2025
Med Lett Drugs Ther. 2025 Mar 17;67(1724):41-43. doi: 10.58347/tml.2025.1724a.
Vanzacaftor, tezacaftor, and deutivacaftor (Alyftrek) for cystic fibrosis. No authors listed
PMID: 40053374 DOI: 10.58347/tml.2025.1724a
Claire Keating, Lael M Yonker, François Vermeulen, Dario Prais, Rachel W Linnemann, Aaron Trimble , Tom Kotsimbo , Joel Mermis , Andrew T Braun, Mark O’Carroll , Sivagurunathan Sutharsa , Bonnie Ramse , Marcus A Mall, Jennifer L Taylor-Cousar , Edward F McKone , Elizabeth Tullis, Tim Floreth, Peter Michelso, Patrick R Sosna , Nitin Nair, Rachel Zahigia, Hannah Martin, Neil Ahluwalia, Anna Lam, Alexander Horsley; VX20-121-102 Study Group; VX20-121-103 Study Group.
Vanzacaftor-tezacaftor-deutivacaftor versus elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE trials VX20-121-102 and VX20-121-103): results from two randomised, active-controlled, phase 3 trials. Lancet Respir Med 2025;13:256-271
Claire Keating
MD.com
Background: The goal of cystic fibrosis transmembrane conductance regulator (CFTR) modulators is to reach normal CFTR function in people with cystic fibrosis. Vanzacaftor-tezacaftor-deutivacaftor restored CFTR function in vitro and in phase 2 trials in participants aged 18 years and older resulting in improvements in CFTR function, as measured by sweat chloride concentrations and lung function as measured by spirometry. We aimed to evaluate the efficacy and safety of vanzacaftor-tezacaftor-deutivacaftor compared with standard of care elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older.
Methods: In two randomised, active-controlled, double-blind, phase 3 trials, individuals aged 12 years and older with stable cystic fibrosis with F508del-minimal function (SKYLINE Trial VX20-121-102) or with F508del-F508del, F508del-residual function, F508del-gating, or elexacaftor-tezacaftor-ivacaftor-responsive-non-F508del genotypes (SKYLINE Trial VX20-121-103) were enrolled at 126 and 159 international sites, respectively. Eligible individuals were entered into a 4-week run-in period, during which they received elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening. They were then randomly assigned (1:1) to either elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening, or vanzacaftor (20 mg once daily), tezacaftor (100 mg once daily), and deutivacaftor (250 mg once daily) as two fixed-dose combination tablets in the morning, for the 52-week treatment period. All participants received matching placebo tablets to maintain the treatment blinding. Randomisation was done using an interactive web-response system and stratified by age, FEV1 % predicted, sweat chloride concentration, and previous CFTR modulator use, and also by genotype for Trial VX20-121-103. The primary endpoint for both trials was absolute change in FEV1 % predicted from baseline (most recent value before treatment on day 1) through week 24 (with non-inferiority of vanzacaftor-tezacaftor-deutivacaftor shown if the lower bound of the 95% CI for the primary endpoint was -3·0 or higher). Efficacy was assessed in all participants with the intended CFTR genotype who were randomly assigned to treatment and received at least one dose of study treatment during the treatment period. Safety was assessed in all participants who received at least one dose of study drug during the treatment period. These trials are registered with ClinicalTrials.gov, NCT05033080 (Trial VX20-121-102) and NCT05076149 (Trial VX20-121-103), and are now complete.
Findings: In Trial VX20-121-102 between Sept 14, 2021, and Oct 18, 2022, 488 individuals were screened, of whom 435 entered the 4-week run-in period, and subsequently 398 were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=202) or vanzacaftor-tezacaftor-deutivacaftor (n=196). Median age was 31·0 years (IQR 22·6-38·5), 163 (41%) of 398 participants were female, 235 (59%) were male, and 388 (97%) were White. In Trial VX20-121-103, between Oct 27, 2021, and Oct 26, 2022, 699 individuals were screened, of whom 597 entered the 4-week run-in period, and subsequently 573 participants were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=289) or vanzacaftor-tezacaftor-deutivacaftor (n=284). Median age was 33·1 years (IQR 24·5-42·2), 280 (49%) of 573 participants were female, 293 (51%) were male, and 532 (93%) were White. The absolute change in least squares mean FEV1 % predicted from baseline through week 24 for Trial VX20-121-102 was 0·5 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·3 (0·3) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference of 0·2 percentage points [95% CI -0·7 to 1·1]; p<0·0001), and for Trial VX20-121-103, was 0·2 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·0 (0·2) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference 0·2 percentage points [95% CI -0·5 to 0·9]; p<0·0001). Most adverse events were mild or moderate, with the most common being infective pulmonary exacerbation (133 [28%] of 480 participants in the pooled vanzacaftor-tezacaftor-deutivacaftor group vs 158 [32%] of 491 in the pooled elexacaftor-tezacaftor-ivacaftor group), cough (108 [23%] vs 101 [21%]), COVID-19 (107 [22%] vs 127 [26%]), and nasopharyngitis (102 [21%] vs 95 [19%]).
Interpretation: Vanzacaftor-tezacaftor-deutivacaftor is non-inferior to elexacaftor-tezacaftor-ivacaftor in terms of FEV1 % predicted, and is safe and well tolerated. Once daily dosing with vanzacaftor-tezacaftor-deutivacaftor reduces treatment burden, potentially improving adherence, compared with the twice daily regimen of the current standard of care. The restoration of CFTR function and the potential variants treated are also considerations that should be compared with currently available CFTR modulators.
Claire Keating is a pulmonologist at CUIMC/Herbert Irving Pavilion in New York,
2025 Mar;13(3):244-255. PMID cystic fibrosis aged 6-11 years.
Jordana Hoppe
childrenscolorado
Methods: In this multicentre, single-arm, phase 3 trial (RIDGELINE Trial VX21-121-105), participants were enrolled across 33 clinical sites that care for children with cystic fibrosis in eight countries (Australia, France, Germany, Netherlands, Sweden, Switzerland, the UK, and the USA). Eligible participants were aged 6-11 years with at least one elexacaftor-tezacaftor-ivacaftor-responsive CFTR variant, FEV1 % predicted of 60% or higher, and stable cystic fibrosis as determined by investigators. Before study treatment, participants were either on stable elexacaftor-tezacaftor-ivacaftor for at least 28 days before screening or received the combination for a 4-week run-in period. Participants then received vanzacaftor-tezacaftor-deutivacaftor (<40 kg bodyweight: vanzacaftor 12 mg, tezacaftor 60 mg, and deutivacaftor 150 mg orally as three fixed-dose combination tablets once daily; ≥40 kg bodyweight: vanzacaftor 20 mg, tezacaftor 100 mg, and deutivacaftor 250 mg orally as two fixed-dose combination tablets once daily (manufactured by Patheon Pharmaceuticals, Cincinnati, OH, USA) from day 1 for 24 weeks. The primary endpoint was safety and tolerability, as measured by adverse events, vital signs, clinical laboratory values, electrocardiograms, and pulse oximetry. Endpoints were analysed in all participants who received at least one dose of vanzacaftor-tezacaftor-deutivacaftor. This trial is registered with ClinicalTrials.gov, NCT05422222, and evaluation of the 6-11-year-old cohort is complete.
Findings: Between Feb 6 and May 18, 2023, 83 children were screened, of whom five were not eligible, and 78 children aged 6-11 years received at least one dose of vanzacaftor-tezacaftor-deutivacaftor. Median age was 9·3 years (IQR 7·6-10·4), 34 (44%) of 78 participants were female, 44 (56%) were male, 71 (91%) were White, one (1%) was Black or African American, and one (1%) was of multiple races. The analysis for these data was completed on Dec 15, 2023. Median exposure of participants to vanzacaftor-tezacaftor-deutivacaftor was 168 days (IQR 166-170). 75 (96%) of 78 participants had adverse events, all of which were mild or moderate; the most common events were generally consistent with cystic fibrosis manifestations, including, cough (36 [46%]), pyrexia (16 [21%]), headache (14 [18%]), infective pulmonary exacerbation of cystic fibrosis (13 [17%]), and oropharyngeal pain (13 [17%]). Serious adverse events occurred in six (8%) participants (two had infective pulmonary exacerbation, one of whom also had failure to thrive; one participant each had adenovirus infection, constipation, pulmonary function test decreased, and cough), and one (1%) participant discontinued due to adverse events of cough and fatigue that were considered possibly related to study drug.
Interpretation: Vanzacaftor-tezacaftor-deutivacaftor was safe and well tolerated and maintained FEV1 % predicted from elexacaftor-tezacaftor-ivacaftor baseline with further improved CFTR function. Improvements in CFTR function compared with baseline elexacaftor-tezacaftor-ivacaftor values demonstrate the potential opportunity to restore normal physiology early and prevent development or progression of cystic fibrosis. Nearly all participants had sweat chloride below the diagnostic threshold for cytstic fibrosis (<60 mmol/L) and more than half had normal levels (<30 mmol/L). Additional long-term data in children with cystic fibrosis are being collected in an open-label extension study to demonstrate clinical benefits and safety. These findings will inform health-care providers and people with cystic fibrosis regarding the benefits of early initiation of CFTR modulators.
Jordanna Hoppe is Associate Professor and pediatric pulmonologist at the children’s Hospital Colorado
Amel Alameeri , Burcu Capraz, Francesca Lucca , Ivan Bambi , Paulina Famulska, Renata W F Cohen. Cystic fibrosis year in review 2024. PMID: 39971692 DOI: 10.1016/j.jcf.2025.02.012 Review J Cyst Fibros. 2025 Feb 18:S1569-1993(25)00063-3. doi: 10.1016/j.jcf.2025.02.012. Online ahead of print.https://pubmed.ncbi.nlm.nih.gov/39971692/
Amel Alameeri
J Med Sci
The year 2024 marks a pivotal moment in the field of cystic fibrosis (CF) treatment, characterised by significant advancements in clinical care and an expanding body of literature on CF transmembrane conductance regulator (CFTR) modulators. These CFTR therapies have transformed the landscape of CF management, offered systemic benefits, and established new guidelines for assessing clinical manifestations and therapies. Additionally, progress has been made in newborn screening (NBS), diagnosis, and understanding outcomes for individuals with CF-related metabolic syndrome or inconclusive diagnostic results. However, amidst these clinical milestones, disparities in global access to CFTR modulators (CFTRm) persist, threatening to exacerbate existing inequities in CF care. This review provides a focused overview of the most impactful articles from 2024, highlighting both the clinical advancements and the pressing global accessibility challenges that define this transformative era in CF research and treatment.
Amel Alameeri is in the Department of adult Pulmonary medicine, ST Shaikh Tahnoon Medical City Hospital, Alain, AbuDhabi, UAE
Dorothea Appelt , Teresa Fuchs , Johannes Eder , Katharina Niedermayr , Anja Siedl , Helmut Ellemunter. Monitoring ETI effects over 1.7 years in an infant treated in utero, via breast milk and granules by repeated faecal elastase measurements. Case Reports J Cyst Fibros. 2025 Jan 28:S1569-1993(25)00012-8. doi: 10.1016/j.jcf.2025.01.012. Online ahead of print.https://pubmed.ncbi.nlm.nih.gov/39880765/
Dorothea Appelt
ResearchGate
Pancreatic insufficiency is a major complication of cystic fibrosis (CF), which traditionally has been managed with pancreatic enzyme replacement therapy in the vast majority of CF patients, even in the era of highly effective cystic fibrosis transmembrane conductance regulator modulator (CFTRm) therapy. We report on a 1.7 year old male infant with CF who was exposed to ETI both in utero and postpartum, via breast milk and oral granules. Repeated faecal elastase analyses were carried out to monitor pancreatic function closely, with normal levels at birth. Although faecal elastase values fluctuated over time, it never dropped below 100 µg/g for several subsequent measurements, while the infant continued to receive breast milk. However, at the age of 8 months PERT was initiated. ETI was introduced at 9 months of age in the form of crushed tablets as an individualised treatment, following a sustained increase in faecal elastase to >200µg/g to date. 3 weeks after starting oral ETI therapy, PERT was discontinued. With this case report we would like to show that continuous pre- and postnatal ETI exposure can maintain pancreatic function in CF for at least 1.7 years.
Dorothea Appelt is a researcher in the Department of Paediatrics III, Cystic Fibrosis Centre Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
L R Caley, L Gillgrass , C Zagoya, H Saumtally, F Duckstein, White H 4, J G Mainz, D G Peckham. Longer term follow-up of abdominal symptoms (CFAbd-Score) after initiation of Elexacaftor / Tezacaftor / Ivacaftor in adults with cystic fibrosis. J Cyst Fibros. 2025 Jan 14:S1569-1993(25)00010-4. doi: 10.1016/j.jcf.2025.01.010. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39814671/
Laura R Caley
ECFS Vienna
Background: Whether improvements in gastrointestinal (GI) symptoms observed with Elexacaftor/Tezacaftor/Ivacaftor (ETI) treatment are sustained in the longer-term requires exploration. This study investigated how GI-symptoms change with longer-term ETI use in pancreatic insufficient adults with cystic fibrosis (awCF).
Methods: Participants completed up to three abdominal symptom questionnaires, employing the validated CFAbd-Score. Changes in total CFAbd-Score and its five domains, pain, gastroesophageal reflux-disease (GERD), disorders of bowel movement (DBM), disorders of appetite (DA) and quality of life (QOL), were analysed pre-ETI (T0) and at ≤1.5 years (T1) and 2-4 years of ETI-therapy (T2).
Results: A total of 165 CFAbd-Scores from 68 participants were analysed (median age: 34 years; IQR: 28-39). Total CFAbd-Score significantly (p < 0.05) and clinically meaningfully decreased from 20.4 ± 1.6 pre-ETI (median:40 weeks pre-treatment) to 15.3 ± 1.9 and 16.8 ± 1.6 at T1 (median: 25 weeks of ETI) and T2 (median: 148 weeks of ETI), respectively. The CFAbd-Score´s domains DA and QoL only significantly decreased between T0 and T1, whereas DBM only significantly decreased after 2-4 years of ETI therapy (T2). GERD scores were significantly lower at both T1 and T2.
Conclusion: While GI symptoms in awCF significantly improve within the first 1.5 years of ETI-therapy, they appear to somewhat wane with longer-term use, despite GI-symptom burden still being lower compared to pre-ETI. However, we cannot differentiate whether this results from reduced adherence, a decrease in ETI effects, or long-term changes in diet, gut microbiota or symptom perception. The longer-term impact of ETI and other potential modulator therapies on GI symptoms requires ongoing monitoring.
Laura Caley is a Research Fellow at the Leeds Institute of Medical Research, University of Leeds, School of Medicine, Leeds, United Kingdom
Laurent Chouchana , Mathis Collier , Clémence Martin, Pierre-Régis Burge, Jean-Marc Treluyer. CFTR modulators and pregnancy outcomes: Early findings from a nationwide cohort study J Cyst ~Fibros 2025 Mar 8:S1569-1993(25)00070-0. doi: 10.1016/j.jcf.2025.03.002. Online ahead print.https://pubmed.ncbi.nlm.nih.gov/40058987/
Laurent houchana
Google`Scholar
Objectives: Recent therapeutic advances, mainly with the advent of CFTR modulators, have been associated with an increasing number of pregnancies in females with cystic fibrosis (fwCF). This study aimed to evaluate the safety of the use of CFTR modulators, specifically elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) during pregnancy.
Methods: A nationwide cohort study was conducted using the French health insurance data warehouse (SNDS), covering nearly all singleton pregnancies ending between January 2018 and December 2023. Exposure to CFTR modulators was defined as using prescriptions through pregnancy, including one month in the preconception period. The study compared pregnancy outcomes amongst fwCF between pregnancies exposed and unexposed to CFTR modulators.
Results: Among 590 pregnancies in fwCF, 148 (24.7 %) were exposed to CFTR modulators, including 136 during first trimester. Of these, 147 (99.3 %) resulted in livebirths. The most common CFTR modulator used was ELX/TEZ/IVA, in 121 (81.8 %) pregnancies. The prevalence of major birth defects was similar between exposed and unexposed fwCF (3.38 % vs. 4.66 %; p = 0.72). The rate of small for gestational age (SGA, <10th percentile) was significantly lower in pregnancies exposed compared to unexposed (6.8 % vs. 16.1 %; p < 0.01).
Discussion: The study provides early reassurance about the safety of CFTR modulators during pregnancy, particularly in terms of teratogenicity and adverse pregnancy outcomes. While findings suggest potential benefits, such as halved rate of SGA, further research is required to confirm these outcomes and investigate long-term effects on the development of children prenatally exposed to CFTR modulators.
Laurent Couchana is at the Regional Center of Pharmacovigilance, Department of perinatal, pediatric and adult pharmacology, Hopital Cochin, Hopital Necker, AP-HP. Paris, France;
Lauren J Clayton , Anthony I Shepherd, Jo Corbett, Maria Perissiou, Gary Connett , Julian Legg , Mark Allenby , Thomas Daniels, Don S Urquhar , Kelly A Mackintosh , Melitta A McNarry , Zoe L Saynor. Cardiovascular function in people with cystic fibrosis on Elexacaftor/Tezacaftor/Ivacaftor: A cross-sectional, observational, single-centre study.J Cyst Fibros. 2025 Feb 15:S1569-1993(25)00052-9. doi: 10.1016/j.jcf.2025.02.001. Online ahead of print.https://pubmed.ncbi.nlm.nih.gov/39956715/
Lauren J Clayton
LinkedIn
Background: Cystic fibrosis (CF) has been associated with impaired cardiovascular and endothelial function. CF transmembrane conductance regulator (CFTR) modulator therapy, most recently Elexacaftor/Tezacaftor/Ivacaftor (ETI), has led to improved CFTR function and life expectancy. However, the rising prevalence of obesity in adults is concerning. This study assessed the micro- and macrovascular endothelial function, cardiovascular disease (CVD) risk factors, and physical activity (PA) profiles in people with CF (pwCF) on ETI compared to healthy matched controls.
Methods: In 15 pwCF and 15 age- and sex-matched controls, microvascular endothelial function (via transdermal delivery of insulin [INS] and acetylcholine [ACh] on the forearm), macrovascular endothelial function (via flow-mediated dilation [FMD] of the brachial artery), central haemodynamic parameters, including heart rate (HR), stroke volume index (SVi) and cardiac output index (Q̇I) (via thoracic impedance cardiography), body mass index (BMI), blood pressure (BP), and accelerometer-assessed PA were measured.
Results: There were no differences in INS or FMD-mediated vasodilation between the groups (P > 0.05). However, a reduced vasodilatory response was evident in pwCF following ACh-mediated vasodilation (P = 0.01) and FMD normalised for shear rate (P = 0.03). No differences in resting HR, SVi, Q̇I, BP, BMI or PA were found (P > 0.05).
Conclusion: This study demonstrated reduced micro- and macrovascular function in pwCF. This dysfunction may have potential health implications, particularly regarding long-term cardiovascular risk and further longitudinal assessments are warranted.
Lauren J Clayton is a PhD Researcher in the School of Psychology, Sport and Health Science, Faculty of Science and Health, University of Portsmouth, Portsmouth, UK; University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Connett Gj, Maguire S, Larcombe Tc, Scanlan N, Shinde Ss, Muthukumarana T , Bevan A , Keogh Rh, Legg Jp. Real-world impact of Elexacaftor-Tezacaftor-Ivacaftor treatment in young people with Cystic Fibrosis: A longitudinal study. Respir Med. 2025 Jan:236:107882. doi: 10.1016/j.rmed.2024.107882. Epub 2024 Nov 22.: DOI: 10.1016/j.rmed.2024.107882 pubmed.ncbi.nlm.nih.gov/39581272/
Gary Connett
childhealthinternational.org
Background: Elexacaftor, Tezacaftor, Ivacaftor (ETI) became available in the UK in August 2020 to treat people with Cystic Fibrosis (CF) aged >12 years. We report a real-world study of clinical outcomes in young people treated with ETI at our CF centre within the first two years of its availability.
Methods: Participants aged 12-17 were identified within our clinic, with demographic data supplemented by the UK CF registry. Comprehensive outcome data spanning two years pre- and two years post-initiation of CFTR modulators were compiled from various local sources, including patient records, medication delivery logs, and clinical notes.
Results: Of the 62 patients started on ETI (32 male, mean age 13.3 years), most (76 %) were homozygous for the F508del mutation. Three discontinuations occurred: one pregnancy, two related to side effects. Adherence was high (Proportion of Days covered >90 % both years). Following ETI initiation there was a significant increase in mean FEV1% (+11.7 units; 95 % CI 7.4-15.6), sustained throughout the two-year treatment period. There was no association between baseline lung function and the degree of improvement or rate of decline post-treatment. Improvements were similar for all treatable genotypes. BMI z-score increased by 0.25 units after four months of treatment, returning to baseline by 24 months. Intravenous antibiotic use decreased by 88 % (median IV days/year reduced from 32 to 4 days, p < 0.01).
Conclusions: ETI use in adolescents in a real-world setting led to sustained improvements in health outcomes, consistent with those seen in open trial extension studies.
Prof. Garry Connett is at the National Institute for Health Research, Southampton Respiratory Biomedical Research Centre, University Hospitals Southampton NHS Foundation Trust, Southampton, UK; Southampton Children’s Hospital, University Hospitals Southampton NHS Foundation Trust, Southampton, UK.
Laurent Chouchana, Mathis Collier, Clémence Martin, Pierre-Régis Burgel, Jean-Marc Treluy. CFTR modulators and pregnancy outcomes: Early findings from a nationwide cohort study J Cyst Fibros 2025 Mar 8:S1569-1993(25)00070-0. doi: 10.1016/j.jcf.2025.03.002. Online ahead of print.https://pubmed.ncbi.nlm.nih.gov/40058987/
Laurent chouchana
Google`Scholar
Objectives: Recent therapeutic advances, mainly with the advent of CFTR modulators, have been associated with an increasing number of pregnancies in females with cystic fibrosis (fwCF). This study aimed to evaluate the safety of the use of CFTR modulators, specifically elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) during pregnancy.
Methods: A nationwide cohort study was conducted using the French health insurance data warehouse (SNDS), covering nearly all singleton pregnancies ending between January 2018 and December 2023. Exposure to CFTR modulators was defined as using prescriptions through pregnancy, including one month in the preconception period. The study compared pregnancy outcomes amongst fwCF between pregnancies exposed and unexposed to CFTR modulators.
Results: Among 590 pregnancies in fwCF, 148 (24.7 %) were exposed to CFTR modulators, including 136 during first trimester. Of these, 147 (99.3 %) resulted in livebirths. The most common CFTR modulator used was ELX/TEZ/IVA, in 121 (81.8 %) pregnancies. The prevalence of major birth defects was similar between exposed and unexposed fwCF (3.38 % vs. 4.66 %; p = 0.72). The rate of small for gestational age (SGA, <10th percentile) was significantly lower in pregnancies exposed compared to unexposed (6.8 % vs. 16.1 %; p < 0.01).
Discussion: The study provides early reassurance about the safety of CFTR modulators during pregnancy, particularly in terms of teratogenicity and adverse pregnancy outcomes. While findings suggest potential benefits, such as halved rate of SGA, further research is required to confirm these outcomes and investigate long-term effects on the development of children prenatally exposed to CFTR modulators.
Lauren Chouchanan is at the Regional Center of Pharmacovigilance, Department of perinatal, pediatric and adult pharmacology, Hopital Cochin, Hopital Necker.Dorina Dobi , Nicoletta Loberto, Laura Mauri, Rosaria Bassi , Elena Chiricozzi, Giulia Lunghi, Massimo Aureli. Effect of CFTR modulators Elexacaftor/Tezacaftor/Ivacaftor on lipid metabolism in human bronchial epithelial cells. Glycoconj J. 2025 Jan 11. doi: 10.1007/s10719-024-10174-7. pubmed.ncbi.nlm.nih.gov/39797966/
Dorina Dobi
LinkedIn
Cystic Fibrosis (CF) is a life-threatening hereditary disease resulting from mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that encodes a chloride channel essential for ion transport in epithelial cells. Mutations in CFTR, notably the prevalent F508del mutation, impair chloride transport, severely affecting the respiratory system and leading to recurrent infections. Recent therapeutic advancements include CFTR modulators such as ETI, a combination of two correctors (Elexacaftor and Tezacaftor) and a potentiator (Ivacaftor), that can improve CFTR function in patients with the F508del mutation. This study investigated ETI’s impact on the maturation of the mutated CFTR, the expression levels of its scaffolding proteins, and lipid composition of cells using bronchial epithelial cell lines expressing both wild-type and F508del CFTR. Our findings revealed that ETI treatment enhances CFTR and its scaffolding proteins expression and aids in rescuing mature F508del CFTR, causing also significant alterations in the lipid profile including reduced levels of lactosylceramide and increased content of gangliosides GM1 and GD1a
These changes were linked to ETI’s influence on enzymes involved in the sphingolipid metabolism, in particular GM3 synthase and sialidase. Through this work, we aim to deepen understanding CFTR interactions with lipids, and to elucidate the mechanisms of action of CFTR modulators. Our findings may support the development of potential therapeutic strategies contributing to the ongoing efforts to design effective correctors and potentiators for CF treatment.
Dorina Dobi is in the Department of Medical Biotechnology and Translational Medicine, University of Milano, Milan, Italy.
Cori L Daines, Deepika Polineni, Elizabeth Tullis, Stefano Costa , Rachel W Linnemann, and theVX17-445-105 Study Group.Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Adults and Adolescents with Cystic Fibrosis and at Least One F508del Allele: A Phase 3, Open-Label Extension StudAm J Respir Crit Care Med 2025 Apr 10. doi: 10.1164/rccm.202411-2231OC. Online ahead of print.pubmed.ncbi.nlm.nih.gov/40209082/
Cori L Daines
medicine.arizona.edu
Rationale: Clinical and real-world studies show elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is efficacious and safe in people with cystic fibrosis (CF) ≥12 years of age with at least one F508del allele.
Objectives: Given the potential for life-long ELX/TEZ/IVA use, long-term safety and efficacy of ELX/TEZ/IVA was assessed.
Methods: In this phase 3, open-label, single-arm extension study, participants with F508del-minimal function genotypes (from 24-week parent study 445-102 [n = 399]) or with the F508del-F508del genotype (from 4-week parent study 445-103 [n = 107]) received ELX/TEZ/IVA (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours) over 192 weeks.
Measurements and main results: Primary endpoint was safety and tolerability. Mean exposure to ELX/TEZ/IVA was 172.6 weeks. Most participants had adverse events classified as mild (12.8%) or moderate (60.7%) in severity. Eighteen participants (3.6%) had adverse events that led to treatment discontinuation. After starting ELX/TEZ/IVA, participants had consistent increases in percent predicted FEV1 (ppFEV1), Cystic Fibrosis Questionnaire-Revised respiratory domain score, and body mass index, with decreases in sweat chloride concentration and pulmonary exacerbations rates; these improvements were maintained through 192 weeks. The mean annualized rate of change in ppFEV1 was 0.02 percentage points (95% CI, -0.14 to 0.19) after initiation of ELX/TEZ/IVA.
Conclusions: During this 192-week open label extension study, the longest clinical study of a CFTR modulator to date, ELX/TEZ/IVA remained generally safe and well-tolerated. Participants had sustained improvements in lung function, respiratory symptoms, CFTR function, pulmonary exacerbation rates, and nutritional status. The estimated annualized rate of change in ppFEV1 suggests no evidence of pulmonary function loss across the study population over the 4-year treatment period. These results confirm the favorable long-term safety profile and durable disease-modifying clinical benefits of ELX/TEZ/IVA in adolescents and adults with CF. Clinical trial registration available at www.
Cori Daines is a professor at the University of Arizona Medical Center.
Rebecca Dobra, Christopher Short, Kiyo Wong, Clare Saunders, Mary Abkir, Samantha Irving, Jane C Davies. Utility and interpretation of multiple breath washout in children with cystic fibrosis. Arch Dis Child Educ Pract Ed. 2025 Jan 13:edpract-2024-328203. doi: 10.1136/archdischild-2024-328203. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39805677/
Rebecca Dobra
ResearchGate
Transformative changes in the health of children with cystic fibrosis (CF) mean that more sensitive outcome measures are needed to monitor paediatric CF lung disease. Multiple breath washout (MBW) and its primary readout lung clearance index are gaining increasing traction as an endpoint for clinical trials in the CF space and show promise as a clinical investigation. In this article, we use four clinically based questions to explore what MBW can and cannot (yet) do and highlight some of its strengths and weaknesses as an investigation. We end by discussing how we can increase the utility of MBW as an investigation in children with CF.
Rebecca Dobra is at the National Heart and Lung Institute, Imperial College London, London, UK and the Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK.
Jennifer L Goralski , Asha N Talati, Emily E Hardisty, Neeta L Vora. Pregnancy in People With Cystic Fibrosis Treated With Highly Effective Modulator Therapy. Review Obstet Gynecol. 2025 Jan 1;145(1):47-54. doi: 10.1097/AOG.0000000000005732. Epub 2024 Sep 19. pubmed.ncbi.nlm.nih.gov/39666984/
Jennifer Goralski
med.unc.edu
With improvements in overall health attributable to newly available medications called highly effective modulator therapy, an increasing number of people with cystic fibrosis (CF) are pursuing pregnancy. However, the safety of these medications for pregnant people with CF and the fetus remains largely unknown. Limited data demonstrate a decline in patients’ health and well-being after withdrawal of highly effective modulator therapy during pregnancy; however, both animal and human studies suggest an association between highly effective modulator therapy and cataracts in the offspring that requires further investigation. Use of highly effective modulator therapy can also affect the results of newborn screening and may influence fetal outcomes among fetuses affected by CF as a result of transplacental passage of highly effective modulator therapy. An ongoing prospective cohort study will likely provide more information for pregnant people with CF. Until then, multidisciplinary counseling continues to be critical for people with CF who are of reproductive age.
Jennifer L Goralski is in the Division of Pulmonary and Critical Care Medicine, the Division of Pediatric Pulmonology, and the Division of Maternal Fetal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Niels Høiby. Cystic fibrosis and the clinical biofilm revolution. A survey of the Danish CF Center’s contribution. Biofilm 2024 Dec 20:9:100246. doi: 10.1016/j.bioflm.2024.100246. eCollection 2025 Jun. pubmed.ncbi.nlm.nih.gov/39811797/
Niels Hoiby
research.reionh.dk
Biofilm infections are chronic infections which are difficult to diagnose. Biofilm infections are tolerant to antibiotics and the defense mechanisms of the host. Patients with the genetic disease cystic fibrosis (CF) produce viscid mucus in the respiratory tract and therefore suffer from chronic biofilm infections in their lungs and paranasal sinuses. The most important microorganism is the mucoid phenotype of Pseudomonas aeruginosa which causes chronic biofilm infections in the lungs of CF patients and untreated patients succumb as children if they contact this biofilm infection. Since CF patients are treated in CF Centers all over the world, it is possible to do longitudinal studies on epidemiology, pathophysiology, diagnosis, prevention and treatment of P. aeruginosa biofilm infection which is not possible if such patients are not followed in specialized centers. This survey describes the research through several decades in the Danish CF Center in Copenhagen which have changed the epidemiology, treatment, prophylaxis and prognosis of CF patients worldwide. Based on these results ESCMID Guidelines for diagnosis and treatment of biofilm infections were published which have influenced biofilm research and treatment in other areas.
Niels Hoiby is with the European Society for Clinical Microbiology and Infectious Disease Study Group for Biofilms (ESGB), Switzerland; the Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Denmark and the
Institute of Immunology and Microbiology, Panum Institute, University of Copenhagen, Denmark.Chiara
Chiara Lanfranchi , Gianfranco Alicandro , Lisa Cariani, Beatrice Silvia Orena, Andrea Gramegna , Carmela Rizza, Francesco Blasi , Valeria Daccò. Respiratory Outcomes and Aspergillus Serology Following Elexacaftor/Tezacaftor/Ivacaftor Therapy in People with Cystic Fibrosis and a History of Aspergillus fumigatus Infection. Lung
. 2025 Jan 6;203(1):24. doi: 10.1007/s00408-024-00781-4. pubmed.ncbi.nlm.nih.gov/39762638/
Chiara Lanfranchi
The Conversation
Purpose: The study evaluated the effects of elexacaftor/tezacaftor/ivacaftor (ETI) therapy in people with cystic fibrosis (pwCF) and a clinical history of Aspergillus fumigatus (AF) infection.
Methods: This prospective cohort study included pwCF who initiated ETI therapy and had received antifungal treatment in the preceding five years due to allergic bronchopulmonary aspergillosis (ABPA group) or other AF-related clinical manifestations (AF group). A control group of pwCF with no prior respiratory cultures positive for AF was also included. Changes from baseline to 12 months in spirometry measures and lung clearance index (LCI2.5), as well as respiratory colonization by AF, were compared across groups. Annual fold changes in the geometric mean of immunological markers were estimated using generalized estimating equations with a piecewise linear spline model, fitted to data collected from three years before to one-year post-ETI.
Results: The study included 16 patients in the ABPA group, 47 in the AF group, and 45 controls. Spirometry and LCI2.5 improvements were comparable across groups. Positive respiratory cultures decreased from 43.8 to 18.8% in the ABPA group (p = 0.30), and from 78.7 to 23.4% in the AF group (p < 0.001). Total IgE and IgG anti-AF decreased in both the ABPA and the AF groups, with annual reductions of 20-42%. No ABPA episodes occurred during ETI therapy.
Conclusion: During ETI therapy, pulmonary outcomes improved, AF colonization and sensitization decreased, and no episodes of ABPA were observed in pwCF with a clinical history of AF infection
Chiara Lanfranchi is in the Mother and Child Department, Cystic Fibrosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy.
Amalia S Magaret, Sonya L Heltshe. Need for re-assessment of impact of repeated pregnancy on lung health in cystic fibrosis. Respir Med. 2025 Jan:236:107890. doi: 10.1016/j.rmed.2024.107890. Epub 2024 Nov 28. pubmed.ncbi.nlm.nih.gov/39615801/
Amalia Sophia Magaret biostst.washington.edu
Cohen-Cymberknoh and others recently reported an increased drop in lung health for pregnant women with cystic fibrosis who are having their 3rd pregnancy, compared to earlier pregnancies. FEV1 percent-predicted was reported to decline 7.8 % over the course of later pregnancies relative to a decline of 2.5 % over earlier pregnancies. If causally related to birth order, this difference may affect decisions by prospective mothers. Considerations regarding pregnancy and family size are increasingly relevant as health and life expectancies for women with cystic fibrosis improve with use of disease-modifying treatments.
Amalia S Magaret is Faculty Director at the University of Washington Depts of Pediatrics and Biostatistics, United States; Seattle Children’s Research Institute, United States
Pharmacological and pre-clinical safety profile of rSIV.F/HN, a hybrid lentiviral vector for cystic fibrosis gene therapy.Eur Respir J 2025😭 jan 30; 6 5(1):23016832025. https://pubmed.ncbi.nlm.nih.gov/39174284/
Aleena Moiseenko
linkedin
Rationale and objective: Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CFTR modulators offer significant improvements, but ∼10% of patients remain nonresponsive or are intolerant. This study provides an analysis of rSIV.F/HN, a lentiviral vector optimised for lung delivery, including CFTR protein expression, functional correction of CFTR defects and genomic integration site analysis in preparation for a first-in-human clinical trial.
Methods: Air-liquid interface cultures of primary human bronchial epithelial cells (HBECs) from CF patients (F508del/F508del), as well as a CFTR-deficient immortalised human lung epithelial cell line mimicking class I (CFTR-null) homozygous mutations, were used to assess transduction efficiency. Quantification methods included a novel proximity ligation assay for CFTR protein expression. For assessment of CFTR channel activity, Ussing chamber studies were conducted. The safety profile was assessed using integration site analysis and in vitro insertional mutagenesis studies.
Results: rSIV.F/HN expressed CFTR and restored CFTR-mediated chloride currents to physiological levels in primary F508del/F508del HBECs as well as in a class I cells. In contrast, the latter could not be achieved by small-molecule CFTR modulators, underscoring the potential of gene therapy for this mutation class. Combination of rSIV.F/HN-CFTR with the potentiator ivacaftor showed a greater than additive effect. The genomic integration pattern showed no site predominance (frequency of occurrence ≤10%), and a low risk of insertional mutagenesis was observed in an in vitro immortalisation assay.
Conclusions: The results underscore rSIV.F/HN as a promising gene therapy vector for CF, providing a mutation-agnostic treatment option.
Alena Moiseenko is a Research Scientist at Boehringer Ingelheim Pharma GmbH
Paul K Mohabir, Fatma Gunturkun , Jennifer Cannon, Yaowei Deng, Ariadna Garcia, Eahsan Shahriary , Alicia Mirza. The impact of pregnancy on mortality and lung function in cystic fibrosis patientJ Cyst Fibros 2025 Feb 20:S1569-1993(25)00053-0. doi: 10.1016/j.jcf.2025.02.004.https://pubmed.ncbi.nlm.nih.gov/39984374/
Paul K Mohabir
Health News today
As the lifespan of cystic fibrosis improves, more individuals are pursuing pregnancy. Historically, pregnancy was not recommended in this population; however, more recent evidence has revealed inconsistent survival and lung function outcomes. Our aim was to assess the differences in survival and lung function between pregnant and never-pregnant pwCF and to provide updated recommendations for contemporary clinical practice.
Methods: In this retrospective matched parallel cohort study, data was collected from the American Cystic Fibrosis Foundation Patient Registry (CFFPR) from 1999 to 2019. 1743 adult pwCF with a reported pregnancy were matched with 1743 never-pregnant patients. Regression models were developed to estimate associations between patient characteristics, pregnancy, and outcomes. The primary endpoint was the probability of survival comparing pregnant and never-pregnant pwCF, while the secondary endpoint was lung function over time.
Results: The study cohort (n = 3486) had a mean age of 24.96 years. There was no significant difference in survival probabilities between pregnant and never-pregnant pwCF (56.2 %, CI95 %: 51.3 %-61.5 % vs. 55.8 %, CI95 %: 52.1 %-59.7 %, p = 0.5). The multivariable time-dependent Cox regression analysis resulted in a significantly lower mortality hazard rate for pregnant cohorts (HR:0.78, p < 0.01). There was no significant association between pregnancy and lung function over time (0.99, p = 0.21).
Conclusion: Pregnancy was associated with a reduced hazard of death compared to never-pregnant pwCF and did not demonstrate a significant impact on lung function. Therefore, pregnancy should not be generally discouraged in pwCF and clinicians should evaluate pregnancy risks and benefits on an individualized basis.
Paul K Mohabir,is a pulmonologist at at the University School of Medicine, Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, 300 Pasteur Drive, Stanford
Akash Pandey , Devendra Mehta , Karoly Horvat. A Review of Exocrine Pancreatic Insufficiency in Children beyond Cystic Fibrosis and the Role of Endoscopic Direct Pancreatic Function Testing.Review Curr Gastroenterol Rep. 2025 Feb 19;27(1):14. https://pubmed.ncbi.nlm.nih.gov/?term=akash+Pandey&sort=date&size=100
Purpose of review: Common indications to evaluate exocrine pancreatic function in children include chronic diarrhea, steatorrhea, failure to thrive, cystic fibrosis and those with chronic abdominal pain due to chronic pancreatitis where imaging studies are normal [1]. Exocrine Pancreatic Insufficiency (EPI) has a spectrum of severity. In children often remains an underdiagnosed condition, particularly in its mild, partial, and isolated enzyme deficiency forms. The purpose of this review is to help understand the different varieties of EPI including isolated pancreatic enzyme deficiencies as possible causes of malnutrition and growth failure in pediatric patients.
Recent findings: Among the indirect diagnostic methods, the fecal elastase-1 (FE-1) testing is the most widely used one. While it has good sensitivity and specificity in severe pancreatic damage, like cystic fibrosis in children, its performance in the diagnosis of mild, partial, and isolated enzyme deficiencies is poor. Direct pancreatic function testing performed during endoscopy (ePFT), has emerged as a more sensitive and specific method for assessing all forms of exocrine pancreatic function. Notably, recent guidelines from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) emphasize the importance of ePFT in pediatric patients. Most of the pediatric practitioners taught that the pancreas has only two diseases, cystic fibrosis and pancreatitis. They are missing the fact that pancreas, like other digestive organs, can have different, many times secondary, dysfunctions that influence the growth of children. Most pediatric gastroenterologists still use the fecal elastase-1 (FE-1) test, however, this lacks sufficient specificity and sensitivity [2-5] especially in patients with mild or early pancreatic disease or those with isolated enzyme deficiencies [5]. The most accurate diagnostic modality to explore these conditions is ePFT. In this review we highlighted the critical importance of direct pancreatic function testing. Enhancing clinical awareness and incorporating direct testing methods can ultimately improve outcomes for affected children.
Lucy Perrem, Stephanie Jeanneret-Manning, Stephanie D Davis , Margaret Rosenfeld, Todd Edwards, Sanja Stanojevic, Felix Ratjen. Does using the Lung Clearance Index (LCI) inform clinical decisions in children with cystic fibrosis? J Cyst Fibros. 2025 Jan 11:S1569-1993(24)01852-6. doi: 10.1016/j.jcf.2024.12.001. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39800642/
Lucy Perem
NACFC 2023
Introduction: The Lung Clearance Index (LCI) is an established research test, but its role in clinical decision-making is not well defined. This study estimated the proportion of treatment decisions that are changed or supported by the added information provided by LCI.
Methods: A mixed methods prospective observational study was conducted in North America. Providers were invited to participate in a clinical vignette survey consisting of 10 hypothetical scenarios involving pediatric cystic fibrosis (CF) management. First, they made a clinical decision based on information captured in routine clinical visits. Then, the LCI value was made available, and providers were asked whether the LCI changed or supported their decision. A prospective study was also conducted at three CF centres to determine how often physicians make pulmonary treatment decisions at CF clinic visits and how often they perceive additional lung function data would be helpful for these decisions.
Results: We received 522 vignette responses from 62 participants. LCI changed the decision in 18.4 % of cases, supported the decision in 57.1 % and did not impact the decision in 24.5 %. Data from patient encounters in the prospective study demonstrated that changes to pulmonary treatments were considered in 98/322 (30.4 %) visits; additional lung function information could potentially have helped in 64.3 % of the treatment decisions.
Conclusion: LCI changes or supports a significant proportion of treatment decisions. Providers perceive that additional information about lung function could be helpful at the majority of encounters where changes in treatment are considered.
Lucy Perrem is a paediatric pulmonologist at Children’s Health Ireland, Dublin, Ireland; University College Dublin, Dublin 4, Ireland.
Christine H Rumpf, Timo Janssen , Robert Jonathan Hai , Karin RommE , Clemens Decker , Janne Peters et al. Mucoid Staphylococcus aureus – Prevalence and Association with Lung Function in People with Cystic Fibrosis.Am J Respir Crit Care Med. 2025 Feb 7. doi: 10.1164/rccm.202407-1474OC. Online ahead of print.https://pubmed.ncbi.nlm.nih.gov/39918841/
Cristine Rumpf
2022 CF Conference Prog.
Measurements and main results: Cross-sectional study: In 41 of 451 S. aureus-positive pwCF (9.1%) from 13 CF-centers, mucoid S. aureus was cultured. Longitudinal study: The distribution of CFTR genotypes, the number of pwCF with highly effective modulator therapy and co-infection with Pseudomonas aeruginosa were equivalent in the mucoid (35 pwCF) versus the control group (only non-mucoid S. aureus, 36 pwCF). While lung function did not differ between groups as a whole, a subgroup analysis revealed significantly worse lung function for female pwCF with mucoid S. aureus as well as for pwCF if P. aeruginosa co-infection was excluded.
Conclusions: In the era of highly effective modulator therapy, worse lung function was associated with female and P. aeruginosa-negative pwCF with mucoid S. aureus compared to pwCF with only non-mucoid S. aureus. Therefore, appropriate culture conditions should be established to detect mucoid S. aureus. Further investigations are needed to elucidate the relationship between mucoid S. aureus and CF lung disease.
Christine Rumpf is at the University Hospital Munster Institute of Medical Microbiology, Munster, Nordrhein-Westfalen, Germany.
Karuna Sapru, Joanna Wilkinson, Anthony K Webb, Muhammad Akhtar, Rowland J Bright-Thomas. Success Rates of Assisted Reproduction for Men With Cystic Fibrosis. Pediatr Pulmonol. 2025 Jan;60(1):e27472. doi: 10.1002/ppul.27472. pubmed.ncbi.nlm.nih.gov/39812352/
Karuna Sapru
NACFC
Background: The vast majority of men with CF (mwCF) are infertile. Improvements in assisted reproductive technology (ART) have made it possible for these patients to become biological fathers.
Methods: Data were examined for all male CF patients attending a large adult CF center over a 23-year period. Azoospermia was confirmed via laboratory analysis of semen and was defined as complete absence of sperm in the ejaculate. Outcome of surgical sperm retrieval (SSR) procedure, post SSR complications, success rate of intracytoplasmic sperm injection (ICSI) and embryo transfer and subsequent live births were evaluated.
Results: Seventy-one mwCF with proven azoospermia were referred to fertility services over the study period. Mean (SD) percentage predicted forced expiratory volume in 1 second (ppFEV1) 67.86 ( ± 25.3), body mass index (BMI) 24.3 ( ± 3.7) kg/m2. Seventy (98.5%) of these men underwent and had successful SSR. 67/71 (94%) couples proceeded to have ICSI post SSR. 11 couples had failed egg fertilisation, implantation, or early miscarriage. 56/67 couples (84%) went on to have live births. To date 10/71 (14%) mwCF referred for fertility treatment have died. Mean ppFEV1 and BMI of mwCF who survived was higher than those who died; FEV1 72.8% ( ± 23.4) versus 38% ( ± 12.0) (p < 0.001), BMI 25.0 ( ± 3.5) kg/m2 versus 20.3 ( ± 2.2) kg/mg2 (p < 0.001).
Conclusion: This is the largest study to investigate success rate of fertility treatment in mwCF and demonstrates that fertility treatment is successful in greater than 75% of patients referred. Clinical status and prognosis remain important factors when considering referral to fertility services.
Karuna Sapru is in the Dept. of Respiratory Medicine, Manchester Adult Cystic Fibrosis Centre, North West Lung Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
Christina Shad
LinkedIn
Background: Elexacaftor/tezacaftor/ivacaftor (ETI) has improved health and increased life expectancy in many patients with cystic fibrosis (pwCF). Family planning issues have become more important since then. Many women decide to remain on modulator therapy during pregnancy despite insufficient evidence-based recommendations for continuing ETI during pregnancy and lactation.
Methods: In this retrospective observational report, we present data on maternal serum concentrations of ETI, assessed via a therapeutic drug monitoring (TDM) program established at our CF center for adults. Blood was taken during routine visits. We retrospectively analyzed the corresponding predicted forced expiratory volume in 1 s (ppFEV1), at five time points before, during, and after pregnancy.
Results: Of seven ETI-exposed pregnancies in six women between February 2021 and September 2023, the intake of ETI resulted in no maternal complications and healthy offspring. The dose was reduced in all women, 71.4 % before and 28.6 % during pregnancy, primarily as a result of side effects and/or increased ETI concentrations. Despite dose reductions, serum concentrations showed a broad distribution, with values below, within, and above the Cmax range according to the pharmacokinetic data in the manufacturer’s product characteristics. Pulmonary function largely remained stable without pulmonary exacerbations requiring intravenous antibiotic treatment.
Conclusion: This observational report shows the most extensive dataset for ETI concentrations during pregnancy. Individualized dose adjustments could help to resolve adverse side effects while continuing CFTR therapy. Specific populations, such as pregnant women, might benefit from a TDM. However, future research with more pharmacokinetic data from pregnant pwCF is needed.
Christina Shad is at the Department of Medicine V, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Germany
Gabrielle Schwartzman , Barrett J Zlotoff , Alejandro A Gru , Darren J Guffey. Cystic fibrosis dermatitis arthritis syndrome: A series of four cases Pediaqitr Dermatol 2025 Jan-Feb;42(1):133-135. doi: 10.1111/pde.15727. Epub 2024 Aug 8.https://pubmed.ncbi.nlm.nih.gov/39117496/
Gabriella Schwartzman
Dermatologic manifestations of cystic fibrosis (CF) include nutrient deficiency dermatoses, vasculitis, transient reactive papulotranslucent acrokeratodema, digital clubbing, and increased rates of atopy and drug reactions. Few cases of a characteristic eruption in patients with episodic arthritis of CF have been described with prior reports primarily occurring outside of the dermatology literature. We report four cases consistent with this presentation to add to the literature and propose a new and unifying name to recognize this entity as cystic fibrosis dermatitis arthritis syndrome (CF-DAS). Clinical suspicion should remain high in young female patients with cystic fibrosis presenting with episodic joint pain and rash, independent of pulmonary exacerbations.
Gabrielle Schwartzman is in the Department of Dermatology, University of Virginia, Charlottesville, Virginia, USA.
Vito Terlizzi, Cristina Fevola, Martina Cecchetti, Alberto Terminiello , Franco Curci , Elisa Bartolini, Chiara Rubino, Mariangela Stinco, Simona Carrera, Paolo Bonomi , Giovanni Taccetti, Zachary M Sellers, Giuseppe Indolfi. Effect of elexacaftor-tezacaftor-ivacaftor on liver transient elastography, fibrosis indices and blood tests in children with cystic fibrosis. J Cyst Fibros. 2025 Jan 12:S1569-1993(24)01861-7. doi: 10.1016/j.jcf.2024.12.010. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39800644/
Vito Terlizzi
ResearchGate
Background: Elexacaftor-tezacaftor-ivacaftor (ETI) has significantly improved the clinical course of people with cystic fibrosis (pwCF) and eligible CFTR variants. In this study, we prospectively evaluated liver elastography, liver fibrosis indices and liver tests in children with CF aged 6-12 years started on ETI therapy.
Methods: Body mass index, sweat test, percent predicted forced expiratory volume in one second, serum markers of liver injury or portal hypertension, liver fibrosis indices, controlled attenuation parameter and liver stiffness were assessed before starting ETI and three and twelve months post-ETI, according to new international guidelines.
Results: 27 children with CF were enrolled, 14 with liver involvement and 13 without liver involvement at baseline. A significant improvement in sweat chloride after ETI was observed in all subjects. In those with liver involvement, liver stiffness significantly decreased at 12 months of ETI, with all individuals achieving normalization or near-normalization of liver stiffness. The majority of individuals with abnormal AST, ALT, GGT, or liver fibrosis indices at baseline experienced normalization by 12 months of ETI (AST: 67%, ALT: 100%, GGT: 50%, APRI: 100%, GPR: 100%). In the no liver involvement group, the only significant change in liver health metrics at 12 months was a significant reduction in platelets (P<0.05) that remained within the normal range.
Conclusions: ETI is associated with improvement in liver stiffness, liver function tests and fibrosis indices in pwCF and liver involvement. ETI may reduce the development of advanced CF liver disease, but longer observations with larger cohorts are needed.
Vito Terlizzi is at the Meyer Children’s Hospital IRCCS, Cystic Fibrosis Regional Reference Centre, Department of Paediatric Medicine, Florence, Italy.
Adrian J Verster, Paige Salerno , Rebecca Valls , Kaitlyn Barrack, Courtney E Price , Emily A McClure , Juliette C Madan , George A O’Toole, Julie L Sanville , Benjamin D Ross.Persistent delay in maturation of the developing gut microbiota in infants with cystic fibrosis. mbio.03420-2mBio. 2025 Feb 13:e0342024. doi: 10.1128/mbio.03420-24. Online ahead of print.https://pubmed.ncbi.nlm.nih.gov/39945545/
The healthy human infant gut microbiome undergoes stereotypical changes in taxonomic composition between birth and maturation to an adult-like stable state. During this time, extensive communication between microbiota and the host immune system contributes to health status later in life. Although there are many reported associations between microbiota compositional alterations and disease in adults, less is known about how microbiome development is altered in pediatric diseases. One pediatric disease linked to altered gut microbiota composition is cystic fibrosis (CF), a multi-organ genetic disease involving impaired chloride secretion across epithelia and heightened inflammation both in the gut and at other body sites. Here, we use shotgun metagenomics to profile the strain-level composition and developmental dynamics of the infant fecal microbiota from several CF and non-CF longitudinal cohorts spanning from birth to greater than 36 months of life. We identify a set of keystone species that define microbiota development in early life in non-CF infants but are missing or decreased in relative abundance in infants with CF, resulting in a delayed pattern of microbiota maturation, persistent entrenchment in a transitional developmental phase, and subsequent failure to attain an adult-like stable microbiota. Delayed maturation is strongly associated with cumulative antibiotic treatments, and we also detect the increased relative abundance of oral-derived bacteria and higher levels of fungi in infants with CF, features that are associated with decreased gut bacterial density. These findings suggest the potential for future directed therapies targeted at overcoming developmental delays in microbiota maturation for infants with CF.
human gastrointestinal tract harbors a diversity of microbes that colonize upon birth and collectively contribute to host health throughout life. Infants with the disease cystic fibrosis (CF) harbor altered gut microbiota compared to non-CF counterparts, with lower levels of beneficial bacteria. How this altered population is established in infants with CF and how it develops over the first years of life is not well understood. By leveraging multiple large non-CF infant fecal metagenomic data sets and samples from a CF cohort collected prior to highly effective modulator therapy, we define microbiome maturation in infants up to 3 years of age. Our findings identify conserved age-diagnostic species in the non-CF infant microbiome that are diminished in abundance in CF counterparts that instead exhibit an enrichment of oral-derived bacteria and fungi associated with antibiotic exposure. Together, our study builds toward microbiota-targeted therapy to restore healthy microbiota dynamics in infants with CF.
LLC on behalf of The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.
Edith T Zemanick, Bonnie Ramsey, Dorota Sands, Edward F McKone, Isabelle Fajac , Jennifer L Taylor-Cousar , Marcus A Mall , Michael W Konstan , Nitin Nair , Jiaqiang Zhu , Emilio Arteaga-Solis Fredrick Van Goor , Lisa McGarry , Valentin Prieto-Centurion , Patrick R Sosnay , Carmen Bozic , David Waltz , Nicole Mayer-Hamblett. Sweat chloride reflects CFTR function and correlates with clinical outcomes following CFTR modulator treatment. J Cyst Fibros. 2025 Jan 3:S1569-1993(24)01854-X. doi: 10.1016/j.jcf.2024.12.006. Online ahead of print. J Cyst Fibros. 2025 Jan 3:S1569-1993(24)01854-X. doi: 10.1016/j.jcf.2024.12.006. Online ahead of print.
Edith Zemanick childrenscolorado.org
Background: Highly effective CFTR modulators improve CFTR function and lead to dramatic improvements in health outcomes in many people with cystic fibrosis (pwCF). The relationship between measures of CFTR function, such as sweat chloride concentration, and clinical outcomes in pwCF treated with CFTR modulators is poorly defined. We conducted analyses to better understand the relationships between sweat chloride and CFTR function in vitro, and between sweat chloride and clinical outcomes following CFTR modulator treatment.
Methods: Mean sweat chloride values in healthy people, CF carriers, and pwCF treated with CFTR modulators at different doses were compared to chloride transport in corresponding human bronchial epithelial (HBE) cells. A pooled analysis of phase 3 CFTR modulator studies was performed to evaluate the relationship between attained values of sweat chloride and improvements in lung function, body mass index (BMI), patient reported outcomes, pulmonary exacerbations, and lung function change over time.
Results: Sweat chloride concentrations in vivo correlated strongly with CFTR-dependent chloride current in HBE cells in vitro. Sweat chloride values of <30 mmol/L and ≥30 to <60 mmol/L in pwCF following CFTR modulator treatment were associated with better clinical outcomes than sweat chloride ≥60 to <80 mmol/L and ≥80 mmol/L.
Conclusions: In pwCF treated with CFTR modulators, lower sweat chloride levels (reflecting greater CFTR function) are associated with better clinical outcomes. These results support the therapeutic strategy of further restoring CFTR function towards normal, as reflected in lowering sweat chloride to below the diagnostic threshold for CF (<60 mmol/L) and to normal (<30 mmol/L), with CFTR modulators.
Edith T Zemanick is in the Department of Pediatrics, University of Colorado Anschutz Medical Campus and Children’s Hospital Colorado, Aurora, CO, U