Clinical Mechanism of the Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Ivacaftor in G551D-mediated Cystic Fibrosis
Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation. To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers. We cond...
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| Published in | American journal of respiratory and critical care medicine Vol. 190; no. 2; pp. 175 - 184 |
|---|---|
| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Thoracic Society
15.07.2014
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 1073-449X 1535-4970 1535-4970 |
| DOI | 10.1164/rccm.201404-0703OC |
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| Abstract | Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.
To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers.
We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor.
Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology. |
|---|---|
| AbstractList | Rationale:
Ivacaftor is a cystic fibrosis transmembrane conductance
regulator (CFTR) potentiator recently approved for patients with CF age 6 and older
with the G551D mutation.
Objectives:
To evaluate ivacaftor in a postapproval setting and
determine mechanism of action and response of clinically relevant markers.
Methods:
We conducted a longitudinal cohort study in 2012–2013 in
G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study
assessments were performed at baseline, 1, 3, and 6 months after ivacaftor
initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat
secretion rate, gastrointestinal pH, and sputum inflammation and microbiology
Measurements and Main Results:
A total of 151 of 153 subjects were
prescribed ivacaftor and 88% completed the study through 6 months. FEV
1
%
predicted improved from baseline to 6 months (mean absolute change, 6.7%;
P
< 0.001). Similarly, body mass index improved from
baseline to 6 months (mean change, 0.8 kg/m
2
;
P
<
0.001). Sweat chloride decreased from baseline to 6 months (mean change, −53.8
mmol/L; 95% confidence interval, −57.7 to −49.9;
P
< 0.001), reflecting augmented CFTR function. There was significant improvement
in hospitalization rate (
P
< 0.001) and
Pseudomonas
aeruginosa
burden (
P
< 0.01). Significant
improvements in mucociliary clearance (
P
< 0.001),
gastrointestinal pH (
P
= 0.001), and microbiome were also
observed, providing clinical mechanisms underlying the therapeutic benefit of
ivacaftor.
Conclusions:
Significant clinical and physiologic improvements were
observed on initiation of ivacaftor in a broad patient population, including reduced
infection with
P. aeruginosa
. Biomarker studies substantially
improve the understanding of the mechanistic consequences of CFTR modulation on
pulmonary and gastrointestinal physiology. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation. To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers. We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, [beta]-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor. Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.RATIONALEIvacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers.OBJECTIVESTo evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers.We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor.METHODSWe conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor.Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.CONCLUSIONSSignificant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation. To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers. We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor. Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology. |
| Author | Sagel, Scott D. Ramsey, Bonnie W. Khan, Umer Heltshe, Sonya L. Gonska, Tanja Joseloff, Elizabeth Van Dalfsen, Jill M. Borowitz, Drucy Gelfond, Daniel Mayer-Hamblett, Nicole Donaldson, Scott H. Rowe, Steven M. |
| Author_xml | – sequence: 1 givenname: Steven M. surname: Rowe fullname: Rowe, Steven M. organization: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama – sequence: 2 givenname: Sonya L. surname: Heltshe fullname: Heltshe, Sonya L. organization: Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, Cystic Fibrosis Foundation Therapeutics Development Network, Seattle Children's Research Institute, Seattle, Washington – sequence: 3 givenname: Tanja surname: Gonska fullname: Gonska, Tanja organization: Department of Pediatrics, University of Toronto, Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada – sequence: 4 givenname: Scott H. surname: Donaldson fullname: Donaldson, Scott H. organization: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina – sequence: 5 givenname: Drucy surname: Borowitz fullname: Borowitz, Drucy organization: Department of Pediatrics, State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York – sequence: 6 givenname: Daniel surname: Gelfond fullname: Gelfond, Daniel organization: Department of Pediatrics, State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York – sequence: 7 givenname: Scott D. surname: Sagel fullname: Sagel, Scott D. organization: Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, Colorado; and – sequence: 8 givenname: Umer surname: Khan fullname: Khan, Umer organization: Cystic Fibrosis Foundation Therapeutics Development Network, Seattle Children's Research Institute, Seattle, Washington – sequence: 9 givenname: Nicole surname: Mayer-Hamblett fullname: Mayer-Hamblett, Nicole organization: Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, Cystic Fibrosis Foundation Therapeutics Development Network, Seattle Children's Research Institute, Seattle, Washington – sequence: 10 givenname: Jill M. surname: Van Dalfsen fullname: Van Dalfsen, Jill M. organization: Cystic Fibrosis Foundation Therapeutics Development Network, Seattle Children's Research Institute, Seattle, Washington – sequence: 11 givenname: Elizabeth surname: Joseloff fullname: Joseloff, Elizabeth organization: Cystic Fibrosis Foundation Therapeutics, Bethesda, Maryland – sequence: 12 givenname: Bonnie W. surname: Ramsey fullname: Ramsey, Bonnie W. organization: Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, Cystic Fibrosis Foundation Therapeutics Development Network, Seattle Children's Research Institute, Seattle, Washington |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24927234$$D View this record in MEDLINE/PubMed |
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| Snippet | Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D... Rationale: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with... |
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| SubjectTerms | Adolescent Adult Age Aminophenols - pharmacology Aminophenols - therapeutic use Biomarkers - metabolism Child Cohort analysis Cystic fibrosis Cystic Fibrosis - drug therapy Cystic Fibrosis - genetics Cystic Fibrosis - metabolism Cystic Fibrosis - microbiology Cystic Fibrosis Transmembrane Conductance Regulator - genetics FDA approval Female Follow-Up Studies Forced Expiratory Volume - drug effects Genetic Markers Hospitalization - statistics & numerical data Humans Hydrogen-Ion Concentration - drug effects Infections Inflammation Intestine, Small - drug effects Intestine, Small - metabolism Lung - drug effects Lung - metabolism Lung - microbiology Lung - physiopathology Male Microbiota - drug effects Mucociliary Clearance - drug effects Mutation Original Patients Pseudomonas aeruginosa - isolation & purification Pseudomonas Infections - complications Pseudomonas Infections - diagnosis Pseudomonas Infections - prevention & control Quinolones - pharmacology Quinolones - therapeutic use Respiratory System Agents - pharmacology Respiratory System Agents - therapeutic use Spirometry Sputum - metabolism Sputum - microbiology Sweat - drug effects Sweat - metabolism Treatment Outcome Young Adult |
| Title | Clinical Mechanism of the Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Ivacaftor in G551D-mediated Cystic Fibrosis |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/24927234 https://www.proquest.com/docview/1547397681 https://www.proquest.com/docview/1545774746 https://pubmed.ncbi.nlm.nih.gov/PMC4226057 |
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