of ATP binding similar to known gating mutants Q1291R and G551D-CFTR. Q1291H and F508del mRNA transcripts composed 32.91% and 67.09% of total mRNA respectively, indicating 50.94% of Q1291H mRNA was misspliced and degraded. Mature Q1291H-CFTR protein expression was reduced (3.18% ± 0.60% of WT/WT) and remained unchanged with ETI. Baseline CFTR activity was minimal (3.45 ± 0.25μA/cm2) and not enhanced with ETI (5.73 ± 0.48μA/cm2), aligning with the individual's clinical evaluation as a non-responder to ETI. Conclusion: The combination of in silico simulations and in vitro theratyping in patient-derived cell models can effectively assess CFTR modulator efficacy for individuals with non-classical CF manifestations or rare CFTR mutations, guiding personalized treatment strategies and optimizing clinical outcomes.

EPS5.03 Elexacaftor/Tezacaftor/Ivacaftor for 76 weeks is associated with a reduced orocaecal transit time: the GIFT-CF3 extension study

Background and objectives: The effect of elexacaftor/tezacaftor/ivacaftor (ETI) on the gut in cystic fibrosis (CF) is currently unknown. The GIFT-CF3 study (NCT04618185), a prospective cohort study, has used MRI to compare gastrointestinal (GI) function before, 12 weeks and 24 weeks after starting ETI. The primary outcome is orocaecal transit time (OCTT), or the time for food to pass from mouth to caecum. We previously found that OCTT at 24 weeks post ETI (median 360 minutes) did not change significantly vs baseline. In the GIFT-CF3 extension study, we invited participants for repeat MRI scans to evaluate whether the use of ETI lead to a reduction in OCTT after 76 weeks of ETI.

P050 Elexacaftor/tezacaftor/ivacaftor for adult cystic fibrosis patients with preserved lung function: a case series

Introduction: Elexacaftor-tezacaftor-ivacaftor (ETI) significantly improves lung function in CF patients. Previous studies have estimated that a delay in ETI initiation could have a negative impact on long-term survival. ETI use has been approved for children aged ≥6 years fulfilling the genetic criteria independent of their lung function. However, there is still controversy regarding ETI use for adult patients with preserved lung function [defined as a percentage of predicted forced expiratory volume in the first second (ppFEV1)>90%] considering that this subgroup of patients was excluded in the screening period of phase III randomized clinical trials.

WS04.03 Elexacaftor/tezacaftor/ivacaftor (ETI) treatment corrects the salt-losing phenotype in people with cystic fibrosis (pwCF)

Objectives: PwCF have an increased risk for fluid and electrolyte imbalances caused by continuous fluid and salt loss. Congruently, guidelines advocate increased salt intake. Understanding how CFTR modulators affect fluid and electrolyte homeostasis is important to provide guidance for pwCF treated with ETI. In this study, we investigate the effect of ETI treatment on blood pressure and fluid- and electrolyte homeostasis in pwCF.

P054 Long-term efficacy and safety of elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic Fibrosis (pwCF) ≥ 50 years of age in a real-world setting

Objectives: To assess long term efficacy and safety of elexacaftor/tezacaftor/ivacaftor (ETI) in people with CF (pwCF) ≥ 50 years of age in a real-world setting.

P244 The impact of CFTR modulators on positive Pseudomonas aeruginosa (Pa) culture and antibiotic susceptibility in adults with cystic fibrosis

CFTR modulators, in particular elexacaftor/tezacaftor/ivacaftor (ETI) has widely reported health benefits in eligible people with CF (pwCF). This study aims to determine the effect of the introduction of ETI on positive PsA culture in sputum and cough swabs in pwCF and any effect on ciprofloxacin susceptibility. ETI was started on 92% of eligible pwCF by the end of September 2020.

EPS3.08 Heightened mitochondrial respiration and succinate levels in cystic fibrosis cells is normalised with triple CFTR modulator therapy through mechanisms involving cell calcium flux

Objectives: Malnutrition is a hallmark of disease in cystic fibrosis (CF). The introduction of elexacaftor/tezacaftor/ivacaftor (ETI) has been associated with increased body mass index (BMI). Preliminary data from a UK cohort study (Igloo-CF), suggests that while BMI increases with ETI therapy, energy intake decreases. We hypothesised that ETI could normalise cellular metabolism in CF, and herein, we assess bioenergetics in two different drug exposed cell models each expressing wild-type (WT) or DF508/DF508 CFTR.