The four cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have revolutionised the treatment of CF by direct action on the protein target behind the disease\'s development. The aim was to develop and validate a quantification method for these CFTR modulators in plasma and breast milk to better understand inter-patient variability in pharmacokinetics and treatment outcome, including the risk of adverse drug reactions. The ability to monitor CFTR modulators in breast milk enables the estimation of the exposure of breastfed infant, with a potential concern for CFTR modulator-induced liver injury. The analysis was performed on a Thermo Vanquish Flex Binary UHPLC system coupled to a high-resolution mass spectrometer (HRMS), Thermo Q Exactive. The analytes were detected using positive electrospray ionisation in full scan mode. After sample preparation by protein precipitation, the supernatant was injected onto the LC system and the analytes were separated using a Zorbax SB-C18 Rapid Res HPLC column (3.5 µm, 4.6 × 75 mm). This is the first published method for CFTR modulators in breast milk. The validated quantification range for ivacaftor is 0.0050-10 µg/mL with a coefficient of variation < 6% and a mean accuracy of 97-106%; for lumacaftor, tezacaftor, and elexacaftor, the validated quantification range is 0.050-100 µg/mL with a coefficient of variation < 8% and a mean accuracy 93-106%. A simple and sensitive quantification method for CFTR modulators has been developed and used for routine analysis of human plasma and breast milk samples since 2022.

BACKGROUND: The objective of this study was to assess the differential times of submission and approval of CFTR modulators in the United States (US) and the European Union (EU).
METHODS: By collecting publicly available data from the websites of the Food and Drug Administration and the European Medicines Agency, we quantified differential times in submission, review duration, and approvals of initial marketing authorization and variation of indications of CFTR modulators in the US and the EU by December 31, 2023.
RESULTS: Applications regarding marketing of 4 CFTR modulators were submitted 103 (SD ±143) days later in the EU than in the US: 31 (SD ±39) days later for initial approval, and 124 (SD ±155) days for supplemental indications. The regulatory review process was completed in 181 days [IQR, 179 - 182] in the US and 325 days [IQR, 276 - 382] in the EU: 167 days [IQR, 102 - 232] in the US and 346 days [IQR, 302 - 400] in the EU for first approvals, 181 days [IQR, 181 - 182] in the US and 324 days [IQR, 264 - 382] in the EU for supplemental indication approvals. CFTR modulators were approved 267 (SD 143) days later in the EU than in the US: 220 (SD ±76) days for initial approval and 280 (SD ±157) days for supplemental indications.
CONCLUSIONS: We found significant differences in times of submission and for approval of CFTR modulators between the US and EU, whereby initial approvals and subsequent indication approvals were always first granted in the US.

UNASSIGNED: The availability of cystic fibrosis transmembrane conductance regulator (CFTR) modulators opens the possibility of discontinuing some chronic pulmonary therapies to decrease cystic fibrosis (CF) treatment burden. However, CFTR modulators may not adequately address neutrophilic inflammation, which contributes to a self-perpetual cycle of viscous CF sputum, airway obstruction, inflammation, and lung function decline.
UNASSIGNED: This review discusses the emerging role of neutrophil extracellular traps in CF and its role in CF sputum viscosity, airway obstruction, and inflammation, based on a literature search of PubMed (1990-present). We summarize clinical trials and real-world studies that support the efficacy of dornase alfa (Pulmozyme) in improving lung function and reducing pulmonary exacerbation in people with CF (PwCF), and we discuss the potential role of dornase alfa in reducing airway inflammation. We also examine the findings of short-term trials evaluating the discontinuation of mucoactive therapy in PwCF receiving CFTR modulators.
UNASSIGNED: Long-term studies are needed to assess the impact of discontinuing mucoactive therapy in PwCF who are clinically stable while receiving CFTR modulatory therapy. Treatment decisions should take into account the severity of underlying lung disease. People with advanced CF will likely require ongoing mucoactive therapy.

UNASSIGNED: People with cystic fibrosis (CF) can experience recurrent chest infections, pancreatic exocrine insufficiency and gastrointestinal symptoms. New cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs improve lung function but gastrointestinal effects are unclear. We aimed to see if a CFTR modulator (tezacaftor-ivacaftor,TEZ/IVA) improves gastrointestinal outcomes in CF.
UNASSIGNED: We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ/IVA on gut physiology were measured using MRI. Participants were randomly assigned to treatment sequences AB or BA (A:TEZ/IVA, B:placebo, each 28 days), with a 28-day washout period. Participants had serial MRI scans at baseline and after 19-23 days of each treatment. Due to the COVID-19 pandemic, a protocol amendment allowed for observer-blind comparisons prior to and during TEZ/IVA. In such cases, participants were not blind to the treatment but researchers remained blind. The primary outcome was oro-caecal transit time (OCTT). Secondary outcomes included MRI metrics, symptoms and stool biomarkers.
UNASSIGNED: We randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ/IVA for OCTT (TEZ/IVA >360minutes [225,>360] vs. placebo 330minutes [285,>360], p=0.8) or secondary outcomes. There were no adverse events.
UNASSIGNED: Our data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators.
UNASSIGNED: NCT04006873 (02/07/2019).

Allergic bronchopulmonary aspergillosis (ABPA) results from complex hypersensitivity reactions to Aspergillus fumigatus, which often occur in patients with asthma, cystic fibrosis (CF), or CF transmembrane conductance regulator (CFTR)-related disorders. Genetic predisposition, particularly variants of the CFTR gene, probably plays a significant role in the development of ABPA. We present the case of a 20-year-old male with ABPA and bronchiectasis that was initially misdiagnosed as a result of normal sweat chloride values and negative first-level genetic testing results. Comprehensive CFTR gene sequencing revealed 2 pathogenic variants, R347H and D1152H, which together with the clinical phenotype and functional tests, supported the diagnosis of CF. Treatment with elexacaftor/tezacaftor/ivacaftor resulted in significant clinical and functional improvement, including a marked decrease in total IgE levels, suggesting a potential role for CFTR modulators in controlling ABPA. This case illustrates the evolving understanding of CF as a spectrum of disorders in which CFTR dysfunction may manifest subtly and variably, necessitating a high index of suspicion and a comprehensive diagnostic approach to ensure timely treatment in the era of highly effective CFTR modulators.

Background/Objectives: Cystic fibrosis is a genetically determined disease that significantly influences and shortens life. Treatment with CFTR modulators (CFTR-T) is a new hope for patients. It can change the predictive values of a poor prognosis (e.g., exacerbation rate and FEV1 value). The aim of the study was to analyse exacerbation incidence and spirometry data before and after one year (+/- 2 weeks) of CFTR-T in 85 CF patients at the CF Centre in Poznań. To our knowledge, this is the first analysis of CFTR-T efficiency in the Central-Eastern Europe population. Methods: We retrospectively analysed the spirometry and exacerbation data of 85 CF adult patients (both men and women), who in the middle of 2022 began treatment with CFTR modulators. Results: The one-year ratio of hospitalisation caused by severe exacerbations lowered from 1.25 to 0.21 per patient per year. We also saw a 66% decline in ambulatory exacerbations. The median FEV1% increased by 9.60% in absolute values and by 460 mL. Even in the group with very severe obstruction (FEV1 < 35%), there was an increase in median FEV1% of 5.9 in absolute values. We also proved the increase in FVC% (median 17.10% in absolute value and 600 mL) in the study group. Conclusions: After one year of treatment, an impressive improvement was observed in two important predictive values of poor prognosis: exacerbation rate and FEV1 values. Further observation is needed to determine how long the improvement will be present and its influence on quality of life and life expectancy.

BACKGROUND: Chronic rhinosinusitis (CRS) is prevalent in cystic fibrosis (CF), significantly affecting quality of life. The introduction of CFTR modulators, including elexacaftor-tezacaftor-ivacaftor (ETI), offers promise for improving sinonasal outcomes.
METHODS: We conducted a retrospective cohort multicenter study analyzing electronic medical records of 45 adult CF patients with CRS, predominantly heterozygous for the ΔF508 mutation, treated with ETI between January 2018 and December 2023. Assessments included Sinonasal Outcome Test 22 (SNOT-22), Nasal Polyp Score (NPS), modified Lund-Kennedy Score (mLKS), Lund-Mackay Score (LMS), and olfactory function using smell loss visual analog scale (VAS) and Sniffin\' Sticks identification test (SSIT).
RESULTS: After 12 months of ETI therapy, significant improvements were observed in pulmonary function parameters (FEV1, FVC), CRS severity scores (SNOT-22, NPS, mLKS), radiological findings (LMS), and olfactory function. Subgroup analysis suggested enhanced efficacy in patients with prior endoscopic sinonasal surgery.
CONCLUSIONS: ETI therapy demonstrates comprehensive improvements in CRS and olfactory function in CF patients, highlighting the potential of CFTR modulators in managing sinonasal manifestations.

People with cystic fibrosis (pwCF) have an altered gastrointestinal microbiome. These individuals also demonstrate propensity toward developing small intestinal bacterial overgrowth (SIBO). The dysbiosis present has intestinal and extraintestinal implications, including potential links with the higher rates of gastrointestinal malignancies described in CF. Given these implications, there is growing interest in therapeutic options for microbiome modulation. Alternative therapies, including probiotics and prebiotics, and current CF transmembrane conductance regulator gene modulators are promising interventions for ameliorating gut microbiome dysfunction in pwCF. This article will characterize and discuss the current state of knowledge and expert opinions on gut dysbiosis and SIBO in the context of CF, before reviewing the current evidence supporting gut microbial modulating therapies in CF.

This past year, there were many important advances for patients with cystic fibrosis (CF). Of the many publications related to CF in 2023, there was further evaluation of highly effective modulator therapy, new assessments and guidelines for clinical manifestations and therapies for CF, advances in newborn screening and diagnosis, and evaluation of outcomes for people with CF transmembrane conductance regulator-related metabolic syndrome/CF screen positive, inconclusive diagnosis. The aim of this review article is not to provide a full assessment of the wide range of articles published in 2023, but to provide a brief review of publication that may lead to changes in clinical care.

The introduction of CFTR modulator drugs like elexacaftor-tezacaftor-ivacaftor (ETI) has transformed the management of cystic fibrosis (CF), significantly improving symptoms, lung function, and quality of life, while reducing reliance on intravenous antibiotics. However, respiratory exacerbations in the CFTR modulators era remain poorly understood from both pathophysiological and clinical perspectives. We present the case of a 20-year-old Caucasian woman with CF (F508del/L1077P) who, after three years of ETI treatment, experienced a severe episode of hemoptysis, despite being almost asymptomatic in the weeks leading up to admission, requiring bronchial artery embolization. Following ETI treatment, auscultatory findings and FEV1 changes may be less significant, making the detection of respiratory exacerbation more challenging. This highlights the need for heightened vigilance in managing such cases and underscores the challenge of diagnosing and managing exacerbations in the era of modulators. Long term real-world studies are essential to comprehend the evolving course of the disease during ETI treatment.