Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation

Boeck, K. De; Munck, À.; Walker, Seth; Faro, Albert; Hiatt, Peter; Gilmartin, Geoffrey; Higgins, Mark

doi:10.1016/j.jcf.2014.09.005

Cited by 335 publications

(318 citation statements)

References 19 publications

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“…9 Diagnosis can also be established on CFTR mutation testing, although, because of the large number of mutations, a negative test cannot rule out the diagnosis unless the entire CFTR gene has been sequenced; this is rarely employed as a first-line diagnostic tool and is reserved for difficult diagnoses. However, whereas previously it may have been sufficient to secure a diagnosis on the basis of a sweat test, with the recent development of mutation-specific small-molecule treatments, 10 it is becoming increasingly necessary for a patient's mutation(s) to be defined.…”

Section: Clinical Presentation Diagnosis and Disease Manifestationmentioning

confidence: 99%

“…Twice-daily oral administration in patients with a G551D mutation led to a 10% absolute improvement in FEV 1 , a reduction in pulmonary exacerbations and improved quality-of-life scores; additionally, it seemed to have benefits outside the lungs, with improvement in weight and body mass index (BMI) thought to be related to gut bicarbonate secretion. It was initially licensed (and is now available in the UK) for patients with the G551D mutation, but a subsequent trial demonstrated similar benefit for the small group of patients with other class III mutations, 10 for which the drug has now also been licensed and is awaiting funding approval. Furthermore, a trial in patients with the class IV mutation R117H (NCT01614457), which demonstrated smaller benefits, has led, to date, to the US Food and Drug Administration approval and is being considered by the European Medicines Agency.…”

Section: Treatments For Class III Mutationsmentioning

confidence: 99%

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A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

Alton¹,

Armstrong²,

Ashby³

et al. 2016

Efficacy Mech Eval

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BackgroundCystic fibrosis (CF) is a chronic, life-limiting disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene leading to abnormal airway surface ion transport, chronic lung infections, inflammation and eventual respiratory failure. With the exception of the small-molecule potentiator, ivacaftor (Kalydeco®, Vertex Pharmaceuticals, Boston, MA, USA), which is suitable for a small proportion of patients, there are no licensed therapies targeting the basic defect. The UK Cystic Fibrosis Gene Therapy Consortium has taken a cationic lipid-mediatedCFTRgene therapy formulation through preclinical and clinical development.ObjectiveTo determine clinical efficacy of the formulation delivered to the airways over a period of 1 year in patients with CF.DesignThis was a randomised, double-blind, placebo-controlled Phase IIb trial of theCFTRgene–liposome complex pGM169/GL67A. Randomisation was performed via InForm™ version 4.6 (Phase Forward Incorporated, Oracle, CA, USA) and was 1 : 1, except for patients in the mechanistic subgroups (2 : 1). Allocation was blinded by masking nebuliser chambers.SettingsData were collected in the clinical and scientific sites and entered onto a trial-specific InForm, version 4.6 database.ParticipantsPatients with CF aged ≥ 12 years with forced expiratory volume in the first second (FEV1) between 50% and 90% predicted and any combination ofCFTRmutations. The per-protocol group (≥ 9 doses) consisted of 54 patients receiving placebo (62 randomised) and 62 patients receiving gene therapy (78 randomised).InterventionsSubjects received 5 ml of nebulised pGM169/G67A (active) or 0.9% saline (placebo) at 28 (±5)-day intervals over 1 year.Main outcome measuresThe primary end point was the relative change in percentage predicted FEV1over the 12-month period. A number of secondary clinical outcomes were assessed alongside safety measures: other spirometric values; lung clearance index (LCI) assessed by multibreath washout; structural disease on computed tomography (CT) scan; the Cystic Fibrosis Questionnaire – Revised (CFQ-R), a validated quality-of-life questionnaire; exercise capacity and monitoring; systemic and sputum inflammatory markers; and adverse events (AEs). A mechanistic study was performed in a subgroup in whom transgene deoxyribonucleic acid (DNA) and messenger ribonucleic acid (mRNA) was measured alongside nasal and lower airway potential difference.ResultsThere was a significant (p = 0.046) treatment effect (TE) of 3.7% [95% confidence interval (CI) 0.1% to 7.3%] in the primary end point at 12 months and in secondary end points, including forced vital capacity (FVC) (p = 0.031) and CT gas trapping (p = 0.048). Other outcomes, although not reaching statistical significance, favoured active treatment. Effects were noted by 1 month and were irrespective of sex, age orCFTRmutation class. Subjects with a more severe baseline FEV1had a FEV1TE of 6.4% (95% CI 0.8% to 12.1%) and greater changes in many other secondary outcomes. However, the more mildly affected group also demonstrated benefits, particularly in small airway disease markers such as LCI. The active group showed a significantly (p = 0.032) greater bronchial chloride secretory response. No difference in treatment-attributable AEs was seen between the placebo and active groups.ConclusionsMonthly application of the pGM169/GL67A gene therapy formulation was associated with an improvement in lung function, other clinically relevant parameters and bronchial CFTR function, compared with placebo.LimitationsAlthough encouraging, the improvement in FEV1was modest and was not accompanied by detectable improvement in patients’ quality of life.Future workFuture work will focus on attempts to increase efficacy by increasing dose or frequency, the coadministration of a CFTR potentiator, or the use of modified viral vectors capable of repeated administration.Trial registrationClinicalTrials.gov NCT01621867.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.

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Section: Clinical Presentation Diagnosis and Disease Manifestationmentioning

confidence: 99%

Section: Treatments For Class III Mutationsmentioning

confidence: 99%

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

Alton¹,

Armstrong²,

Ashby³

et al. 2016

Efficacy Mech Eval

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“…Trials confirmed efficacy in Asp551Gly (G551D) the commonest mutation in this class (7,8) and subsequently in rarer gating mutations (9). Significant improvements in FEV 1 , exacerbation rate, weight and health-related quality of life led to ivacaftor being licensed for use in these patients aged 6 years and above; long term follow up demonstrates a slowing in the rate of decline of lung function, confirming true disease 'modulation'.…”

Section: Potentiatorsmentioning

confidence: 92%

Disease-modifying drug therapy in cystic fibrosis

Harman

Dobra

Davies

2018

Paediatric Respiratory Reviews

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“…Reductions were also seen in pulmonary exacerbations, patient-reported respiratory symptoms, and concentration of sweat chloride (2), and children aged 6-11 years with a G551D mutation also experienced improvements with ivacaftor in pulmonary function, weight, and CFTR activity (29). Additional work demonstrated significant improvements in lung function, body mass index, sweat chloride, and CF quality-of-life scores in patients with a non-G551D gating mutation (30), although marginal effects were seen in those with the class IV altered conductance mutation R117H (31). Assessments of physiological effects of ivacaftor postapproval note that ivacaftor restores mucociliary clearance, normalizes duodenal pH, and has been associated with a reduction in culturing P. aeruginosa in patients with G551D mutations (32,33).…”

Section: Cftr-based Therapeutic Approachesmentioning

confidence: 99%

Cystic Fibrosis: The Dawn of a New Therapeutic Era

Heltshe

Cogen²,

Ramos

et al. 2017

Am J Respir Crit Care Med

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Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation

Abstract: Ivacaftor was efficacious in a group of patients with CF who had selected non-G551D gating mutations.

Cited by 335 publications

References 19 publications

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

Disease-modifying drug therapy in cystic fibrosis

Cystic Fibrosis: The Dawn of a New Therapeutic Era

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