Cystic Fibrosis Modulator Therapies.

Cystic fibrosis (CF) is an inherited multisystemic disease that can cause progressive bronchiectasis, pancreatic endocrine and exocrine insufficiency, distal intestinal obstruction syndrome, liver dysfunction, and other disorders. Traditional therapies focused on the treatment or prevention of damage to each organ system with incremental modalities such as nebulized medications for the lungs, insulin for diabetes, and supplementation with pancreatic enzymes. However, the advent of highly effective modulator therapies that target specific cystic fibrosis transmembrane conductance regulator protein malformations resulting from individual genetic mutations has transformed the lives and prognosis for persons with CF.

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 CFTR Modulation on Pseudomonas aeruginosa Infection in People With Cystic Fibrosis.

BACKGROUND: Pseudomonas aeruginosa is a multidrug-resistant pathogen causing recalcitrant pulmonary infections in people with cystic fibrosis (pwCF). Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been developed that partially correct the defective chloride channel driving disease. Despite the many clinical benefits, studies in adults have demonstrated that while P. aeruginosa sputum load decreases, chronic infection persists. Here, we investigate how P. aeruginosa in pwCF may change in the altered lung environment after CFTR modulation. METHODS: P. aeruginosa strains (n = 105) were isolated from the sputum of 11 chronically colonized pwCF at baseline and up to 21 months posttreatment with elexacaftor-tezacaftor-ivacaftor or tezacaftor-ivacaftor. Phenotypic characterization and comparative genomics were performed. RESULTS: Clonal lineages of P. aeruginosa persisted after therapy, with no evidence of displacement by alternative strains. We identified commonly mutated genes among patient isolates that may be positively selected for in the CFTR-modulated lung. However, classic chronic P. aeruginosa phenotypes such as mucoid morphology were sustained, and isolates remained just as resistant to clinically relevant antibiotics. CONCLUSIONS: Despite the clinical benefits of CFTR modulators, clonal lineages of P. aeruginosa persist that may prove just as difficult to manage in the future, especially in pwCF with advanced lung disease.

Nasal Epithelium Transcriptomics Predict Clinical Response to Elexacaftor/Tezacaftor/Ivacaftor.

Elexacaftor/tezacaftor/ivacaftor (ETI) has made a substantial positive impact for people living with CF (pwCF). However, there can be substantial variability in efficacy, and we lack adequate biomarkers to predict individual response. We thus aimed to identify transcriptomic profiles in nasal respiratory epithelium that predict clinical response to ETI treatment. We obtained nasal epithelial samples from pwCF prior to ETI initiation and performed a transcriptome-wide analysis of baseline gene expression to predict changes in FEV1 (∆FEV1), year's best FEV1 (∆ybFEV1), and body mass index (∆BMI). Using the top differentially expressed genes (DEGs), we generated transcriptomic risk scores (TRS) and evaluated their predictive performance. The study included 40 pwCF aged ≥6 years (mean 27.7 [SD=15.1] years; 40% female). After ETI initiation, FEV1 improved ≥5% in 22 (61.1%) participants and ybFEV1 improved ≥5% in 19 (50%). TRS were constructed using top over-expressed and under-expressed genes for each. Adding the ∆FEV1 TRS for to a model with age, sex, and baseline FEV1 increased the AUC from 0.41 to 0.88; the ∆ybFEV1 TRS increased the AUC from 0.51 to 0.88; and the ∆BMI TRS increased the AUC from 0.46 to 0.92. Average accuracy was thus ~85% in predicting the response to the three outcomes. Results were similar in models further adjusted for F508del zygosity and previous CFTR modulator use. In conclusion, we identified nasal epithelial transcriptomic profiles that help accurately predict changes in FEV1 and BMI with ETI treatment. These novel TRS could serve as predictive biomarkers for clinical response to modulator treatment in pwCF.

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.

Predicting lung function decline in cystic fibrosis: the impact of initiating ivacaftor therapy.

BACKGROUND: Modulator therapies that seek to correct the underlying defect in cystic fibrosis (CF) have revolutionized the clinical landscape. Given the heterogeneous nature of lung disease progression in the post-modulator era, there is a need to develop prediction models that are robust to modulator uptake. METHODS: We conducted a retrospective longitudinal cohort study of the CF Foundation Patient Registry (N = 867 patients carrying the G551D mutation who were treated with ivacaftor from 2003 to 2018). The primary outcome was lung function (percent predicted forced expiratory volume in 1 s or FEV1pp). To characterize the association between ivacaftor initiation and lung function, we developed a dynamic prediction model through covariate selection of demographic and clinical characteristics. The ability of the selected model to predict a decline in lung function, clinically known as an FEV1-indicated exacerbation signal (FIES), was evaluated both at the population level and individual level. RESULTS: Based on the final model, the estimated improvement in FEV1pp after ivacaftor initiation was 4.89% predicted (95% confidence interval [CI]: 3.90 to 5.89). The rate of decline was reduced with ivacaftor initiation by 0.14% predicted/year (95% CI: 0.01 to 0.27). More frequent outpatient visits prior to study entry and being male corresponded to a higher overall FEV1pp. Pancreatic insufficiency, older age at study entry, a history of more frequent pulmonary exacerbations, lung infections, CF-related diabetes, and use of Medicaid insurance corresponded to lower FEV1pp. The model had excellent predictive accuracy for FIES events with an area under the receiver operating characteristic curve of 0.83 (95% CI: 0.83 to 0.84) for the independent testing cohort and 0.90 (95% CI: 0.89 to 0.90) for 6-month forecasting with the masked cohort. The root-mean-square errors of the FEV1pp predictions for these cohorts were 7.31% and 6.78% predicted, respectively, with standard deviations of 0.29 and 0.20. The predictive accuracy was robust across different covariate specifications. CONCLUSIONS: The methods and applications of dynamic prediction models developed using data prior to modulator uptake have the potential to inform post-modulator projections of lung function and enhance clinical surveillance in the new era of CF care.

Evaluation of the drug-drug interaction between triazole antifungals and cystic fibrosis transmembrane conductance regulator modulators in a real-life cohort.

Limited data on the clinical management of drug-drug interactions between triazoles and Cystic Fibrosis transmembrane conductance regulator (CFTR) modulators are available. We retrospectively evaluated azole target attainment and dose adaptations in patients from two Dutch CF centres concomitantly receiving triazoles and CFTR modulators. In total, 21 patients with 59 triazole trough concentrations were evaluated. Subtherapeutic concentrations were frequently observed, especially for itraconazole and voriconazole. Of the investigated antifungal agents, posaconazole appears the most preferable option. Our results emphasize the importance of adequate management of this interaction and underpin the added value of therapeutic drug monitoring of triazoles in this population.

Fungal infections are serious complications in Cystic Fibrosis (CF) patients. We evaluated patients concomitantly receiving triazoles and CF transmembrane conductance regulator modulators: subtherapeutic triazole exposure was frequently observed. Posaconazole appears the preferable antifungal agent.

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.

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.

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.

Use of elexacaftor/tezacaftor/ivacaftor combination in pregnancy.

INTRODUCTION: Management of cystic fibrosis has recently stepped forward with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, although data on potential adverse effects are lacking for many categories of patients, such as pregnant women. METHODS: We report one of the first reports on the outcome of pregnancy in a woman treated with Elexacaftor/Tezacaftor/Ivacaftor during the second and third trimester of pregnancy, showing a significant improvement of respiratory status, compared with the first trimester when the medication was discontinued due to unknown and, therefore, potential teratogenic effects. Also, we performed the review of the existing literature on the topic. RESULTS: The course of pregnancy was uneventful, with reference to major obstetric complications, and the patient delivered a healthy neonate. These results were similar to those coming from other short series of pregnant women affected by cystic fibrosis and treated with CFTR modulators during pregnancy. CONCLUSIONS: Thus, despite the lack of evidence on the topic, the use of Elexacaftor/Tezacaftor/Ivacaftor in pregnancy seems to be apparently not associated with major adverse events, thus opening optimistic scenarios in terms of management of these patients.

Efficacy of Elexacaftor-Tezacaftor-Ivacaftor on chronic rhinosinusitis in cystic fibrosis.

PURPOSE: Our work aims to add evidence on the effectiveness of Elexacaftor-Tezacaftor-Ivacaftor on chronic rhinosinusitis in cystic fibrosis. MATERIALS AND METHODS: We conducted an observational retrospective cohort study at the Cystic Fibrosis Center of a tertiary care hospital to investigate the effect of Elexacaftor-Tezacaftor-Ivacaftor on chronic rhinosinusitis in cystic fibrosis patients, aged 12 or older. The study's endpoints were the change in the occurrence of acute exacerbations of chronic rhinosinusitis, and the variation of the endoscopic and radiologic findings scored using the Lund-Kennedy endoscopic scale, Lund-Mackay, and modified Lund-Mackay radiologic scales, in patients who underwent both pre-treatment and post-treatment examinations. RESULTS: The study population comprised 136 patients, of which 28 underwent both pre-treatment and post-treatment nasal endoscopy and 15 had pre- and post-treatment CT scans. Elexacaftor-Tezacaftor-Ivacaftor provided a significant improvement in chronic rhinosinusitis. The mean number of acute exacerbations of chronic rhinosinusitis per year in the pre-treatment time was 0.55 versus 0.35 during the treatment (p < 0.0021). The Lund-Kennedy scale had a pre-treatment average score of 4.21 points versus 1.5 points after the start of Elexacaftor-Tezacaftor-Ivacaftor (p < 0.0001). The average Lund-Mackay and modified Lund-Mackay scores in the pre-treatment time were respectively 14.6 and 16.45 points; and after the start of the therapy, they became 5.87 and 6.73 (p < 0.0001). CONCLUSION: Elexacaftor-Tezacaftor-Ivacaftor was associated with fewer acute exacerbations of chronic rhinosinusitis, and a significant improvement of chronic rhinosinusitis evaluated endoscopically and radiologically. To our knowledge, this is the first study investigating the change in the occurrence of acute exacerbation of chronic rhinosinusitis in patients affected by cystic fibrosis in therapy with Elexacaftor-Tezacaftor-Ivacaftor.

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.

Estimation of Chloride Channel Residual Function and Assessment of Targeted Drugs Efficiency in the Presence of a Complex Allele [L467F;F508del] in the CFTR Gene.

Complex alleles of the CFTR gene complicate the diagnosis of cystic fibrosis (CF), the classification of its pathogenic variants, affect the clinical picture of the disease and can affect the efficiency of targeted drugs. The total frequency of complex allele [L467F;F508del] in the Russian population of patients with CF is 0.74%, and in patients with the F508del/F508del genotype, its frequency reaches 8%. This article presents multi-faceted study of the complex allele [L467F;F508del] in a cohort of patients with genotypes [L467F;F508del]/class I (c.3532_3535dup, c.1766+2T>C, W1310X, 712-1G>T), and data for a unique patient with the genotype [L467F;F508del]/[L467F;F508del]. Using the intestinal current measurement method, it was demonstrated the absence of CFTR function for [L467F;F508del]/class I and [L467F;F508del]/[L467F;F508del] genotypes. In intestinal organoids, it was shown that [L467F;F508del] in combination with class I variants and in the homozygotes abolishes the efficacy of both two-component (ivacaftor+lumacaftor; ivacaftor+tezacaftor) and three-component (ivacaftor+tezacaftor+elexacaftor) targeted drugs. When prescribing ivacaftor+tezacaftor+elexacaftor to three patients, they did not have a clinical effect after 6-12 months.

Functional Consequences of CFTR Interactions in Cystic Fibrosis.

Cystic fibrosis (CF) is a fatal autosomal recessive disorder caused by the loss of function mutations within a single gene for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). CFTR is a chloride channel that regulates ion and fluid transport across various epithelia. The discovery of CFTR as the CF gene and its cloning in 1989, coupled with extensive research that went into the understanding of the underlying biological mechanisms of CF, have led to the development of revolutionary therapies in CF that we see today. The highly effective modulator therapies have increased the survival rates of CF patients and shifted the epidemiological landscape and disease prognosis. However, the differential effect of modulators among CF patients and the presence of non-responders and ineligible patients underscore the need to develop specialized and customized therapies for a significant number of patients. Recent advances in the understanding of the CFTR structure, its expression, and defined cellular compositions will aid in developing more precise therapies. As the lifespan of CF patients continues to increase, it is becoming critical to clinically address the extra-pulmonary manifestations of CF disease to improve the quality of life of the patients. In-depth analysis of the molecular signature of different CF organs at the transcriptional and post-transcriptional levels is rapidly advancing and will help address the etiological causes and variability of CF among patients and develop precision medicine in CF. In this review, we will provide an overview of CF disease, leading to the discovery and characterization of CFTR and the development of CFTR modulators. The later sections of the review will delve into the key findings derived from single-molecule and single-cell-level analyses of CFTR, followed by an exploration of disease-relevant protein complexes of CFTR that may ultimately define the etiological course of CF disease.

The multiple ubiquitination mechanisms in CFTR peripheral quality control.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated anion channel, which is expressed on the apical plasma membrane (PM) of epithelial cells. Mutations in the CFTR gene cause cystic fibrosis (CF), one of the most common genetic diseases among Caucasians. Most CF-associated mutations result in misfolded CFTR proteins that are degraded by the endoplasmic reticulum quality control (ERQC) mechanism. However, the mutant CFTR reaching the PM through therapeutic agents is still ubiquitinated and degraded by the peripheral protein quality control (PeriQC) mechanism, resulting in reduced therapeutic efficacy. Moreover, certain CFTR mutants that can reach the PM under physiological conditions are degraded by PeriQC. Thus, it may be beneficial to counteract the selective ubiquitination in PeriQC to enhance therapeutic outcomes for CF. Recently, the molecular mechanisms of CFTR PeriQC have been revealed, and several ubiquitination mechanisms, including both chaperone-dependent and -independent pathways, have been identified. In this review, we will discuss the latest findings related to CFTR PeriQC and propose potential novel therapeutic strategies for CF.

The impact of SARS-CoV-2 infection in patients with cystic fibrosis undergoing CFTR channel modulators treatment: a literature review.

Several risk factors for Coronavirus-2019 (COVID-19) disease have been highlighted in clinical evidence. Among the various risk factors are advanced age, metabolic illness such as diabetes, heart disease, and diseases of the respiratory system. Cystic Fibrosis (CF) is a rare disease with autosomal recessive transmission, characterised by a lack of synthesis of the CFTR channel protein, and multi-organ clinical symptoms mainly affecting the respiratory tract with recurrent pulmonary exacerbations. In view of the pathophysiological mechanisms, CF disease should be in theory considered a risk factor for SARS-CoV2 or severe COVID-19. However, recent clinical evidence seems to point in the opposite direction, suggesting that CF could be a protective factor against severe COVID-19. Possibly, the lack of presence or function of the CFTR channel protein could be linked to the expression of the membrane glycoprotein ACE-2, a key enzyme for the endocellular penetration of SARS-CoV-2 and related to the pathophysiology of COVID-19 disease. Furthermore, CFTR channel modulating agents could indirectly influence the expression of ACE-2, playing an important role in restoring the proper functioning of mucociliary clearance and the pulmonary microbiome in the host response to SARS-CoV-2 infection. In this review, the authors attempt to shed light on these important associations of issues that are not yet fully elucidated.

Heterogeneity of weight gain after initiation of Elexacaftor/Tezacaftor/Ivacaftor in people with cystic fibrosis.

BACKGROUND: The introduction of the novel therapy, Elexacaftor/Tezacaftor/Ivacaftor (ETI) has been effective in improving weight gain in both clinical trials and real-world studies. However, the magnitude of this effect appears to be heterogeneous across patient subgroups. This study aims to identify potential determinants of heterogeneity in weight gain following 6-month ETI therapy. METHODS: We conducted a multicenter, prospective cohort study enrolling 92 adults with CF at two major CF centers in Italy with follow-up visit at one month and six months from ETI initiation. The treatment's effect on weight changes was evaluated using mixed effect regression models that included subject-specific random intercepts and fixed effects for potential predictors of treatment response, time and a predictor-by-time interaction term. RESULTS: The mean weight gain at six months from the start of treatment was 4.6 kg (95% CI: 2.3-6.9) for the 10 patients with underweight, 3.2 kg (95% CI: 2.3-4.0) for the 72 patients with normal weight, and 0.7 kg (95% CI: -1.6-3.0) for the 10 patients with overweight. After six months of ETI treatment, 8 (80%) of the patients with underweight transitioned to the normal weight category, while 11 (15.3%) of the normal-weight patients became overweight. The major determinants of heterogeneity in weight gain were the baseline BMI and the presence of at least one CFTR residual function mutation, explaining 13% and 8% of the variability, respectively. CONCLUSIONS: Our results indicate that ETI is highly effective in improving weight gain in underweight subjects with CF. However, our data also suggests the need for close monitoring of excess weight gain to prevent potential cardiometabolic complications.

Real world outcomes of CFTR modulator therapy in Australian adults and children.

BACKGROUND: Recent advances in CFTR modulator therapy have the potential to change the face of cystic fibrosis (CF). This retrospective observational study describes real world experience of the four available CFTR modulators in adults and children with CF in a single centre in Melbourne, Australia. METHOD: Data were collected for all patients treated with CFTR modulators at MonashCF between May 2012 and September 2020. Primary outcomes included lung function, admission days and BMI/BMI centile over time. Adverse events and reasons for changing or ceasing medications were also analysed. RESULTS: 55% (74/133) adult and 46% (55/119) paediatric patients were treated with CFTR modulators. FEV1 increased in adults treated with ivacaftor (IVA) and elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) by 4.73% and 10.07% respectively, and BMI also improved in these groups. Nutrition improved in adults and children treated with lumacaftor/ivacaftor (LUM/IVA). There was no significant improvement in FEV1 or admission days with LUM/IVA or tezacaftor/ivacaftor (TEZ/IVA). 36% (31/85) ceased LUM/IVA, due to adverse effects in 81% (25/31). Of these, 92% (23/25) changed to TEZ/IVA, 78% (18/23) without significant adverse effects. CONCLUSIONS: Our findings for LUM/IVA and TEZ/IVA are less encouraging than those seen in clinical trials, with no significant improvement in lung function or admission days and a higher rate of adverse effects with LUM/IVA compared with phase 3 clinical trials. TEZ/IVA was generally well tolerated by those who experienced side effects with LUM/IVA. The small number of patients treated with ELX/TEZ/IVA had improvements in all parameters. These findings support ongoing use of IVA for individuals with gating mutations, and transition to ELX/TEZ/IVA once available for patients with at least one Phe508del mutation.

An innovative strategy for personalised medicine in a CFSPID case that evolved with time.

We present a challenging case that illustrates how the clinical manifestations in children with CFTR mutations of uncertain significance may change over time. This case highlights the evolution of confirming a diagnosis of CF and emphasises the importance of regular review and monitoring of this patient cohort.