Author
Claudia L. Ordoñez
Bio: Claudia L. Ordoñez is an academic researcher from Vertex Pharmaceuticals. The author has contributed to research in topics: Cystic fibrosis & Ivacaftor. The author has an hindex of 7, co-authored 12 publications receiving 3561 citations.
Papers
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Seattle Children's1, National Health Service2, Beaumont Hospital3, University of Toronto4, University of Queensland5, Charles University in Prague6, Ludwig Maximilian University of Munich7, University College Dublin8, Case Western Reserve University9, Stanford University10, University of Paris11, University of Alabama at Birmingham12, Vertex Pharmaceuticals13, Queen's University Belfast14
TL;DR: Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks and substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride.
Abstract: Background Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis. Methods We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV1). Results The change from baseline through week 24 in the percent of predicted FEV1 was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained...
1,835 citations
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Anschutz Medical Campus1, University of Alabama at Birmingham2, Johns Hopkins University3, University of Minnesota4, University of Toronto5, University of Iowa6, University of North Carolina at Chapel Hill7, Stanford University8, University of Pittsburgh9, University of Pennsylvania10, Harvard University11, University of Washington12, Boston Children's Hospital13, Vertex Pharmaceuticals14, Cystic Fibrosis Foundation15
TL;DR: This study showed that VX-770 was associated with within-subject improvements in CFTR and lung function and provides support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis.
Abstract: Background A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cellsurface CFTR in vitro. Methods We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study). Results At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was −3.5 mV (range, −8.3 to 0.5; P = 0.02 for the within-subject comparison, P = 0.13 vs. placebo), and the median change in the level of sweat chloride was −59.5 mmol per liter (range, −66.0 to −19.0; P = 0.008 within-subject, P = 0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P = 0.008 for the within-subject comparison, P = 0.56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770. Conclusions This study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis. (Funded by Vertex Pharmaceuticals and others; ClinicalTrials.gov number, NCT00457821.)
709 citations
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Cincinnati Children's Hospital Medical Center1, University of Alabama at Birmingham2, University of Colorado Denver3, University of Washington4, Cystic Fibrosis Foundation5, Hannover Medical School6, Johns Hopkins University7, Utrecht University8, Katholieke Universiteit Leuven9, University of North Carolina at Chapel Hill10, Harvard University11, University of Minnesota12, University of Toronto13, Northwestern University14, Université catholique de Louvain15, Nationwide Children's Hospital16, Stanford University17, University of Pittsburgh18, Washington University in St. Louis19, University of Pennsylvania20, Emory University21, Vertex Pharmaceuticals22
TL;DR: In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland.
Abstract: BACKGROUND: VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. METHODS: A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. RESULTS: The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens. CONCLUSIONS: In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. CLINICAL TRIAL NUMBER: NCT00865904.
518 citations
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TL;DR: In patients who are younger and healthier than those in previously studied populations, ivacaftor demonstrated a significant improvement in pulmonary function, weight, and CFTR activity compared with placebo.
Abstract: Rationale: Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, has been shown to improve lung function, pulmonary exacerbation rate, respiratory symptoms, and weight gain compared with placebo in patients with cystic fibrosis aged 12 years or older with a G551D-CFTR mutation.Objectives: This randomized, double-blind, placebo-controlled trial evaluated ivacaftor in patients with cystic fibrosis aged 6–11 years with a G551D-CFTR mutation on at least one allele.Methods: Patients were randomly assigned to receive ivacaftor administered orally at 150 mg (n = 26) or placebo (n = 26) every 12 hours for 48 weeks in addition to existing prescribed cystic fibrosis therapies.Measurements and Main Results: Despite near-normal mean baseline values in FEV1, patients receiving ivacaftor had a significant increase in percent predicted FEV1 from baseline through Week 24 versus placebo group (treatment effect, 12.5 percentage points; P < 0.001). Effects on pulmonary function were e...
442 citations
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TL;DR: Lack of a clinical effect suggests that a CFTR potentiator alone is not an effective therapeutic approach for patients who have CF and are homozygous for F508del-CFTR.
290 citations
Cited by
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University of Amsterdam1, Ghent University2, University of Chicago3, University of Pennsylvania4, Lund University5, Auckland City Hospital6, University of Antwerp7, University of New South Wales8, Katholieke Universiteit Leuven9, Guy's and St Thomas' NHS Foundation Trust10, Queen's University11, University of Zagreb12, Northwestern University13, Medical University of Łódź14, University of Aberdeen15, Medical University of South Carolina16, University of North Carolina at Chapel Hill17, University of Southampton18, University of São Paulo19, National University of Singapore20, Flinders University21
TL;DR: The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012 and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery.
Abstract: The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.
2,853 citations
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Seattle Children's1, National Health Service2, Beaumont Hospital3, University of Toronto4, University of Queensland5, Charles University in Prague6, Ludwig Maximilian University of Munich7, University College Dublin8, Case Western Reserve University9, Stanford University10, University of Paris11, University of Alabama at Birmingham12, Vertex Pharmaceuticals13, Queen's University Belfast14
TL;DR: Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks and substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride.
Abstract: Background Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis. Methods We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV1). Results The change from baseline through week 24 in the percent of predicted FEV1 was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained...
1,835 citations
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TL;DR: These data show that lumacaftor in combination with ivacaftors provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation.
Abstract: A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV 1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor–ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV 1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor–ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor–ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor–ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor–ivacaftor versus 1.6% among those who received placebo. CONCLUSIONS These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.)
1,355 citations
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TL;DR: Elexacaftor-tezacaft or-ivacaft or was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective.
Abstract: Background Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one ...
1,029 citations
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TL;DR: Cell-cycle and JAK-STAT pathways are significantly altered in lung cancer, along with perturbations in 54 genes that are potentially targetable with currently available drugs, including ROS1 and ALK, as well as novel metabolic enzymes.
1,021 citations