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 (FEV₁) 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 FEV₁ 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 FEV₁ had a FEV₁ 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 FEV₁ 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.

Article history

The research reported in this issue of the journal was funded by the EME programme as project number 11/14/25. The contractual start date was in March 2012. The final report began editorial review in February 2015 and was accepted for publication in October 2015. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The EME editors and production house have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the final report document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

All authors report grants from the National Institute for Health Research, grants from Cystic Fibrosis Trust, grants from Just Gene Therapy, grants from Medicor Foundation and report that Genzyme, a Sanofi company, manufactured and provided Lipid 67. Ian A Pringle also has a patent WO200711062 issued. Ronald K Scheule also reports other funding from Genzyme, a Sanofi company, outside the submitted work and has a patent US5783565 issued, a patent US5840710 issued, and a patent US5935936 issued. Michelle C Manvell also reports grants from Royal Brompton Biomedical Research Unit (National institute for Health Research funds), outside the submitted work. Steve Cunningham also reports personal fees from Gilead, outside the submitted work and is a principle investigator for Vertex Pharmaceuticals studies in children with cystic fibrosis. Nicholas J Simmonds also reports personal fees from cystic fibrosis Adherence Steering Committee, personal fees from Vertex advisory board, personal fees from Pharmaxis advisory board and lecture fee, personal fees from Gilead advisory boards and lecture fee, personal fees from Eumedica lecture fee, personal fees from Forest Laboratories honorarium, outside the submitted work. Eric WFW Alton also has a patent WO2013061091 pending. Christopher Boyd also has a patent WO2013061091 pending. Alexandra L Quittner is a member of the advisory board for Genentech Inc., reports consulting for AbbVie Pharmaceuticals, grants from Cystic Fibrosis Foundation, grants from Vertex Pharmaceuticals and grants from Novartis Pharmaceuticals, outside the submitted work. Uta Griesenbach also has a patent WO2013061091 pending, and a patent European Patent Application Number 12784648.3 pending. Seng H Cheng is an employee of Genzyme, a Sanofi Company and also has a patent US5650096 issued, a patent US5747471 issued, and a patent US5840710 issued. David J Porteous also has a patent WO2013061091 pending. J Alastair Innes also has a patent WO2013061091 pending. Jane C Davies also reports fees paid to employing institution from Vertex for her role as clinical trials lead, educational meetings and advisory board participation, fees paid to employing institution from Novartis for advisory board participation and fees paid to employing institution from Proteostasis for advisory board participation, outside the submitted work, and has a patent WO2013061091 pending. Stephen C Hyde also has a patent WO200711062 issued, and a patent WO2013061091 pending. Lee A Davies has a patent US 20140242690 A1 pending, and a patent WO2013061091 pending. Deborah R Gill also has a patent WO200711062 issued, and a patent WO2013061091 pending. James M Wilson is a founder of, holds equity in, an advisor to and grant recipient from, REGENXBIO and Dimension Therapeutics. He is an advisor to Solid Gene Therapy. He is an inventor on patents licensed to various biopharmaceutical companies.