Use of CFTR Modulators for Cystic Fibrosis in a Patient with Liver Transplant and ESRD on Hemodialysis.

Cystic fibrosis is an autosomal recessive disorder caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most recent therapeutic approach to cystic fibrosis aims to correct structural and functional abnormalities of CFTR protein. CFTR modulators including ivacaftor-tezacaftor-elexacaftor are used in patients with F508del mutation, with clinical improvement. To date, there are no experiences of CFTR modulator therapy in cystic fibrosis patients with organ transplantation and severe renal impairment. We report the case of a patient diagnosed with cystic fibrosis with F508del mutation, who underwent liver transplantation at the age of 19 and started hemodialysis at the age of 24 due to end-stage renal disease secondary to membranous glomerulonephritis. She was treated with Kaftrio (ivacaftor-tezacaftor-elexacaftor) with clinical benefits on appetite, improvement of body mass index, and reduction of pulmonary exacerbations. A reduction of dosage to 75% of the standard dose was required due to alterations of the liver function. Conclusions. Use of CFTR modulators in patient with cystic fibrosis, liver transplant and end-stage renal disease could be considered safe but a clinical and laboratoristic monitoring of hepatic function is needed.

Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy.

BACKGROUND: A major breakthrough in cystic fibrosis (CF) therapy was achievedAQ1 with CFTR modulators. The lumacaftor/ivacaftor combination is indicated for the treatment of CF in pediatric patients above 6 years old. Pharmacokinetic (PK) studies of lumacaftor/ivacaftor in these vulnerable pediatric populations are AQ2crucial to optimize treatment protocols. OBJECTIVES AND METHODS: The objectives of this study were to describe the population PK (PPK) of lumacaftor and ivacaftor in children with CF, and to identify factors associated with interindividual variability. The association between drug exposure and clinical response was also investigated. RESULTS: A total of 75 children were included in this PPK study, with 191 concentrations available for each compound and known metabolites (lumacaftor, ivacaftor, ivacaftor-M1, and ivacaftor-M6). PPK analysis was performed using Monolix software. A large interindividual variability was observed. The main sources of interpatient variability identified were patient bodyweight and hepatic function (aspartate aminotransferase). Forced expiratory volume in the first second (FEV1) was statistically associated with the level of exposure to ivacaftor after 48 weeks of treatment. CONCLUSIONS: This study is the first analysis of lumacaftor/ivacaftor PPK in children with CF. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy. The use of therapeutic drug monitoring as a basis for dose adjustment in children with CF may be useful.

Inhibition of mucus secretion by niclosamide and benzbromarone in airways and intestine.

The Ca2+ activated Cl- channel TMEM16A (anoctamin 1; ANO1) is expressed in secretory epithelial cells of airways and intestine. Previous studies provided evidence for a role of ANO1 in mucus secretion. In the present study we investigated the effects of the two ANO1-inhibitors niclosamide (Niclo) and benzbromarone (Benz) in vitro and in vivo in mouse models for cystic fibrosis (CF) and asthma. In human CF airway epithelial cells (CFBE), Ca2+ increase and activation of ANO1 by adenosine triphosphate (ATP) or ionomycin was strongly inhibited by 200 nM Niclo and 1 µM Benz. In asthmatic mice airway mucus secretion was inhibited by intratracheal instillation of Niclo or Benz. In homozygous F508del-cftr mice, intestinal mucus secretion and infiltration by CD45-positive cells was inhibited by intraperitoneal injection of Niclo (13 mg/kg/day for 7 days). In homozygous F508del-cftr rats intestinal mucus secretion was inhibited by oral application of Benz (5 mg/kg/day for 60 days). Taken together, well tolerated therapeutic concentrations of niclosamide and benzbromarone corresponding to plasma levels of treated patients, inhibit ANO1 and intracellular Ca2+ signals and may therefore be useful in inhibiting mucus hypersecretion and mucus obstruction in airways and intestine of patients suffering from asthma and CF, respectively.

Calcium-sensing receptor activator cinacalcet for treatment of cyclic nucleotide-mediated secretory diarrheas.

Cyclic nucleotide elevation in intestinal epithelial cells is the key pathology causing intestinal fluid loss in secretory diarrheas such as cholera. Current secretory diarrhea treatment is primarily supportive, and oral rehydration solution is the mainstay of cholera treatment. There is an unmet need for safe, simple and effective diarrhea treatments. By promoting cAMP hydrolysis, extracellular calcium-sensing receptor (CaSR) is a regulator of intestinal fluid transport. We studied the antidiarrheal mechanisms of FDA-approved CaSR activator cinacalcet and tested its efficacy in clinically relevant human cell, mouse and intestinal organoid models of secretory diarrhea. By using selective inhibitors, we found that cAMP agonists-induced secretory short-circuit currents (Isc) in human intestinal T84 cells are mediated by collective actions of apical membrane cystic fibrosis transmembrane conductance regulator (CFTR) and Clc-2 Cl- channels, and basolateral membrane K+ channels. 30 µM cinacalcet pretreatment inhibited all 3 components of forskolin and cholera toxin-induced secretory Isc by ∼75%. In mouse jejunal mucosa, cinacalcet inhibited forskolin-induced secretory Isc by ∼60% in wild type mice, with no antisecretory effect in intestinal epithelia-specific Casr knockout mice (Casr-flox; Vil1-cre). In suckling mouse model of cholera induced by oral cholera toxin, single dose (30 mg/kg) oral cinacalcet treatment reduced intestinal fluid accumulation by ∼55% at 20 hours. Lastly, cinacalcet inhibited forskolin-induced secretory Isc by ∼75% in human colonic and ileal organoids. Our findings suggest that CaSR activator cinacalcet has antidiarrheal efficacy in distinct human cell, organoid and mouse models of secretory diarrhea. Considering its excellent clinical safety profile, cinacalcet can be repurposed as a treatment for cyclic nucleotide-mediated secretory diarrheas including cholera.

Effect of CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor on pulmonary ventilation derived by 3D phase-resolved functional lung MRI in cystic fibrosis patients.

OBJECTIVES: To investigate whether 3D phase-resolved functional lung (PREFUL)-MRI parameters are suitable to measure response to elexacaftor/tezacaftor/ivacaftor (ETI) therapy and their association with clinical outcomes in cystic fibrosis (CF) patients. METHODS: Twenty-three patients with CF (mean age: 21; age range: 14-46) underwent MRI examination at baseline and 8-16 weeks after initiation of ETI. Morphological and 3D PREFUL scans assessed pulmonary ventilation. Morphological images were evaluated using a semi-quantitative scoring system, and 3D PREFUL scans were evaluated by ventilation defect percentage (VDP) values derived from regional ventilation (RVent) and cross-correlation maps. Improved ventilation volume (IVV) normalized to body surface area (BSA) between baseline and post-treatment visit was computed. Forced expiratory volume in 1 second (FEV1) and mid-expiratory flow at 25% of forced vital capacity (MEF25), as well as lung clearance index (LCI), were assessed. Treatment effects were analyzed using paired Wilcoxon signed-rank tests. Treatment changes and post-treatment agreement between 3D PREFUL and clinical parameters were evaluated by Spearman's correlation. RESULTS: After ETI therapy, all 3D PREFUL ventilation markers (all p < 0.0056) improved significantly, except for the mean RVent parameter. The BSA normalized IVVRVent was significantly correlated to relative treatment changes of MEF25 and mucus plugging score (all |r| > 0.48, all p < 0.0219). In post-treatment analyses, 3D PREFUL VDP values significantly correlated with spirometry, LCI, MRI global, morphology, and perfusion scores (all |r| > 0.44, all p < 0.0348). CONCLUSIONS: 3D PREFUL MRI is a very promising tool to monitor CFTR modulator-induced regional dynamic ventilation changes in CF patients. CLINICAL RELEVANCE STATEMENT: 3D PREFUL MRI is sensitive to monitor CFTR modulator-induced regional ventilation changes in CF patients. Improved ventilation volume correlates with the relative change of mucus plugging, suggesting that reduced endobronchial mucus is predominantly responsible for regional ventilation improvement. KEY POINTS: • 3D PREFUL MRI-derived ventilation maps show significantly reduced ventilation defects in CF patients after ETI therapy. • Significant post-treatment correlations of 3D PREFUL ventilation measures especially with LCI, FEV1 %pred, and global MRI score suggest that 3D PREFUL MRI is sensitive to measure improved regional ventilation of the lung parenchyma due to reduced inflammation induced by ETI therapy in CF patients. • 3D PREFUL MRI-derived improved ventilation volume (IVV) correlated with MRI mucus plugging score changes suggesting that reduced endobronchial mucus is predominantly responsible for regional ventilation improvement 8-16 weeks after ETI therapy.

Nanoparticle-based platforms for targeted drug delivery to the pulmonary system as therapeutics to curb cystic fibrosis: A review.

Cystic fibrosis (CF) is a genetic disorder of the respiratory system caused by mutation of the Cystic Fibrosis Trans-Membrane Conductance Regulator (CFTR) gene that affects a huge number of people worldwide. It results in difficulty breathing due to a large accumulation of mucus in the respiratory tract, resulting in serious bacterial infections, and subsequent death. Traditional drug-based treatments face hindered penetration at the site of action due to the thick mucus layer. Nanotechnology offers possibilities for developing advanced and effective treatment platforms by focusing on drugs that can penetrate the dense mucus layer, fighting against the underlying bacterial infections, and targeting the genetic cause of the disease. In this review, current nanoparticle-mediated drug delivery platforms for CF, challenges in therapeutics, and future prospects have been highlighted. The effectiveness of the different types of nano-based systems conjugated with various drugs to combat the symptoms and the challenges of treating CF are brought into focus. The toxic effects of these nano-medicines and the various factors that are responsible for their effectiveness are also highlighted.

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

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

Use of CFTR modulators in special populations, part 1: Pregnancy and lactation.

Safety and efficacy data regarding cystic fibrosis transmembrane conductance regulator (CFTR) modulator use in the setting of pregnancy or breastfeeding remains lacking due to exclusion from key trials and lack of multicenter prospective and retrospective studies in the post-CFTR modulator era. A scoping review of English articles from the period of January 1, 2012, to July 31, 2023, was conducted utilizing PubMed and EmBase databases with the following terms: "special population (pregnancy, lactation, breastfeeding)" AND "ivacaftor OR lumacaftor OR tezacaftor OR elexacaftor"; "cystic fibrosis transmembrane conductance regulator" AND "off label drug use." Search results were reviewed by title and abstract for duplications and relevance. Relative to pregnancy or breastfeeding, a total of 18 publications were included for review. Majority of case reports and surveys concluded maternal and infant health were preserved throughout gestation. Likewise, breastfeeding infant case reports show possible changes in liver function and lens opacities, though risk may be increased with both in-utero and breastfeeding exposure. Ivacaftor (IVA) and lumacaftor (LUM) concentrations in fetal cord blood and maternal blood were found to be equivalent. Yet, low concentrations of IVA and LUM were detectable in breastmilk and infant plasma. Current safety data surrounding CFTR modulator use in the setting of pregnancy and lactation is relatively reassuring; however, long-term safety remains unclear, necessitating ongoing observation, and reporting by care teams. As such, treatment decisions should be individualized and coproduced.

[Cystic fibrosis - ETI and type 2 N-of-1 trials : the next step]. / Mucoviscidose : valider un traitement révolutionnaire par de brefs essais thérapeutiques individuels bien supervisés.

In evidence-based medicine, N-of-1 trials are increasingly attractive for rare and heterogeneous conditions. A recent French study illustrates this convincingly in the field of cystic fibrosis. A highly effective triple therapy (ETI) is currently available in Europe, which will eventually help the 85 % of Belgian patients carrying at least one copy of the F508del mutation. Most other 2.000 or so putative mutations of this gene are poorly characterised and very rare or private. To predict the efficacy of ETI at the individual level in currently ineligible patients, sophisticated tools are advocated, but they are expensive, not widely available, often partially standardised and there still remains a «grey area¼ concerning their reliability in this context. With-out using them, the French study suggests that more than half of these patients show clinically meaningful responses to a 4-6 weeks trial of ETI. What makes this pragmatic, cost-effective, non-invasive and simplified approach possible (type 2 N-of-1 trials) is the dramatic and rapid efficacy of a life-saving treatment without alternative and the fact that it can be assessed using simple and robust clinical and paraclinical outcomes. Here, we describe one such trial and discuss the value and limitations of this approach.

Dans la médecine basée sur les preuves, les essais de taille 1 suscitent un intérêt croissant dans les affections rares et hétérogènes. Une récente étude française l'illustre de manière convaincante dans la mucoviscidose. Une trithérapie extrêmement efficace (ETI) est actuellement disponible en Europe, concernant à terme en Belgique les 85 % de patients porteurs d'au moins une copie de la mutation F508del. La majorité des quelque 2.000 autres mutations putatives de ce gène sont mal caractérisées et rarissimes. Des techniques sophistiquées sont évoquées pour prédire, à l'échelle individuelle, l'efficacité d'ETI chez les patients actuellement non éligibles, mais elles sont peu disponibles, coûteuses, souvent imparfaitement standardisées et leur interprétabilité conserve une «zone grise¼. Sans y recourir, l'étude française montre que plus de la moitié de ces patients répondent d'une manière évidente à un essai d'ETI pendant quelques semaines seulement. Ce qui permet cette approche pragmatique, économique, non invasive et simplifiée (essai de taille 1, de type 2), c'est l'efficacité spectaculaire et rapide d'un traitement salvateur sans alternative et le fait qu'elle puisse être appréhendée à partir de critères cliniques et paracliniques simples et robustes. Nous rapportons ici un essai de ce type et discutons l'intérêt et les limites de cette approche.

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

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

Real-life experience with a generic formulation of lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation.

INTRODUCTION: Cystic fibrosis (CF) is the most frequent recessive autosomal disorder in the Caucasian population. It is caused by mutations that result in a deficient or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Among CFTR modulators, potentiator compounds increase channel opening, whereas corrector compounds increase CFTR quantity in the cell surface. OBJECTIVE: To report real-life effects of a generic formulation of lumacaftor-ivacaftor use in patients with CF homozygous for the Phe508del CFTR mutation. PATIENTS AND METHODS: Clinical variables (body mass index [BMI], pulmonary exacerbations, sweat test, and pulmonary function) were analyzed in 30 CF patients homozygous for the Phe508del CFTR mutation, treated with lumacaftor-ivacaftor for 12 months, at the Respiratory Center of Hospital de Niños Ricardo Gutiérrez. These clinical variables were compared with those before the use of modulators. RESULTS: A total of 30 patients with CF homozygous for the Phe508del CFTR mutation receiving lumacaftor-ivacaftor therapy were included in this study. The median (interquartile range [IQR]) age at the start of treatment was 10.79 (7.08-14.05) years. Nineteen patients were male. Before treatment, median (IQR) sweat chloride concentration was 80 (72-92) mEq/L, and it had decreased to 74 (68-78) mEq/L (p = .05) 12 months after treatment. Median (IQR) BMI z-score improved from -0.33 (-0.86 to 0.21) to -0.13 (-0.66 to 0.54) (p = .003). A spirometry was performed in 28 of 30 patients. Median (IQR) ppFEV1 was 83.5 (71-91) before treatment and 86.5 (67-103) after treatment (p = .38), 73.3% of patients referred decreased sputum production and 40% reported improvement in their dyspnea at 12 months. Severe pulmonary exacerbations significantly decreased from 60% in the year before treatment, to 30% at 12 months after treatment (p = .037); 13 patients showed an improvement in their exacerbation rates, 2 showed an increased rate, and 15 showed no change. CONCLUSIONS: The use of a generic formulation of lumacaftor-ivacaftor in patients homozygous for the Phe508del CFTR mutation was associated with improvement in nutritional status and respiratory symptoms, and a significant reduction in severe pulmonary exacerbations.

Improvement in Lung Clearance Index and Chest Computed Tomography Scores with Elexacaftor/Tezacaftor/Ivacaftor Treatment in People with Cystic Fibrosis Aged 12 Years and Older - The RECOVER Trial.

Rationale: Clinical trials have shown that use of elexacaftor/tezacaftor/ivacaftor (ETI) is associated with improvements in sweat chloride, pulmonary function, nutrition, and quality of life in people with cystic fibrosis (CF). Little is known about the impact of ETI on ventilation inhomogeneity and lung structure. Objectives: RECOVER is a real-world study designed to measure the impact of ETI in people with CF. The primary endpoints were lung clearance (lung clearance index; LCI2.5) and FEV1. Secondary endpoints included spirometry-controlled chest computed tomography (CT) scores. Methods: The study was conducted in seven sites in Ireland and the United Kingdom. Participants ages 12 years and older who were homozygous for the F508del mutation (F508del/F508del) or heterozygous for F508del and a minimum-function mutation (F508del/MF) were recruited before starting ETI and were followed up over 12 months. LCI2.5 was measured using nitrogen multiple breath washout (MBW) at baseline and at 6 and 12 months. Spirometry was performed as per the criteria of the American Thoracic Society and the European Respiratory Society. Spirometry-controlled chest CT scans were performed at baseline and at 12 months. CT scans were scored using the Perth Rotterdam Annotated Grid Morphometric Analysis (PRAGMA) system. Other outcome measures include weight, height, Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R), and sweat chloride. Measurements and Main Results: One hundred seventeen people with CF ages 12 and older were recruited to the study. Significant improvements were seen in LCI scores (-2.5; 95% confidence interval [CI], -3.0, -2.0) and in the percents predicted for FEV1 (8.9; 95% CI, 7.0, 10.9), FVC (6.6; 95% CI, 4.9, 8.3), and forced expiratory flow between 25% and 75% of expired volume (12.4; 95% CI, 7.8, 17.0). Overall PRAGMA-CF scores reflecting airway disease improved significantly (-3.46; 95% CI, -5.23, -1.69). Scores for trapped air, mucus plugging, and bronchial wall thickening improved significantly, but bronchiectasis scores did not. Sweat chloride levels decreased in both F508del/F508del (-43.1; 95% CI, -47.4, -38.9) and F508del/MF (-42.8; 95% CI, -48.5, -37.2) groups. Scores on the Respiratory Domain of the CFQ-R improved by 14.2 points (95% CI, 11.3, 17.2). At 1 year, sweat chloride levels were significantly lower for the F508del/F508del group compared with scores for the F508del/MF group (33.93 vs. 53.36, P < 0.001). Conclusions: ETI is associated with substantial improvements in LCI2.5, spirometry, and PRAGMA-CF CT scores in people with CF ages 12 years and older. ETI led to improved nutrition and quality of life. People in the F508del/F508del group had significantly lower sweat chloride on ETI treatment compared with the F508del/MF group. Clinical trial registered with www.clinicaltrials.gov (NCT04602468).

Experience With Elexacaftor/Tezacaftor/Ivacaftor in Patients With Cystic Fibrosis and Advanced Disease

Introduction: Elexacaftor/tezacaftor/ivacaftor (ETI) was used through the early access programme in Spain from December 2019 in cystic fibrosis (CF) patients with homozygous or heterozygous F508del mutation with advanced lung disease. Methodology: Multicentre, ambispective, observational, study in which 114 patients in follow-up in 16 national CF units were recruited. Clinical data, functional tests, nutritional parameters, quality of life questionnaires, microbiological isolates, number of exacerbations, antibiotic treatments and side effects were collected. The study also compared patients with homozygous and heterozygous F508del mutations. Results: Of the 114 patients, 85 (74.6%) were heterozygous for F508del mutation, and the mean age was 32.2±9.96 years. After 30 months of treatment, lung function measured by FEV1% showed improvement from 37.5 to 48.6 (p<0.001), BMI increased from 20.5 to 22.3 (p<0.001), and all isolated microorganisms decreased significantly. The total number of exacerbations was also significantly reduced from 3.9 (±2.9) to 0.9 (±1.1) (p<0.001). All items in the CFQ-R questionnaire showed improvement, except for the digestive domain. Oxygen therapy use decreased by 40%, and only 20% of patients referred for lung transplantation remained on the active transplant list. ETI was well-tolerated, with only 4 patients discontinuing treatment due to hypertransaminemia. Conclusions: ETI decreases the number of exacerbations, increases lung function and nutritional parameters, decrease in all isolated microorganisms, for 30 months of treatment. There is an improvement in the CFQ-R questionnaire score except for the digestive item. It is a safe and well-tolerated drug. (AU)

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.

Update on Cystic Fibrosis in Pediatric Patients.

PURPOSE OF REVIEW: Cystic fibrosis is an inherited, multisystem disease that affects the gastrointestinal system in numerous ways. This article reviews the nutritional, gastrointestinal, and hepatobiliary manifestations of cystic fibrosis with an emphasis on the effects of CFTR modulator therapy. RECENT FINDINGS: The life expectancy of individuals with cystic fibrosis has increased substantially in recent years. CFTR modulator therapy improves pulmonary function and results in weight gain. An individualized approach to nutrition is encouraged. Pancreatic exocrine function may improve with intervention early in life. The use of non-invasive methods to screen for hepatobiliary involvement is recommended. Highly effective CFTR modulators lead to increased survival and improved quality of life for many individuals. Their effects on gastrointestinal symptoms and hepatobiliary disease are not fully understood. Patient-reported outcome measures and biomarkers are important clinical endpoints for studying the effects of modulators.

Effects of elexacaftor-tezacaftor-ivacaftor on daily treatment burden and airflow obstruction in adults with cystic fibrosis.

BACKGROUND: The drug combination elexacaftor-tezacaftor-ivacaftor (ETI) proved highly effective in the improvement of the respiratory symptoms, the percentage of predicted forced expiratory volume in 1 s (FEV1), and to reduce rates of pulmonary exacerbations in people with cystic fibrosis (CF) with at least one F508del mutation. The objectives of the study were to evaluate the impact of ETI on the daily treatment burden due to patient decision and the evolution of lung function parameters at 6 months of treatment in real life. METHODS: A single-center observational study was realized including adult patients starting ETI therapy from March 10, 2020 to April 5, 2022. Clinical characteristics were collected at initiation (T0) and at 6 months (T6) of treatment. Outcome measures included names and number of chronic daily medications, respectively lung function parameters: FEV1, forced vital capacity (FVC), FEV1/FVC ratio, peak expiratory flow (PEF), forced expiratory flow at 25-75% of FVC (FEF25-75), ß-angle and FEF50/PEF ratio. RESULTS: Sixty-five patients were included with a mean age of 29.4 ± 8.5 years old, 48% of them F508del homozygous previously treated by lumacaftor-ivacaftor. At T6, the median number of daily medications decreased from 13 [2-24] to 9 [1-19] (p < 0.001). All the studied functional respiratory parameters were improved: FEV1 +18%, FVC +14%, FEF25-75% + 18% (all p < 0.001), as well the airflow obstruction: FEV1/FVC +6%, FEF50/PEF by 0.1 ± 0.1 and ß-angle by 10° ± 13° (all p ≤ 0.007). CONCLUSION: ETI therapy can reduce the daily treatment burden in real-life at 6 months of treatment, increase a large number of lung function parameters and improve airflow obstruction.

Elexacaftor/Tezacaftor/Ivacaftor para o tratamento de pacientes com fibrose cística com 6 anos de idade ou mais com ao menos uma mutação f508del no gene regulador de condução transmembrana de fibrose cística / Elexacaftor/Tezacaftor/Ivacaftor for the treatment of cystic fibrosis patients 6 years of age and older with at least one f508del mutation in the cystic fibrosis transmembrane conduction regulator gene

INTRODUÇÃO: A fibrose cística (FC) é uma doença rara grave que afeta crianças causando redução significativa da qualidade de vida. O gene CFTR, que codifica uma proteína reguladora da condutância transmembrana do íon cloreto, é afetado na FC, pois essa proteína está ausente ou sua atividade é reduzida. A doença acomete vários sistemas do corpo, porém a manifestação clínica primária é a do sistema respiratório. O envolvimento pulmonar causado por inflamação persistente e infecções respiratórias é responsável pelo aumento da morbimortalidade. O Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA), um modulador da proteína CFTR, foi aprovado em março de 2022 pela ANVISA para pacientes com idade > 6 anos e com pelo menos uma mutação do gene F508del-CFTR. Atualmente, o Protocolo Clínico e Diretrizes Terapêuticas (PCDT) publicado pelo Ministério da Saúde não recomenda tratamento específico para pacientes com essa mutação. PERGUNTA: O uso de elexacaftor/tezacaftor/ivacaftor apresenta eficácia, segurança e custo-efetividade no tratamento de indivíduos com fibrose cística a partir de 6 anos de idade que apresentem pelo menos uma mutação F508del no gene CFTR da fibrose cística? EVIDÊNCIAS CLÍNICAS: O tratamento com ELX/TEZ/IVA em pacientes com FC com idade igual ou superior a 12 anos foi avaliado por 6 ensaios clínicos, cinco tinham ELX/TEZ/IVA como intervenção e o grupo comparador ativo com ivacaftor ou ivacaftor+tezacaftor, com baixo risco de viés que foram sintetizados em uma metanálise, e em outros dois ensaios mostraram o benefício para a população de

Impact of lumacaftor/ivacaftor and tezacaftor/ivacaftor on treatment response in pulmonary exacerbations of F508del/F508del cystic fibrosis.

BACKGROUND: Pulmonary exacerbations (PEx) remain a major cause of morbidity and mortality in people with cystic fibrosis (PWCF). Although the combination cystic fibrosis transmembrane conductance regulator (CFTR) modulators lumacaftor/ivacaftor and tezacaftor/ivacaftor have been shown to reduce PEx frequency, their influence on clinical and biochemical responses to acute PEx treatment is unknown. METHODS: We performed a secondary analysis of STOP2, a large multicenter randomized controlled trial of antimicrobial treatment durations for adult PWCF presenting with PEx. Propensity score matching was used to compare outcomes in antibiotic-treated F508del/F508del PWCF receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor with those observed in antibiotic-treated F508del/F508del controls not receiving CFTR modulator therapy. The primary outcome measure was the change in percent predicted FEV1 (ppFEV1) following completion of intravenous (IV) antibiotics, with post-antibiotic changes in symptoms, serum C-reactive protein (CRP) concentrations and weight included as secondary endpoints. RESULTS: Among 982 PEx events in randomized PWCF, 480 were homozygous for F508del, of whom 289 were receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor at initiation of antibiotic therapy. Modulator-treated F508del/F508del PWCF did not demonstrate greater improvements in ppFEV1, symptoms, serum CRP or weight following antibiotic treatment compared to modulator-naïve controls matched for age, sex, baseline ppFEV1, genotype, body mass index, initial CRP, initial symptoms, exacerbation history, diabetic status, randomization arm and concomitant medical therapy. CONCLUSION: In the acute setting, CFTR modulator therapy with lumacaftor/ivacaftor or tezacaftor/ivacaftor does not convey additional clinical or biochemical advantage above standardized PEx treatment in F508del/F508del PWCF.

Nutritional management of people living with cystic fibrosis throughout life and disease continuum: Changing times, new challenges.

Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding for the ion channel cystic fibrosis transmembrane conductance regulator (CFTR). The management of CF disease has evolved in recent decades from treating downstream disease manifestations affecting the airways, the lungs and the gastrointestinal system to addressing the CFTR gene defect. The advent of CFTR modulators, which correct the functionality of the defective CFTR, contributes to reshaping the landscape of CF demographics, prognosis and therapies, including nutritional management. A spectrum of clinical manifestations is emerging within the same patient population where undernutrition and nutritional deficiencies coexist with excessive weight gain and metabolic derangements. Such contrasting presentations challenge current practices, require adjustments to traditional approaches, and involve more individualised interventions. This narrative review examines the current state of knowledge on the nutritional management of people living with cystic fibrosis from early life to adulthood in the era of CFTR modulation.

Experience With Elexacaftor/Tezacaftor/Ivacaftor in Patients With Cystic Fibrosis and Advanced Disease.

INTRODUCTION: Elexacaftor/tezacaftor/ivacaftor (ETI) was used through the early access programme in Spain from December 2019 in cystic fibrosis (CF) patients with homozygous or heterozygous F508del mutation with advanced lung disease. METHODOLOGY: Multicentre, ambispective, observational, study in which 114 patients in follow-up in 16 national CF units were recruited. Clinical data, functional tests, nutritional parameters, quality of life questionnaires, microbiological isolates, number of exacerbations, antibiotic treatments and side effects were collected. The study also compared patients with homozygous and heterozygous F508del mutations. RESULTS: Of the 114 patients, 85 (74.6%) were heterozygous for F508del mutation, and the mean age was 32.2±9.96 years. After 30 months of treatment, lung function measured by FEV1% showed improvement from 37.5 to 48.6 (p<0.001), BMI increased from 20.5 to 22.3 (p<0.001), and all isolated microorganisms decreased significantly. The total number of exacerbations was also significantly reduced from 3.9 (±2.9) to 0.9 (±1.1) (p<0.001). All items in the CFQ-R questionnaire showed improvement, except for the digestive domain. Oxygen therapy use decreased by 40%, and only 20% of patients referred for lung transplantation remained on the active transplant list. ETI was well-tolerated, with only 4 patients discontinuing treatment due to hypertransaminemia. CONCLUSIONS: ETI decreases the number of exacerbations, increases lung function and nutritional parameters, decrease in all isolated microorganisms, for 30 months of treatment. There is an improvement in the CFQ-R questionnaire score except for the digestive item. It is a safe and well-tolerated drug.