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1. Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial

Author

Aurora, Paul, Verhulst, Stijn, Watson, Danie, Lorenz, Michael, Roehmel, Jobst, Gleiber, Wolfgang, Naehrig, Susanne, Stehling, Florian, Sutharsan, Sivagurunathan, van Koningsbruggen-Rietschel, Silke, Fischer, Rainald, Downey, Damian, Haworth, Charles, Duckers, Jamie, Legg, Julian, Barry, Peter, Thursfield, Rebecca, Doe, Simon James, Hilliard, Tom, MacGregor, Gordon, Nash, Edward F, Withers, Nicholas John, Peckham, Daniel, Barr, Helen Louise, Lee, Timothy, Gray, Robert, Vermeulen, Francois, Van Braeckel, Eva, Vanderhelst, Eef, Robinson, Philip J, Wainwright, Claire E, Smith, Daniel J, Mulrennan, Siobhain A, Clements, Barry S, Wark, Peter, McKone, Edward F, Downey, Damian G, Tullis, Elizabeth, Ahluwalia, Neil, Bruinsma, Bote G, Harris, Christopher, Lam, Anna P, Lou, Yiyue, Moskowitz, Samuel M, Tian, Simon, Yuan, Jason, Waltz, David, and Mall, Marcus A

Published
2022
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2. Rhesus θ-defensin-1 (RTD-1) exhibits in vitro and in vivo activity against cystic fibrosis strains of Pseudomonas aeruginosa

Author

Beringer, Paul M, Bensman, Timothy J, Ho, Henry, Agnello, Melissa, Denovel, Nicole, Nguyen, Albert, Wong-Beringer, Annie, She, Rosemary, Tran, Dat Q, Moskowitz, Samuel M, and Selsted, Michael E

Subjects
Rare Diseases, Cystic Fibrosis, Lung, Antimicrobial Resistance, Infectious Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Respiratory, Animals, Anti-Bacterial Agents, Bacterial Load, Body Weight, Defensins, Disease Models, Animal, Humans, Leukocyte Count, Macaca mulatta, Male, Mice, Inbred C57BL, Microbial Sensitivity Tests, Microbial Viability, Pseudomonas Infections, Pseudomonas aeruginosa, Treatment Outcome, Microbiology, Medical Microbiology, Pharmacology and Pharmaceutical Sciences
Abstract

ObjectivesChronic endobronchial infections with Pseudomonas aeruginosa contribute to bronchiectasis and progressive loss of lung function in patients with cystic fibrosis. This study aimed to evaluate the therapeutic potential of a novel macrocyclic peptide, rhesus θ-defensin-1 (RTD-1), by characterizing its in vitro antipseudomonal activity and in vivo efficacy in a murine model of chronic Pseudomonas lung infection.MethodsAntibacterial testing of RTD-1 was performed on 41 clinical isolates of P. aeruginosa obtained from cystic fibrosis patients. MIC, MBC, time-kill and post-antibiotic effects were evaluated following CLSI-recommended methodology, but using anion-depleted Mueller-Hinton broth. RTD-1 was nebulized daily for 7 days to cystic fibrosis transmembrane conductance regulator (CFTR) F508del-homozygous mice infected using the agar bead model of chronic P. aeruginosa lung infection. In vivo activity was evaluated by change in lung bacterial burden, airway leucocytes and body weight.ResultsRTD-1 exhibited potent in vitro bactericidal activity against mucoid and non-mucoid strains of P. aeruginosa (MIC90 = 8 mg/L). Cross-resistance was not observed when tested against MDR and colistin-resistant isolates. Time-kill studies indicated very rapid, concentration-dependent bactericidal activity of RTD-1 with ≥3 log10 cfu/mL reductions at concentrations ≥4× MIC. No post-antibiotic effect was observed. In vivo, nebulized treatment with RTD-1 significantly decreased lung P. aeruginosa burden (mean difference of -1.30 log10 cfu; P = 0.0061), airway leucocytes (mean difference of -0.37 log10; P = 0.0012) and weight loss (mean difference of -12.62% at day 7; P

Published
2016

3. Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in People With Cystic Fibrosis and at Least OneF508delAllele: 144-Week Interim Results From a 192-Week Open-label Extension Study

Author

Daines, Cori L., primary, Tullis, Elizabeth, additional, Costa, Stefano, additional, Linnemann, Rachel W., additional, Mall, Marcus A., additional, McKone, Edward F., additional, Polineni, Deepika, additional, Quon, Bradley S., additional, Ringshausen, Felix C., additional, Rowe, Steven M., additional, Selvadurai, Hiran, additional, Taylor-Cousar, Jennifer L., additional, Withers, Nicholas J., additional, Ahluwalia, Neil, additional, Moskowitz, Samuel M., additional, Prieto-Centurion, Valentin, additional, Tan, Yaoyuan Vincent, additional, Tian, Simon, additional, Weinstock, Tanya, additional, Xuan, Fengjuan, additional, Zhang, Yaohua, additional, Ramsey, Bonnie, additional, and Griese, Matthias, additional

Published
2023
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7. Lung function and microbiota diversity in cystic fibrosis

Author

Cuthbertson, Leah, Walker, Alan W., Oliver, Anna E., Rogers, Geraint B., Rivett, Damian W., Hampton, Thomas H., Ashare, Alix, Elborn, J. Stuart, De Soyza, Anthony, Carroll, Mary P., Hoffman, Lucas R., Lanyon, Clare, Moskowitz, Samuel M., O’Toole, George A., Parkhill, Julian, Planet, Paul J., Teneback, Charlotte C., Tunney, Michael M., Zuckerman, Jonathan B., Bruce, Kenneth D., and van der Gast, Christopher J.

Published
2020
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10. Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study

Author

Mall, Marcus A., primary, Brugha, Rossa, additional, Gartner, Silvia, additional, Legg, Julian, additional, Moeller, Alexander, additional, Mondejar-Lopez, Pedro, additional, Prais, Dario, additional, Pressler, Tacjana, additional, Ratjen, Felix, additional, Reix, Philippe, additional, Robinson, Paul D., additional, Selvadurai, Hiran, additional, Stehling, Florian, additional, Ahluwalia, Neil, additional, Arteaga-Solis, Emilio, additional, Bruinsma, Bote G., additional, Jennings, Mark, additional, Moskowitz, Samuel M., additional, Noel, Sabrina, additional, Tian, Simon, additional, Weinstock, Tanya G., additional, Wu, Pan, additional, Wainwright, Claire E., additional, and Davies, Jane C., additional

Published
2022
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12. Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for F508del-CFTR and a gating or residual function mutation

Author

Chmiel, J, Barry, Peter J, Colombo, Carla, De Wachter, Elke, Fajac, Isabelle, Mall, Marcus A, McBennett, Kimberly A, McKone, Edward F, Mondejar-Lopez, Pedro, Quon, Bradley, Ramsey, Bonnie W, Robinson, Padraic Sean, Sutharsan, S, Ahluwalia, Neil, Lu, M, Moskowitz, Samuel M, Prieto-Centurion, Valentin, Tian, Simon, Waltz, David, Weinstock, T, Xuan, Fengjuan, Zelazoski, L, Y, Zhang, Polineni, Deepika, Growth and Development, Physiotherapy, Human Physiology and Anatomy, Clinical sciences, and Pediatrics

Abstract

Background: The triple combination regimen of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with CF aged ≥ 12 years with cystic fibrosis (CF) and heterozygous for F508del-CFTR and either a CFTR gating mutation (F508del-gating genotypes) or residual function mutation (F508del-residual function genotypes). A 96-week Phase 3, open-label extension study was conducted to assess long-term safety and efficacy in these participants. Methods: Participants received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours. The primary endpoint was safety and tolerability; secondary endpoints included absolute changes in percent predicted FEV1 (ppFEV1), sweat chloride concentration, body mass index (BMI) and associated z-score, body weight, and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. The annualized rate of change in ppFEV1 was assessed as a post hoc analysis. Results: 251 participants (F508del-gating genotypes, n=92; F508del-residual function genotypes, n=159) were enrolled and dosed. The last patient visit will take place on April 8, 2022. Results from primary and secondary endpoints and post hoc analysis will be presented. Sponsor: Vertex Pharmaceuticals Incorporated

Published
2022

15. Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation : A Phase 3b, Randomized, Placebo-controlled Study

Author

Mall, Marcus A, Brugha, Rossa, Gartner, Silvia, Legg, Julian, Moeller, Alexander, Mondejar-Lopez, Pedro, Prais, Dario, Pressler, Tacjana, Ratjen, Felix, Reix, Philippe, Robinson, Paul D, Selvadurai, Hiran, Stehling, Florian, Ahluwalia, Neil, Arteaga-Solis, Emilio, Bruinsma, Bote G, Jennings, Mark, Moskowitz, Samuel M, Noel, Sabrina, Tian, Simon, Weinstock, Tanya G, Wu, Pan, Wainwright, Claire E, Davies, Jane C, University of Zurich, and Wainwright, Claire E

Subjects
Pulmonary and Respiratory Medicine, 10036 Medical Clinic, 2740 Pulmonary and Respiratory Medicine, Medizin, 610 Medicine & health, 2706 Critical Care and Intensive Care Medicine, Critical Care and Intensive Care Medicine
Abstract

Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children,30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children >30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results: The primary endpoint was absolute change in lung clearance index₂.₅ from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index₂.₅ of 2.29 units (95% confidence interval [CI], 1.97–2.60) compared with 0.02 units (95% CI, 20.29 to 0.34) in children given placebo (between-group treatment difference, 22.26 units; 95% CI, 22.71 to 21.81; P, 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, 251.2 mmol/L; 95% CI, 255.3 to 247.1) and in the other endpoints of percent predicted FEV₁ (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9–15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0–10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions: In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings.

Published
2022

17. Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial

Author

Sutharsan, Sivagurunathan, primary, McKone, Edward F, additional, Downey, Damian G, additional, Duckers, Jamie, additional, MacGregor, Gordon, additional, Tullis, Elizabeth, additional, Van Braeckel, Eva, additional, Wainwright, Claire E, additional, Watson, Danie, additional, Ahluwalia, Neil, additional, Bruinsma, Bote G, additional, Harris, Christopher, additional, Lam, Anna P, additional, Lou, Yiyue, additional, Moskowitz, Samuel M, additional, Tian, Simon, additional, Yuan, Jason, additional, Waltz, David, additional, Mall, Marcus A, additional, Aurora, Paul, additional, Verhulst, Stijn, additional, Lorenz, Michael, additional, Roehmel, Jobst, additional, Gleiber, Wolfgang, additional, Naehrig, Susanne, additional, Stehling, Florian, additional, Sutharsan, Sivagurunathan, additional, van Koningsbruggen-Rietschel, Silke, additional, Fischer, Rainald, additional, Downey, Damian, additional, Haworth, Charles, additional, Legg, Julian, additional, Barry, Peter, additional, Thursfield, Rebecca, additional, Doe, Simon James, additional, Hilliard, Tom, additional, Nash, Edward F, additional, Withers, Nicholas John, additional, Peckham, Daniel, additional, Barr, Helen Louise, additional, Lee, Timothy, additional, Gray, Robert, additional, Vermeulen, Francois, additional, Vanderhelst, Eef, additional, Robinson, Philip J, additional, Smith, Daniel J, additional, Mulrennan, Siobhain A, additional, Clements, Barry S, additional, and Wark, Peter, additional

Published
2022
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20. Triple Therapy for Cystic Fibrosis Phe508del –Gating and –Residual Function Genotypes

Author

VX18-445-104 Study Group, Barry, Peter J, Mall, Marcus A, Álvarez, Antonio, Colombo, Carla, de Winter-de Groot, Karin M, Fajac, Isabelle, McBennett, Kimberly A, McKone, Edward F, Ramsey, Bonnie W, Sutharsan, Sivagurunathan, Taylor-Cousar, Jennifer L, Tullis, Elizabeth, Ahluwalia, Neil, Jun, Lucy S, Moskowitz, Samuel M, Prieto-Centurion, Valentin, Tian, Simon, Waltz, David, Xuan, Fengjuan, Zhang, Yaohua, Rowe, Steven M, Polineni, Deepika, Vanderhelst, Eef, De Wachter, Elke, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiotherapy, Human Physiology and Anatomy, Clinical sciences, Pneumology, and Pediatrics

Subjects
Male, [SDV]Life Sciences [q-bio], Medizin, Gating, Cystic fibrosis, Gastroenterology, 0302 clinical medicine, Genotype, 030212 general & internal medicine, Child, biology, General Medicine, respiratory system, Cystic fibrosis transmembrane conductance regulator, 3. Good health, Drug Combinations, Chlorides/analysis, Indoles/adverse effects, Female, Benzodioxoles/adverse effects, Adult, Pulmonary and Respiratory Medicine, medicine.medical_specialty, 2019-20 coronavirus outbreak, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Chloride Channel Agonists/adverse effects, Aminophenols/adverse effects, Sweat/chemistry, Article, 03 medical and health sciences, Double-Blind Method, Pyrazoles/adverse effects, Internal medicine, medicine, Humans, In patient, Pyridines/adverse effects, Quinolines/adverse effects, business.industry, medicine.disease, respiratory tract diseases, Regimen, 030228 respiratory system, biology.protein, Cystic Fibrosis Transmembrane Conductance Regulator/genetics, Cystic Fibrosis/drug therapy, business, Function (biology)
Abstract

BACKGROUND: Elexacaftor–tezacaftor–ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor–ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear. METHODS: We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del–gating or Phe508del–residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor–ivacaftor, patients were randomly assigned to receive elexacaftor–tezacaftor–ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV(1)) from baseline through week 8 in the elexacaftor–tezacaftor–ivacaftor group. RESULTS: After the run-in period, 132 patients received elexacaftor–tezacaftor–ivacaftor and 126 received active control. Elexacaftor–tezacaftor–ivacaftor resulted in a percentage of predicted FEV(1) that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P

Published
2021

21. Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study.

Author

Mall, Marcus A., Brugha, Rossa, Gartner, Silvia, Legg, Julian, Moeller, Alexander, Mondejar-Lopez, Pedro, Prais, Dario, Pressler, Tacjana, Ratjen, Felix, Reix, Philippe, Robinson, Paul D., Selvadurai, Hiran, Stehling, Florian, Ahluwalia, Neil, Arteaga-Solis, Emilio, Bruinsma, Bote G., Jennings, Mark, Moskowitz, Samuel M., Noel, Sabrina, and Tian, Simon

Subjects
LAXATIVES, RESEARCH, GENETIC mutation, PHENOLS, CLINICAL trials, HETEROCYCLIC compounds, RESEARCH methodology, EVALUATION research, CYSTIC fibrosis, COMPARATIVE studies, RANDOMIZED controlled trials, FORCED expiratory volume, MEMBRANE proteins
Abstract

Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results: The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index2.5 of 2.29 units (95% confidence interval [CI], 1.97-2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81; P < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1) and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9-15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0-10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions: In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings. [ABSTRACT FROM AUTHOR]

Published
2022
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22. Triple Therapy for Cystic Fibrosis Phe508del–Gating and –Residual Function Genotypes

Author

Barry, Peter J., primary, Mall, Marcus A., additional, Álvarez, Antonio, additional, Colombo, Carla, additional, de Winter-de Groot, Karin M., additional, Fajac, Isabelle, additional, McBennett, Kimberly A., additional, McKone, Edward F., additional, Ramsey, Bonnie W., additional, Sutharsan, Sivagurunathan, additional, Taylor-Cousar, Jennifer L., additional, Tullis, Elizabeth, additional, Ahluwalia, Neil, additional, Jun, Lucy S., additional, Moskowitz, Samuel M., additional, Prieto-Centurion, Valentin, additional, Tian, Simon, additional, Waltz, David, additional, Xuan, Fengjuan, additional, Zhang, Yaohua, additional, Rowe, Steven M., additional, and Polineni, Deepika, additional

Published
2021
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25. A Phase 3 Open-Label Study of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One F508del Allele

Author

Zemanick, Edith T., primary, Taylor-Cousar, Jennifer L., additional, Davies, Jane, additional, Gibson, Ronald L., additional, Mall, Marcus A., additional, McKone, Edward F., additional, McNally, Paul, additional, Ramsey, Bonnie W., additional, Rayment, Jonathan H., additional, Rowe, Steven M., additional, Tullis, Elizabeth, additional, Ahluwalia, Neil, additional, Chu, Chenghao, additional, Ho, Thang, additional, Moskowitz, Samuel M., additional, Noel, Sabrina, additional, Tian, Simon, additional, Waltz, David, additional, Weinstock, Tanya G., additional, Xuan, Fengjuan, additional, Wainwright, Claire E., additional, and McColley, Susanna A., additional

Published
2021
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30. Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor for 24 Weeks or Longer in People with Cystic Fibrosis and One or More F508del Alleles: Interim Results of an Open-Label Phase 3 Clinical Trial

Author

Griese, Matthias, primary, Costa, Stefano, additional, Linnemann, Rachel W., additional, Mall, Marcus A., additional, McKone, Edward F., additional, Polineni, Deepika, additional, Quon, Bradley S., additional, Ringshausen, Felix C., additional, Taylor-Cousar, Jennifer L., additional, Withers, Nicholas J., additional, Moskowitz, Samuel M., additional, and Daines, Cori L., additional

Published
2021
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32. Additional file 1 of Lung function and microbiota diversity in cystic fibrosis

Author

Cuthbertson, Leah, Walker, Alan W., Oliver, Anna E., Rogers, Geraint B., Rivett, Damian W., Hampton, Thomas H., Ashare, Alix, J. Stuart Elborn, Soyza, Anthony De, Carroll, Mary P., Hoffman, Lucas R., Lanyon, Clare, Moskowitz, Samuel M., O’Toole, George A., Parkhill, Julian, Planet, Paul J., Teneback, Charlotte C., Tunney, Michael M., Zuckerman, Jonathan B., Bruce, Kenneth D., and Gast, Christopher J. Van Der

Abstract

Additional file 1: Table S1. Core taxa within each lung disease category. Given is prevalence, the number of samples a given core taxon was detected in, and average relative abundance across those samples. Operational taxonomic unit (OTU) identifications have been used for bacterial taxon names. OTU numbers have been used to differentiate between taxa within the same genus. Given the length of the ribosomal sequences analysed, species identities should be considered putative.

Published
2020
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33. Additional file 5 of Lung function and microbiota diversity in cystic fibrosis

Author

Cuthbertson, Leah, Walker, Alan W., Oliver, Anna E., Rogers, Geraint B., Rivett, Damian W., Hampton, Thomas H., Ashare, Alix, J. Stuart Elborn, Soyza, Anthony De, Carroll, Mary P., Hoffman, Lucas R., Lanyon, Clare, Moskowitz, Samuel M., O’Toole, George A., Parkhill, Julian, Planet, Paul J., Teneback, Charlotte C., Tunney, Michael M., Zuckerman, Jonathan B., Bruce, Kenneth D., and Gast, Christopher J. Van Der

Abstract

Additional file 5: Table S4. PERMANOVA summary statistics from testing for significant differences in microbiota composition between lung function categories. Given in each instance are mean Bray-Curtis similarity within and between categories (± standard deviation of the mean), F-statistic, and significance (P). Asterisks denote significant differences in composition following one-way PERMANOVA tests with Bonferroni correction.

Published
2020
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34. Additional file 2 of Lung function and microbiota diversity in cystic fibrosis

Author

Cuthbertson, Leah, Walker, Alan W., Oliver, Anna E., Rogers, Geraint B., Rivett, Damian W., Hampton, Thomas H., Ashare, Alix, J. Stuart Elborn, Soyza, Anthony De, Carroll, Mary P., Hoffman, Lucas R., Lanyon, Clare, Moskowitz, Samuel M., O’Toole, George A., Parkhill, Julian, Planet, Paul J., Teneback, Charlotte C., Tunney, Michael M., Zuckerman, Jonathan B., Bruce, Kenneth D., and Gast, Christopher J. Van Der

Subjects
parasitic diseases, respiratory system, human activities
Abstract

Additional file 2: Table S2. Kruskal-Wallis summary statistics for testing for significant differences in diversity between lung function categories. Given for each test is the mean Fisher's alpha diversity index, standard deviation of the mean, H-statistic, and significance (P), and mean of ranks values. Asterisks denote significant differences in diversity following Kruskal-Wallis with post-hoc Dunn test.

Published
2020
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36. The Pseudomonas aeruginosa lipid A deacylase: selection for expression and loss within the cystic fibrosis airway

Author

Ernst, Robert K., Adams, Kristin N., Moskowitz, Samuel M., Kraig, Gretchen M., Kawasaki, Kiyoshi, Stead, Christopher M., Trent, M. Stephen, and Miller, Samuel I.

Subjects
Cystic fibrosis -- Analysis, Pseudomonas aeruginosa -- Physiological aspects, Pseudomonas aeruginosa -- Research, Gram-negative bacteria -- Physiological aspects, Gram-negative bacteria -- Research, Biological sciences
Abstract

Lipopolysaccharide (LPS) is the major surface component of gram-negative bacteria, and a component of LPS, lipid A, is recognized by the innate immune system through the Toll-like receptor 4/MD-2 complex. Pseudomonas aeruginosa, an environmental gram-negative bacterium that opportunistically infects the respiratory tracts of patients with cystic fibrosis (CF), can synthesize various structures of lipid A. Lipid A from P. aeruginosa strains isolated from infants with CF has a specific structure that includes the removal of the 3 position 3-OH C10 fatty acid. Here we demonstrate increased expression of the P. aeruginosa lipid A 3-O-deacylase (PagL) in isolates from CF infants compared to that in environmental isolates. PagL activity was increased in environmental isolates by growth in medium limited for magnesium and decreased by growth at low temperature in laboratory-adapted strains of P. aeruginosa. P. aeruginosa PagL was shown to be an outer membrane protein by isopycnic density gradient centrifugation. Heteroiogous expression ofP. aeruginosa pagL in Salmonella enterica serovar Typhimurium and Escherichia coli resulted in removal of the 3-OH C14 fatty acid from lipid A, indicating that P. aeruginosa PagL recognizes either 3-OH C10 or 3-OH C14. Finally, deacylated lipid A species were not observed in some clinical P. aeruginosa isolates from patients with severe pulmonary disease, suggesting that loss of PagL function can occur during long-term adaptation to the CF airway.

Published
2006

37. PmrAB, a two-component regulatory system of Pseudomonas aeruginosa that modulates resistance to cationic antimicrobial peptides and addition of aminoarabinose to lipid A

Author

Moskowitz, Samuel M., Ernst, Robert K., and Miller, Samuel I.

Subjects
Biological sciences
Abstract

Spontaneous polymyxin-resistant mutants of Pseudomonas aeruginosa were isolated. The mutations responsible for this phenotype were mapped to a two-component signal transduction system similar to PmrAB of Salmonella enterica serovar Typhimurium. Lipid A of these mutants contained aminoarabinose, an inducible modification that is associated with polymyxin resistance. Thus, P. aeruginosa possesses a mechanism that induces resistance to cationic antimicrobial peptides in response to environmental conditions.

Published
2004

40. Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

Author

Middleton, Peter G., primary, Mall, Marcus A., additional, Dřevínek, Pavel, additional, Lands, Larry C., additional, McKone, Edward F., additional, Polineni, Deepika, additional, Ramsey, Bonnie W., additional, Taylor-Cousar, Jennifer L., additional, Tullis, Elizabeth, additional, Vermeulen, François, additional, Marigowda, Gautham, additional, McKee, Charlotte M., additional, Moskowitz, Samuel M., additional, Nair, Nitin, additional, Savage, Jessica, additional, Simard, Christopher, additional, Tian, Simon, additional, Waltz, David, additional, Xuan, Fengjuan, additional, Rowe, Steven M., additional, and Jain, Raksha, additional

Published
2019
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41. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial

Author

Heijerman, Harry G M, primary, McKone, Edward F, additional, Downey, Damian G, additional, Van Braeckel, Eva, additional, Rowe, Steven M, additional, Tullis, Elizabeth, additional, Mall, Marcus A, additional, Welter, John J, additional, Ramsey, Bonnie W, additional, McKee, Charlotte M, additional, Marigowda, Gautham, additional, Moskowitz, Samuel M, additional, Waltz, David, additional, Sosnay, Patrick R, additional, Simard, Christopher, additional, Ahluwalia, Neil, additional, Xuan, Fengjuan, additional, Zhang, Yaohua, additional, Taylor-Cousar, Jennifer L, additional, McCoy, Karen S, additional, McCoy, Karen, additional, Donaldson, Scott, additional, Walker, Seth, additional, Chmiel, James, additional, Rubenstein, Ronald, additional, Froh, Deborah K., additional, Neuringer, Isabel, additional, Jain, Manu, additional, Moffett, Kathryn, additional, Taylor-Cousar, Jennifer L., additional, Barnett, Bruce, additional, Mueller, Gary, additional, Flume, Patrick, additional, Livingston, Floyd, additional, Mehdi, Nighat, additional, Teneback, Charlotte, additional, Welter, John, additional, Jain, Raksha, additional, Kissner, Dana, additional, Patel, Kapilkumar, additional, Calimano, Francisco J., additional, Johannes, Jimmy, additional, Daines, Cori, additional, Keens, Thomas, additional, Scher, Herschel, additional, Chittivelu, Subramanyam, additional, Reddivalam, Sudhakar, additional, Klingsberg, Ross Carl, additional, Johnson, Larry G., additional, Verhulst, Stijn, additional, Macedo, Patricia, additional, Downey, Damien, additional, Connett, Gary, additional, Nash, Edward, additional, Withers, Nicholas, additional, Lee, Timothy, additional, Bakker, Marleen, additional, Heijerman, Harry, additional, Vermeulen, Francois, additional, Knoop, Christiane, additional, De Wachter, Elke, additional, van der Meer, Renske, additional, Merkus, Petrus, additional, and Majoor, Christof, additional

Published
2019
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45. A Phase 3 Open-Label Study of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One Allele.

Author

Zemanick, Edith T., Taylor-Cousar, Jennifer L., Davies, Jane, Gibson, Ronald L., Mall, Marcus A., McKone, Edward F., McNally, Paul, Ramsey, Bonnie W., Rayment, Jonathan H., Rowe, Steven M., Tullis, Elizabeth, Ahluwalia, Neil, Chenghao Chu, Thang Ho, Moskowitz, Samuel M., Noel, Sabrina, Tian, Simon, Waltz, David, Weinstock, Tanya G., and Fengjuan Xuan

Subjects
CYSTIC fibrosis treatment, LUNG disease diagnosis, LUNG disease treatment, ALLELES, CHILD care, LAXATIVES, RESEARCH, INDOLE compounds, GENETICS, COMBINATION drug therapy, CLINICAL trials, HETEROCYCLIC compounds, RESEARCH methodology, MEDICAL cooperation, EVALUATION research, CYSTIC fibrosis, COMPARATIVE studies, GENOTYPES, MEMBRANE proteins, QUINOLONE antibacterial agents
Abstract

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients ≥12 years of age with cystic fibrosis and at least one F508del-CFTR (cystic fibrosis transmembrane conductance regulator) allele, but it has not been evaluated in children <12 years of age. Objectives: To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with F508del-minimal function or F508del-F508del genotypes. Methods: In this 24-week open-label phase 3 study, children (N = 66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 h) whereas children weighing ⩾30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 h). Measurements and Main Results: The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most commonly reported adverse events included cough, headache, and pyrexia; in most of the children who had adverse events, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the percentage of predicted FEV1 (10.2 percentage points; 95% confidence interval [CI], 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index2.5 (-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age z-score increased over the 24-week treatment period when compared with the pretreatment baseline. Conclusions: Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one F508del-CFTR allele, supporting its use in this patient population. Clinical trial registered with www.clinicaltrials.gov (NCT03691779). [ABSTRACT FROM AUTHOR]

Published
2021
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46. Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles

Author

Taylor-Cousar, Jennifer L., primary, Mall, Marcus A., additional, Ramsey, Bonnie W., additional, McKone, Edward F., additional, Tullis, Elizabeth, additional, Marigowda, Gautham, additional, McKee, Charlotte M., additional, Waltz, David, additional, Moskowitz, Samuel M., additional, Savage, Jessica, additional, Xuan, Fengjuan, additional, and Rowe, Steven M., additional

Published
2019
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47. Effects of a primary palliative care intervention on quality of life and mental health in cystic fibrosis

Author

Friedman, Deborah, primary, Linnemann, Rachel W., additional, Altstein, Lily L., additional, Georgiopoulos, Anna M., additional, Islam, Suhayla, additional, Bach, Kieu‐Tram, additional, John, Anita, additional, Fracchia, M. Shannon, additional, Neuringer, Isabel, additional, Lapey, Allen, additional, Sicilian, Leonard, additional, Moskowitz, Samuel M., additional, and Yonker, Lael M., additional

Published
2019
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50. VX-445–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles

Author

Keating, Dominic, primary, Marigowda, Gautham, additional, Burr, Lucy, additional, Daines, Cori, additional, Mall, Marcus A., additional, McKone, Edward F., additional, Ramsey, Bonnie W., additional, Rowe, Steven M., additional, Sass, Laura A., additional, Tullis, Elizabeth, additional, McKee, Charlotte M., additional, Moskowitz, Samuel M., additional, Robertson, Sarah, additional, Savage, Jessica, additional, Simard, Christopher, additional, Van Goor, Fredrick, additional, Waltz, David, additional, Xuan, Fengjuan, additional, Young, Tim, additional, and Taylor-Cousar, Jennifer L., additional

Published
2018
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