Effects on growth, weight and body composition after CFTR modulators in children with cystic fibrosis.

BACKGROUND: Cystic Fibrosis (CF) is associated with compromised nutrition status, which is responsible for morbidity and mortality along with lung function decline. This study was designed to examine changes in anthropometric markers and body composition parameters by bioelectrical impedance analysis after CFTR modulator (CFTRm) treatment. METHODS: We compared anthropometric parameters and body composition before and after 6 and 12 months of CFTRm treatment. Results are stratified into subgroups according to the modulator used with dual therapy with lumacaftor + ivacaftor or tezacaftor + ivacaftor (LUMA/TEZ + IVA) or triple therapy with elexacaftor + tezacaftor + ivacaftor (ELE + TEZ + IVA). Body composition data are available in patients treated with ELE + TEZ + IVA. RESULTS: Two hundred and thirty-four children (55.1% male) were recruited. The median age was 13.6 years (inter-quartile range [IQR] 10.7-16.1). We can observe a statistically significant increase in the weight Z score and BMI Z score after CFTRm. In terms of changes in body composition, we observe a significant increase in fat mass (FM) expressed both in kilograms and as a percentage at 6 months (p < .05; Wilcoxon-test), with no such differences found at 12 months. We also observe a statistically significant increase in fat-free-mass (FFM), expressed in kilograms at 6 and 12 months (p < .05; Wilcoxon-test). CONCLUSION: Weight status improved and changes in body composition occurred in children after CFTRm therapy, including an increase of fat mass. Further studies are needed to confirm these changes in body composition and their impact on disease progression.

Ivacaftor for Chronic Obstructive Pulmonary Disease - Results from a Phase 2, Randomized Controlled Trial.

RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) exhibit acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. CFTR modulators may improve outcomes in patients with COPD, although recent data regarding magnitude of benefit have been inconclusive and effects on mucociliary clearance are unknown. We conducted a phase 2, randomized, double blind placebo control trial to determine safety and tolerability, and explore the potential mechanism of ivacaftor for the treatment of COPD. METHODS: We randomized 40 patients with moderate to severe COPD and symptoms of chronic bronchitis to ivacaftor (N=30) or placebo (N=10) 150mg BID for 12 weeks. Primary endpoints included evaluation of safety of ivacaftor and pharmacokinetics (PK). Secondary endpoints included measures of CFTR activity and clinical outcomes. RESULTS: Ivacaftor was safe and tolerable with similar rates of adverse events rates between groups. Most common adverse event was diarrhea in the ivacaftor group and acute COPD exacerbation in the placebo group. PK analysis found the mean area under the curve over 12 hours (AUC12) to be 72% of the previously reported AUC12 in cystic fibrosis (CF). Treatment with ivacaftor did not improve sweat chloride, whole lung mucociliary clearance, lung function or respiratory symptoms. CONCLUSION: Ivacaftor was safe and well tolerated, but did not improve measures of CFTR activity or mucus clearance. As serum concentrations achieved were lower than observed in CF at the same dose, and modulation of wild type CFTR differs from G551D, further dose determination studies are needed to better understand treatment efficacy of CFTR potentiators in COPD. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT03085485.

Impact of Cystic Fibrosis Transmembrane Conductance Regulator Modulators on Maternal Outcomes During and After Pregnancy.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are available to the majority of people with CF in the United States (US); little is known about pregnancy outcomes with modulator use. This retrospective study aims to determine the impact of CFTR modulators on maternal outcomes. RESEARCH QUESTION: Does pregnancy differentially impact outcomes in females with CF with and without CFTR modulators? STUDY DESIGN AND METHODS: We collected data on pregnancies from 2010-2021 from 11 US adult CF centers. We conducted multivariable longitudinal regression analysis to assess whether changes in percent predicted forced expiratory volume in 1 second (ppFEV1), body mass index (BMI), pulmonary exacerbations (PEx), and Pseudomonas aeruginosa prevalence differed from before, during, and after pregnancy by CFTR modulator use, while adjusting for confounders. We also describe infant outcomes based on maternal modulator use. RESULTS: Among 307 pregnancies, mean age at conception was 28.5 years (range: 17-42), pre-pregnancy ppFEV1 was 74.2 and BMI was 22.3 kg/m2. One hundred and fourteen pregnancies (37.1%) had CFTR modulator exposure during pregnancy (77 with highly effective modulator therapy [HEMT] and 37 with other modulators). The adjusted mean change in ppFEV1 from pre- to during pregnancy was -2.36 (95%CI: -3.56, -1.16) in the unexposed group and +2.60(95%CI: 0.23, 4.97) in the HEMT group, with no significant change from during to one-year post-pregnancy. There was an overall decline in ppFEV1 from pre- to post-pregnancy in the no modulator group (-2.56; 95%CI:-3.62, -1.49) that was not observed in the HEMT group (1.10; 95%CI: -1.13, 3.34). PEx decreased from pre- to post-pregnancy in the HEMT group and BMI increased from pre- to during pregnancy in all groups but without a significant change post-pregnancy. Missing infant outcome data precluded firm conclusions. INTERPRETATION: We observed superior pregnancy and post-pregnancy pulmonary outcomes in individuals who used HEMT, including a preservation of ppFEV1, compared with those unexposed to HEMT.

CFTR modulators response of S737F and T465N CFTR variants on patient-derived rectal organoids.

BACKGROUND: Predictions based on patient-derived materials of CFTR modulators efficacy have been performed lately in patient-derived cells, extending FDA-approved drugs for CF patients harboring rare variants. Here we developed intestinal organoids from subjects carrying S737F- and T465N-CFTR in trans with null alleles to evaluate their functional impact on CFTR protein function and their restoration upon CFTR modulator treatment. The characterization of S737F-CFTR was performed in two subjects recently assessed in nasal epithelial cells but not in colonoids. RESULTS: Our functional analysis (Ussing chamber) confirmed that S737F-CFTR is a mild variant with residual function as investigated in colonoids of patients with S737F/Dele22-24 and S737F/W1282X genotypes. An increase of current upon Elexacaftor/Tezacaftor/Ivacaftor (ETI) treatment was recorded for the former genotype. T465N is a poorly characterized missense variant that strongly impacts CFTR function, as almost no CFTR-mediated anion secretion was registered for T465N/Q39X colonoids. ETI treatment substantially improved CFTR-mediated anion secretion and increased the rescue of mature CFTR expression compared to either untreated colonoids or to dual CFTR modulator therapies. CONCLUSIONS: Our study confirms the presence of a residual function of the S737F variant and its limited response to CFTR modulators while predicting for the first time the potential clinical benefit of Trikafta® for patients carrying the rare T465N variant.

Theranostics vs theratyping or theranostics plus theratyping?

Treating all people with Cystic Fibrosis (pwCF) to the level of benefit achieved by highly efficient CFTR modulator therapies (HEMT) remains a significant challenge. Theratyping and theranostics are two distinct approaches to advance CF treatment. Both theratyping in cell lines and pwCF-derived biomaterials theranostics have unique strengths and limitations in the context of studying and treating CF. The challenges, advantages and disadvantages of both approaches are discussed here. While theratyping in cell lines offers ease of use, cost-effectiveness, and standardized platforms for experimentation, it misses physiological relevance and patient-specificity. Theranostics, on the other hand, provides a more human-relevant model for personalized medicine approaches but requires specialized expertise, resources, and access to patient samples. Integrating these two approaches in parallel and leveraging their respective strengths may enhance our understanding of CF and facilitate the development of more effective therapies for all pwCF.

Allergic Bronchopulmonary Aspergillosis (ABPA) in the Era of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity disease caused by Aspergillus fumigatus (Af), prevalent in persons with cystic fibrosis (CF) or asthma. In ABPA, Af proteases drive a T-helper cell-2 (Th2)-mediated allergic immune response leading to inflammation that contributes to permanent lung damage. Corticosteroids and antifungals are the mainstays of therapies for ABPA. However, their long-term use has negative sequelae. The treatment of patients with CF (pwCF) has been revolutionized by the efficacy of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Pharmacological improvement in CFTR function with highly effective elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes of pwCF. The mechanism behind the improvement in patient outcomes is a continued topic of investigation as our understanding of the role of CFTR function evolves. As ETI therapy gains traction in CF management, understanding its potential impact on ABPA, especially on the allergic immune response pathways and Af infection becomes increasingly crucial for optimizing patient outcomes. This literature review aims to examine the extent of these findings and expand our understanding of the already published research focusing on the intersection between ABPA therapeutic approaches in CF and the rapid impact of the evolving CFTR modulator landscape. While our literature search yielded limited reports specifically focusing on the role of CFTR modulator therapy on CF-ABPA, findings from epidemiologic and retrospective studies suggest the potential for CFTR modulator therapies to positively influence pulmonary outcomes by addressing the underlying pathophysiology of CF-ABPA, especially by decreasing inflammatory response and Af colonization. Thus, this review highlights the promising scope of CFTR modulator therapy in decreasing the overall prevalence and incidence of CF-ABPA.

Exploring the complexity of cystic fibrosis (CF) and psychosocial wellbeing in the 2020s: Current and future challenges.

Cystic fibrosis (CF) is traditionally associated with considerable and progressive multisystem pathology, onerous treatment burden, complex psychosocial challenges, and reduced life-expectancy [1-9].This decade has seen transformative change in management for many, but not all, people with CF. The most notable change comes from Cystic Fibrosis Transmembrane Receptor (CFTR) modulators, which bring significant benefits for people who are eligible for, and able to access, them [10]. However alongside, or perhaps because of, this exciting progress, the past few years have also brought important novel challenges to the psychosocial wellbeing of people with CF. This article, written as a collaboration between CF psychologists, social workers, physicians and nurses aims to provide an accessible overview of the novel psychosocial challenges now faced by children, their families, and adults with CF, and to invite consideration of their changing psychosocial requirements to inform future holistic care. Themes include geopolitical stressors such as the pandemic and its wake, a growing divide between those able or unable to access CFTR modulators, potential rapid changes in life expectancy secondary to these drugs and the inevitable associated challenges this brings; evolving body image, mental health side effects of CFTR modulators, the challenges of adherence in apparently well children and young adults, as well as the diagnostic conundrum and associated anxiety of the cystic fibrosis screen positive inconclusive diagnosis (CFSPID) label. It also highlights some unmet research and service delivery needs in the area.

Self-reported chronic therapy use after 24-weeks of follow-up by participants who completed the simplify randomized, controlled trial.

BACKGROUND: Highly effective CFTR modulator therapy (HEMT) has improved the health of many people with cystic fibrosis (pwCF), offering opportunities to discontinue burdensome therapies. SIMPLIFY included randomized, controlled trials that confirmed non-inferiority of discontinuing versus continuing dornase alfa (DA) or hypertonic saline (HS) for 6 weeks in pwCF on HEMT. In this study of post-trial treatment use by SIMPLIFY participants, we hypothesized that randomization to discontinue DA or HS during the trial would be associated with a higher likelihood of non-use of each medication during follow-up. METHODS: We electronically surveyed SIMPLIFY participants every 4 weeks for 24 weeks after trial completion but before the main trial results were publicly disclosed. We asked them how often they used medications during the previous week. We estimated covariate-adjusted odds ratios (ORs) of DA or HS non-use by logistic regression with generalized estimating equations. RESULTS: After exclusions mostly due to lack of any surveys, 472 participants were included in the analysis population, 181 from the HS trial and 291 from the DA trial. Approximately half of the analysis population completed all six surveys. At every month of follow-up in both trials, the percentage of individuals reporting non-use of DA or HS during the previous week was greater among those randomized to discontinue therapy. Among participants with responses at 24 weeks, 30/122 (24.6 %) in the HS trial and 79/222 (35.6 %) in the DA trial reported non-use of the respective study medication. After adjusting for covariates, participants randomized to discontinue DA were 8.7-times (95 % CI: 4.3-17.7) more likely to not use DA during follow-up than those randomized to continue DA, and participants randomized to discontinue HS were 5.2-times (95 % CI: 2.1-12.8) more likely to not use HS during follow-up compared to those randomized to continue. CONCLUSIONS: In healthy pwCF on ETI, randomization to discontinue DA or HS during SIMPLIFY was associated with greater odds of not using each medication after the trial compared to randomization to continue. These findings suggest that participation in a treatment discontinuation trial can influence participants' post-trial treatment decisions. This possibility may be relevant during discussions about research participation and clinical care.

CFTR Modulators Therapy Efficacy in Reducing Cystic Fibrosis (CF) Exacerbation and Improving Selected Spirometry Parameters: A Real-Life Study in a Single-Centre Polish Population.

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 Poznan. 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.

The continuing need for dornase alfa for extracellular airway DNA hydrolysis in the era of CFTR modulators.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Development and clinical implementation of an LC-HRMS method for ivacaftor, lumacaftor, tezacaftor and elexacaftor in human plasma and breast milk.

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.

Differential times of submission and approval of CFTR modulators for the treatment of Cystic Fibrosis in the United States and the European Union.

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. CONCLUSION: 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.

Cystic fibrosis-related chronic rhinosinusitis: the key role of a comprehensive evaluation in the era of highly effective modulator therapy.

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.

The gastrointestinal microbiome, small bowel bacterial overgrowth, and microbiome modulators in cystic fibrosis.

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.

Allergic bronchopulmonary aspergillosis as an initial manifestation of cystic fibrosis: Diagnostic and therapeutic implications in the era of CFTR modulators.

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.

Efficacy and safety of LAU-7b in a Phase 2 trial in adults with cystic fibrosis.

BACKGROUND: Lung inflammation is associated with tissue damage in cystic fibrosis (CF). LAU-7b, a novel oral drug candidate, was shown to control inflammation and stabilize CFTR protein in the epithelial membrane during inflammatory stress in preclinical models of CF. METHODS: A double-blind, randomized, placebo-controlled Phase 2 study was conducted to evaluate efficacy and safety of LAU-7b in adults with CF. LAU-7b or placebo was administered over 24 weeks as six 21-day treatment cycles each separated by 7 days. The primary efficacy endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) at 24 weeks. RESULTS: A total of 166 subjects received at least one dose of study drug (Intent-To-Treat population, ITT), of which 122 received ≥5 treatment cycles (Per-Protocol population, PP). Both treatment arms showed a mean lung function loss at 24 weeks of 1.18 ppFEV1 points with LAU-7b and 1.95 ppFEV1 with placebo, a 0.77 ppFEV1 (40 s) difference, p=0.345, and a 0.95 ppFEV1 (49 %) difference in the same direction in PP population, p=0.263. Primary analysis of mean ppFEV1 through 24 weeks showed differences of 1.01 and 1.23 ppFEV1, in the ITT (65 % less loss, p=0.067) and PP populations (78 % less loss, reaching statistical significance p=0.049), respectively. LAU-7b had an acceptable safety profile. CONCLUSION: Although the study did not meet its primary efficacy endpoint in the ITT population, LAU-7b was generally well tolerated and showed evidence of preservation of lung function to support further development.

Cystic fibrosis year in review 2023.

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.

A case of severe pulmonary exacerbation in a young patient with cystic fibrosis in the era of CFTR modulators.

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.

Enhanced CFTR modulator efficacy in ΔF508 CFTR mouse organoids by ablation of RFFL ubiquitin ligase.

The most common CFTR mutant in cystic fibrosis (CF), ΔF508 CFTR, is eliminated by ubiquitination even in the presence of CF drugs, reducing their therapeutic efficacy. RFFL is one of the ubiquitin ligases that remove ΔF508 CFTR from the cell surface despite treatment with the triple combination of CFTR modulators (TEZ/ELX/IVA) used clinically. Although RFFL knockdown has been shown to enhance the efficacy of TEZ/ELX/IVA in cell culture models, its impact in mouse models has not been evaluated. Here, we demonstrate that RFFL ablation significantly improves the effect of TEZ/ELX/IVA, resulting in enhanced function of ΔF508 CFTR in mouse organoids. Since RFFL knockout mice showed no significant abnormalities, our findings support RFFL inhibition as a promising strategy to improve CFtreatment.

A rapid LC-MS/MS method for the simultaneous quantification of ivacaftor, lumacaftor, elexacaftor, tezacaftor, hexyl-methyl ivacaftor and ivacaftor carboxylate in human plasma.

Cystic fibrosis is one of the most common genetic diseases among caucasian population. This disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding for the CFTR protein. Lumacaftor, elexacaftor, tezacaftor, and ivacaftor were currently used as the treatment to Cystic fibrosis. In this study, we describe a new method for the simultaneous quantification of four molecules: lumacaftor, elexacaftor, tezacaftor, and ivacaftor, alongside two metabolites of ivacaftor, specifically hexyl-methyl ivacaftor and ivacaftor carboxylate by liquid chromatography-tandem mass spectrometry. This method holds significant utility for therapeutic drug monitoring and the optimization of treatments related to CFTR modulators. Molecules were extracted from 100 µL of plasma by a simple method of protein precipitation using acetonitrile. Following extraction, chromatographic separation was carried out by reverse chromatography on a C18 analytical column, using a gradient elution of water (0.05 % formic acid, V/V) and acetonitrile (0.05 % formic acid, V/V). The run time was 7 minutes at a flow rate of 0.5 mL/min. After separation, molecules were detected by electrospray ionization on a Xevo TQD triple-quadrupole-mass-spectrometer (Waters®, Milford, USA). The calibration range were: 0.053-20.000 mg/L for elexacaftor, tezacaftor and lumacaftor, 0.075-14.000 mg/L for ivacaftor, and 0.024-6.500 mg/L for hexyl-methyl ivacaftor and ivacaftor carboxylate. The proposed method underwent throughout validation demonstrating satisfactory precision (inter- and intra-day coefficients of variation less than 14.3 %) and a good accuracy (inter- and intra-day bias ranging between -13.7 % and 14.7 %) for all the analytes. The presented method for the simultaneous quantification of CFTR modulators and their metabolites in human plasma has undergone rigorous validation process yielding good results including strong precision and accuracy for all analytes. This method has been effectively used in routine analytical analysis and clinical investigations within our laboratory.