A new phase of CFTR treatment for cystic fibrosis?
Authors: Scott C Bell
Journal: The Lancet Respiratory Medicine (2015)

Cloning of the gene responsible for cystic fibrosis has led to remarkable advances in our understanding of the disease.1Rommens JM Iannuzzi MC Kerem B et al.Identification of the cystic fibrosis gene: chromosome walking and jumping.Science. 1989; 245: 1059-1065Crossref PubMed Scopus (2556) Google Scholar Since then, roughly 2000 mutations have been identified in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In the past decade, rapid progress has been made towards the development of CFTR treatments to target the basic defect in cystic fibrosis.2Davies JC Wainwright CE Canny GJ et al.Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation.Am J Respir Crit Care Med. 2013; 187: 1219-1225Crossref PubMed Scopus (405) Google Scholar, 3De Boeck K Munck A Walker S et al.Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation.J Cyst Fibros. 2014; 13: 674-680Summary Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 4Ramsey BW Davies J McElvaney NG et al.A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.N Engl J Med. 2011; 365: 1663-1672Crossref PubMed Scopus (1650) Google Scholar Ivacaftor was approved for patients with the Gly551Asp-CFTR mutation, which affects about 3% of the global cystic fibrosis population, and for patients with other CFTR-gating mutations. In May, 2015, Wainwright and colleagues reported results for the combination of ivacaftor and lumacaftor in patients homozygous for the phe508del mutation (about 50% of the global cystic fibrosis population) and reported improved lung function (improvement in absolute forced expiratory volume in 1 s [FEV1] % predicted 2·6–4·0 percentage points) and reduced pulmonary exacerbations (30–39% reduction) over 24 weeks.5Wainwright CE Elborn JS Ramsey BW et al.Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR.N Engl J Med. 2015; 373: 220-231Crossref PubMed Scopus (990) Google Scholar This combination of ivacaftor and lumacaftor has since been approved by the US Food and Drug Administration, under the trade name Orkambi. Soon after discovery of the cystic fibrosis gene, initial enthusiasm for the potential role of gene therapy to cure cystic fibrosis was quickly dampened by the complexity of replacement of the defective CFTR protein. Many challenges were identified, including determining the optimum vector for gene transfer based on studies of safety, how to ensure enduring gene expression, and how to restrict systemic inflammatory responses. To date, more than 25 clinical trials have been completed, with most being of short duration with small populations and undertaken to examine safety or the extent of gene transfer.6Griesenbach U Pytel KM Alton EW Cystic fibrosis gene therapy in the uk and elsewhere.Hum Gene Ther. 2015; 26: 266-275Crossref PubMed Scopus (71) Google Scholar Established in 2001, the UK Cystic Fibrosis Gene Therapy Consortium has pioneered the development of non-viral approaches for gene therapy. The Consortium has led pre-clinical and early phase clinical trials to optimise vector formulation, gene dosing, delivery modes, safety, and the establishment of endpoints for efficacy studies. In The Lancet Respiratory Medicine, Eric Alton and colleagues7Alton EWFW Armstrong DK Ashby D et al.Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial.Lancet Respir Med. 2015; (published online July 3.)http://dx.doi.org/10.1016/S2213-2600(15)00245-3PubMed Google Scholar report the results of a randomised, double-blind, placebo-controlled, phase 2b study of multi-dose nebulised gene–liposome complex (pGM169/GL67A) in patients with cystic fibrosis (FEV1 50–90% predicted) and any combination of CFTR mutation. Monthly application of pGM169/GL67A was associated with a significant benefit in FEV1 compared with placebo at 12 months' follow up (3·7%, 95% CI 0·1–7·3%; p=0·046). Importantly, therapy with pGM169/GL67A was well tolerated, with no excess treatment-associated adverse effects. Secondary endpoints did not differ significantly between gene therapy and placebo groups. Several substudies, including nasal and lower airway gene transfer analyses, showed modest concentrations of pGM169 plasmid DNA. In a post-hoc analysis, of the roughly one in five participants who had an improvement in FEV1 of more than 5%, 70% received the gene–liposome complex. Another notable finding was that patients with more severe lung disease (FEV1 49·6–69·2% predicted) tended to have a greater treatment effect (6·4%) than those with milder lung disease (FEV1 69·6–89·9% predicted; treatment effect 0·2%; p=0·065). This outcome warrants further study to establish whether this result can be replicated. This study represents the most recent scientific output following almost 15 years of intensive preparatory work, but the path travelled by the Consortium has not always been smooth. In 2011, the viability of the trial was at risk because of a funding shortfall.8Brimelow A 'Funding shortfall' puts cystic fibrosis research on hold.www.bbc.co.uk/news/health-13643267Google Scholar Further funding from the Medical Research Council and the National Institute for Medical Research enabled the programme to continue. Although the findings of this study are modest, it is important to acknowledge the crucial preparatory work and its potential to provide important direction for future clinical trials. Online supplementary files for many publications are obscure to many readers and are often the reserve of scientists working directly in the field. I would encourage readers to delve into this online supplementary file (the appendix) because it provides insights into the logistical triumph in successful completion of this study, and into the potential challenges of moving such therapies into the clinic. Several aspects of the study design and its findings are worthy of further consideration. The first point is the use of nebulised physiological saline as placebo, motivated by inadequate funding and potential risks. The larger than anticipated decline in lung function in the placebo group would argue against a favourable effect of physiological saline. Future gene therapy trials should include a CFTR-depleted plasma–liposome complex because this study was completed without major safety signals. Rates of lung-function decline have been decreasing in the cystic fibrosis population (FEV1 about 1% predicted per year).9Que C Cullinan P Geddes D Improving rate of decline of FEV1 in young adults with cystic fibrosis.Thorax. 2006; 61: 155-157Crossref PubMed Scopus (110) Google Scholar In view of this, the lung function decline in the placebo group in this trial was surprisingly large. Alton and colleagues argue that this finding might be explained by participants' increasing health maintenance during the pre-screening period to fulfil trial inclusion criteria and this was not able to be sustained during the 12 month study period. Another clinical trial10Kerem E Konstan MW De Boeck K et al.Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial.Lancet Respir Med. 2014; 2: 539-547Summary Full Text Full Text PDF PubMed Scopus (272) Google Scholar has reported a similar rate of lung function decline as reported in the present study, but other trials have reported lower rates of decline.2Davies JC Wainwright CE Canny GJ et al.Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation.Am J Respir Crit Care Med. 2013; 187: 1219-1225Crossref PubMed Scopus (405) Google Scholar, 3De Boeck K Munck A Walker S et al.Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation.J Cyst Fibros. 2014; 13: 674-680Summary Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 4Ramsey BW Davies J McElvaney NG et al.A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.N Engl J Med. 2011; 365: 1663-1672Crossref PubMed Scopus (1650) Google Scholar, 5Wainwright CE Elborn JS Ramsey BW et al.Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR.N Engl J Med. 2015; 373: 220-231Crossref PubMed Scopus (990) Google Scholar Notably, health-related quality of life was not improved by gene therapy, despite improved lung function. Future studies should examine the effect on pulmonary exacerbations (which was not an endpoint here) and patient-reported outcomes including health-related quality of life. Ironically, there has been a rapid increase in clinical trials to address CFTR over the past decade, creating competition for trial participants despite coordinating cystic fibrosis trial networks.11De Boeck K Bulteel V Tiddens H et al.Guideline on the design and conduct of cystic fibrosis clinical trials: the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN).J Cyst Fibros. 2011; 10: S67-S74Summary Full Text PDF PubMed Scopus (23) Google Scholar, 12Goss CH Mayer-Hamblett N Kronmal RA Ramsey BW The cystic fibrosis therapeutics development network (CF TDN): a paradigm of a clinical trials network for genetic and orphan diseases.Adv Drug Deliv Rev. 2002; 54: 1505-1528Crossref PubMed Scopus (35) Google Scholar This situation is exemplified by the observation that three trial participants withdrew from Alton and colleagues' study to begin ivacaftor treatment. Nevertheless, for about 50% of the cystic fibrosis population for whom no evidence for pharmacological correction yet exists, a therapy that is potentially suitable for patients with any CFTR combination is of great interest. The next step that these authors will take is worth considering. The investigators sagely do not recommend moving to a phase 3 trial, but rather emphasise the need to assess more effective gene-transfer vectors. This assessment might include revisiting viral vectors, such as lentiviral platforms.6Griesenbach U Pytel KM Alton EW Cystic fibrosis gene therapy in the uk and elsewhere.Hum Gene Ther. 2015; 26: 266-275Crossref PubMed Scopus (71) Google Scholar, 13Farrow N Miller D Cmielewski P Donnelley M Bright R Parsons DW Airway gene transfer in a non-human primate: lentiviral gene expression in marmoset lungs.Sci Rep. 2013; 3: 1287Crossref PubMed Scopus (22) Google Scholar Finally, whilst acknowledging the early and yet substantial steps in the development of effective CFTR therapies for people with cystic fibrosis, awareness is growing of the complexity of the interactions between the CFTR protein and complex intracellular protein networks.14Bozoky Z Krzeminski M Chong PA Forman-Kay JD Structural changes of CFTR R region upon phosphorylation: a plastic platform for intramolecular and intermolecular interactions.FEBS J. 2013; 280: 4407-4416Crossref PubMed Scopus (41) Google Scholar, 15Wiseman RL Powers ET Buxbaum JN Kelly JW Balch WE An adaptable standard for protein export from the endoplasmic reticulum.Cell. 2007; 131: 809-821Summary Full Text Full Text PDF PubMed Scopus (133) Google Scholar An even broader understanding of the cellular biology of CFTR is needed for successful correction of the numerous CFTR mutations. SCB reports speakers fees and non-financial support from Vertex Pharmaceuticals, non-financial support from Gilead, and non-financial support from Novartis, outside the submitted work. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trialMonthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials. Full-Text PDF Open Access