Disease-modifying drug therapy in cystic fibrosis Harman, Katharine; Dobra, Rebecca; Davies, Jane C.
Paediatric respiratory reviews,
March 2018, 2018-Mar, 2018-03-00, 20180301, Volume:
26
Journal Article
Peer reviewed
Open access
Whilst substantial progress has been made in the treatment of cystic fibrosis, the disease still carries a significant burden in terms of symptoms, requirement for treatment and early mortality. The ...last decade has witnessed a new era in the development of small molecule drugs targeting the CFTR protein, which for the first time may provide a truly disease-modifying approach to treatment. This article reviews progress and highlights some of the current and future challenges in CFTR modulator therapies.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary Whilst substantial progress has been made in the treatment of cystic fibrosis, the disease still carries a significant burden in terms of symptoms, requirement for treatment and early ...mortality. The last decade has witnessed a new era in the development of small molecule drugs targeting the CFTR protein, which for the first time may provide a truly disease-modifying approach to treatment. This article reviews progress and highlights some of the current and future challenges in CFTR modulator therapies.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ObjectiveDiagnosis of obstructive sleep apnoea (OSA) is made on overnight polysomnography (PSG). Given the widespread availability of smartphone video technology, we aimed to develop and test a ...standardised scoring system for smartphone videos and compare these scores to PSG results.MethodsChildren aged 1–16 years undergoing PSG for suspected OSA were included. Parents were asked to take 1–2 min videos of the breathing they were concerned about. Videos were scored using a newly developed and tested tool on five components: inspiratory obstructive noises (1–4), presence of obstructive events (0–1), increased work of breathing (0–1), mouth breathing (0–1) and neck extension (0–1). Video scores and the Obstructive Apnoea Hypopnoea Index (OAHI) were compared using Spearman correlation. Sensitivity, specificity, positive predictive value and negative predictive value were calculated for different cut-off scores to achieve the best results.ResultsVideos from 43 children (28 men (65.1%), median age 5.7 years (range 2.6–14.0 years), median OAHI 3.8/hour (range 0–82 events/hour) were included. Nine children (20.9%) had a video score of <3, all of whom had an OAHI of ≤5 events/hour. For a video score of ≥3, sensitivity was 100%; specificity was 36%; positive predictive value was 53%; and negative predictive value 100% for moderate to severe OSA (OAHI>5 events/hour) .ConclusionWe have developed and validated a simple clinical tool (the Monash Obstructive Sleep Apnoea Video Score) to quantify abnormalities in breathing seen on short video recordings made on a smartphone. A low score rules out moderate–severe OSA and may be valuable in the triage of children with symptoms of OSA.
Cystic fibrosis (CF) and Primary Ciliary Dyskinesia (PCD) are chronic suppurative lung diseases (CSLD). CF is characterised by inherited mutations affecting the cystic fibrosis transmembrane ...regulator (CFTR) protein, which is thought to be normal in PCD, however the role of CFTR in disease is incompletely understood. This thesis investigates the relationship between CFTR, inflammation and airway health, firstly in the context of the CF gene therapy Multidose trial followed by contrasting CF, PCD and control patients. The first study explored the relationship between lower airway potential difference (LAPD) measurements performed in the Multidose trial as a measure of CFTR function, and physiological, radiographic and inflammatory markers of disease severity. At baseline, FEV1 correlated with basal LAPD measurements, however not between restored chloride secretion and change in airway disease following treatment; implicating the role of sodium transport, not chloride in disease pathogenesis. As no direct correlation was seen, I went on to explore an alternative theory that a bi-directional relationship exists between CFTR and inflammation; CFTR dysfunction triggers a hyper-inflammatory state and inflammation causes secondary CFTR dysfunction. Cell cultures were cultivated from the nasal epithelium of patients with CF, PCD and controls. Both at baseline and following stimulation with common respiratory pathogens, the levels of inflammatory mediators in the supernatant from each group of cells were comparable. The numbers involved with this study were small, however did not indicate that CF cells cultured in these conditions (in vitro) were hyper-inflammatory. The final study explored in vivo whether inflammation causes secondary CFTR dysfunction. Nasal potential difference (NPD) measurements were compared with localised levels of inflammation in subjects with CF, PCD and controls. PCD traces showed reduced chloride secretion, however it was not possible to differentiate secondary CFTR dysfunction from damage to epithelial cell integrity. Elevated levels of inflammatory mediators were detected in PCD nasal fluid, however the results were variable and these levels did not correlate with NPD measurements of ion channel function. These studies did not support the hypothesis that there is a direct relationship between CFTR function and airway disease, that in vitro CF cells are hyperinflammatory, or in vivo that inflammation leads to secondary CFTR dysfunction. The experiments performed in this thesis provide a basis for future work exploring this relationship, and may help guide future trials for novel therapies in CF.
Background
Cystic 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-mediated
CFTR
gene therapy formulation through preclinical and clinical development.
Objective
To determine clinical efficacy of the formulation delivered to the airways over a period of 1 year in patients with CF.
Design
This was a randomised, double-blind, placebo-controlled Phase IIb trial of the
CFTR
gene–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.
Settings
Data were collected in the clinical and scientific sites and entered onto a trial-specific InForm, version 4.6 database.
Participants
Patients with CF aged ≥ 12 years with forced expiratory volume in the first second (FEV
1
) between 50% and 90% predicted and any combination of
CFTR
mutations. The per-protocol group (≥ 9 doses) consisted of 54 patients receiving placebo (62 randomised) and 62 patients receiving gene therapy (78 randomised).
Interventions
Subjects received 5 ml of nebulised pGM169/G67A (active) or 0.9% saline (placebo) at 28 (±5)-day intervals over 1 year.
Main outcome measures
The primary end point was the relative change in percentage predicted FEV
1
over 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.
Results
There 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 or
CFTR
mutation class. Subjects with a more severe baseline FEV
1
had a FEV
1
TE 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.
Conclusions
Monthly 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.
Limitations
Although encouraging, the improvement in FEV
1
was modest and was not accompanied by detectable improvement in patients’ quality of life.
Future work
Future 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 registration
ClinicalTrials.gov NCT01621867.
Funding
This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.
Cystic fibrosis (CF) and Primary Ciliary Dyskinesia (PCD) are chronic suppurative lung diseases (CSLD). CF is characterised by inherited mutations affecting the cystic fibrosis transmembrane ...regulator (CFTR) protein, which is thought to be normal in PCD, however the role of CFTR in disease is incompletely understood. This thesis investigates the relationship between CFTR, inflammation and airway health, firstly in the context of the CF gene therapy Multidose trial followed by contrasting CF, PCD and control patients. The first study explored the relationship between lower airway potential difference (LAPD) measurements performed in the Multidose trial as a measure of CFTR function, and physiological, radiographic and inflammatory markers of disease severity. At baseline, FEV1 correlated with basal LAPD measurements, however not between restored chloride secretion and change in airway disease following treatment; implicating the role of sodium transport, not chloride in disease pathogenesis. As no direct correlation was seen, I went on to explore an alternative theory that a bi-directional relationship exists between CFTR and inflammation; CFTR dysfunction triggers a hyper-inflammatory state and inflammation causes secondary CFTR dysfunction. Cell cultures were cultivated from the nasal epithelium of patients with CF, PCD and controls. Both at baseline and following stimulation with common respiratory pathogens, the levels of inflammatory mediators in the supernatant from each group of cells were comparable. The numbers involved with this study were small, however did not indicate that CF cells cultured in these conditions (in vitro) were hyper-inflammatory. The final study explored in vivo whether inflammation causes secondary CFTR dysfunction. Nasal potential difference (NPD) measurements were compared with localised levels of inflammation in subjects with CF, PCD and controls. PCD traces showed reduced chloride secretion, however it was not possible to differentiate secondary CFTR dysfunction from damage to epithelial cell integrity. Elevated levels of inflammatory mediators were detected in PCD nasal fluid, however the results were variable and these levels did not correlate with NPD measurements of ion channel function. These studies did not support the hypothesis that there is a direct relationship between CFTR function and airway disease, that in vitro CF cells are hyperinflammatory, or in vivo that inflammation leads to secondary CFTR dysfunction. The experiments performed in this thesis provide a basis for future work exploring this relationship, and may help guide future trials for novel therapies in CF.
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