Treatment options for cystic fibrosis lung disease: latest evidence and clinical implications

Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The most common globally is F508del, however there are over 2000 variations reported, although not all are disease-causing. The subsequent CFTR protein defect causes abnormalities in both salt and fluid transport across epithelia, which, in the lung leads to dehydration of the airway surface and impaired mucociliary clearance (MCC) [Matsui et al.,1998]. This failure of innate defence, and mucus accumulation, possibly in conjunction with impaired bacterial killing, provides an undefended environment for opportunistic pathogens such as Pseudomonas aeurginosa, Staphyloccocus aureus and Haemophilus influenza. . The host inflammatory response and subsequent tissue damage contribute to the characteristic decline in lung function as disease progresses. [Rowe et al.,2005].

Conventional treatment of CF has targeted the downstream consequences of the disease, namely mucus plugging and infection. The last few years have seen the emergence of more upstream therapeutic targets, several of which are in clinical trials, or have progressed to licensed treatments. Here, we discuss treatment options based on function, presenting those currently available, and highlighting progress in research. Treatments for other organs involved in CF for example, the pancreas, liver, bones and sinuses, are outside the scope of this article but can be found in Plant et al. 2013. The importance of optimal nutrition in respiratory health cannot be underestimated; evidence in support of this and a review of the field can be found in both Sanders et al., (2015) and Munck (2010) articles on the subject.

Airway clearance

Physiotherapy and exercise

Physiotherapy to aid clearance of airway secretions has been one of the mainstays of treatment for CF and is likely responsible in large part for the improved prognosis over the last few decades. However, multiple different techniques are used, and the optimal approach(es) is not clear. A recent Cochrane review found no evidence in support of oscillating devices (vests) when compared to other airway clearing techniques and actually found a higher level of pulmonary exacerbations requiring antibiotics associated with their use [Morrison et al., 2014]. Multiple interventions to promote health and exercise have been trialled although there is no unanimous verdict over which technique has been the most successful [Cox et al., 2013]. A current trial is examining the effect of a 12 month partially supervised exercise intervention with regular motivation on Forced expiratory volume in 1 second (FEV1) with secondary end points including levels of depression, anxiety, quality of life and blood sugar levels (clinicaltrials.gov NCT01744561).

Mucolytic agents

Dornase Alfa

Dornase Alfa is a recombinant human deoxyribonuclease (DNase). As part of the inflammatory process in CF there is a significant accumulation and breakdown of neutrophils in the lungs leading to large amounts of extracellular DNA, which significantly increases the viscocity of the sputum. DNase has been show to cleave the extracellular DNA and subsequently aid airway clearance [Konstan et al., 2012]. Although UK clinical practice historically tended to lean towards reserving DNase for more severe patients, evidence is mounting for earlier intervention. Amin et al showed a significant improvement in lung clearance index (LCI, a sensitive measure of gas mixing inhomogeneity) in children aged between 6-18 years of age who had normal baseline spirometry [Amin et al., 2011]. It has also been shown in younger children to indirectly effect their nutritional status with a 10 percentile increase in BMI in children who commenced DNase at less than 2 years of age [Konstan et al., 2012]. The Bronchoalveolar Lavage in the Evaluation of Anti-inflammatory Treatment (BEAT) study compared changes in neutrophilic inflammation over time in bronchoalveolar lavage (BAL) fluid from patients treated with DNase and controls [Paul et al., 2004]. DNase led a a significant reduction in inflammation and in DNA concentrations, suggesting that treatment should be commenced earlier in the disease course rather than when lung function has already deteriorated.

N-acetyl-L –cysteine

N-acetyl-L –cysteine (NAC) has previously been shown to be a mucolytic in CF and may also increase levels of the intracellular antioxidant glutathione (GSH), thereby protecting against the neutrophil driven tissue damage in the lungs (ref please). Clinical trials have however resulted in somewhat conflicting results, [Conrad et al., 2015, Dauletbaev et al., 2009] so consensus is lacking on the clinical utility of NAC for CF.

 

Airway surface rehydration strategies

Hypertonic saline

Hypertonic saline (HS) aids MCC by increasing hydration of the airway surface in the short term [Donaldson et al., 2006]. As it may cause bronchoconstriction, it is commonly used with an associated bronchodilator. When compared to a placebo HS was safe, inexpensive and effective in improving FEV1 and reducing the number of pulmonary exacerbations requiring IV antibiotics [Elkins et al., 2006]. Effects in children were less marked, possibly relating to the preponderance of viral exacerbations in this age group [Rosenfeld et al., 2012]. However, in this age group, a beneficial effect could be detected on LCI, and HS is currently being studied in more detail using such sensitive physiology and CT scans in this age group (clinicaltrials.gov NCT02378467).

Mannitol

Mannitol is a non-absorbable sugar alcohol which provides an osmotic gradient on the airway surface leading to rehydration, and an increase in volume surface liquid, which aid in the clearance of mucus. An international phase 3 trial showed a sustained and clinically meaningful benefit (increase in FEV1 and a decrease in the number of pulmonary exacerbations) even with concomitant DNase use in patients 18 years and above. However they also showed an increased number of adverse events such as haemoptysis and cough. Current evidence suggests mannitol is safe to use in patients who are able to tolerate it [Bilton et al., 2011]. Further work is ongoing to confirm clinical benefit in younger patients.

Denufosol

Denufosol tertrasodium, a P2Y2 purinergic receptor agonist, stimulates chloride secretion and ciliary beat frequency independent of CFTR. Phase 3 study results were initially promising, showing a small but statistically significant increase in lung function compared to the placebo [Accurso et al., 2011]. However these findings were not replicated in a subsequent study [Ratjen et al., 2012] and there are no current clinical studies of this agent ongoing.

P-1037

In addition to its function as a chloride ion channel, CFTR interacts with a number of neighbouring proteins, the best recognised being the epithelial sodium channel, ENaC. The loss of normal inhibitory function is thought to lead to ENaC over-activity and sodium hyperabsorption which contributes to airway surface and mucus dehydration. Blocking of ENaC with amiloride led to disappointing clinical results, likely related to a very short half-life on the airway surface [Pons et al., 2000, Graham et al., 1993]. More recently, Parion have developed P-1037 an inhaled ENaC blocker which is currently progressing to phase 2 clinical trials (clinicaltrials.gov NCT02343445). One potential drawback of this approach generally is hyperkalaemia as a side effect of renal exposure, so low dose or poorly absorbed formulations are required.

Anti-infective agents

Conventional antibiotics

Antibiotics in CF are used in 4 different contexts in CF: prophylaxis, eradication of early infection, ‘suppression’ of chronic and in the treatment of exacerbations. The pathogens found in CF lungs vary with age. In infancy the most common bacteria cultured is Staphylococcus aureus (S.aureus), with Haemophilus influenzae (H.influenzae) increasing during childhood; by adolescence and young adulthood by far the commonest pathogen cultured is Pseudomonas aeruginosa (P.aeruginosa)[www.cysticfibrosis.org.uk/media/82010/CD_Antibiotic_treatment_for_CF_May_09.pdf]. However, the advent of culture-independent molecular tools to identify bacterial species, has revealed the highly polymicrobial nature of the CF lower airway. The relevance of the microbiome to health and disease progression is currently the focus of much research [Rogers et al., 2015].

Prophylaxis

Current guidelines in the UK and much of Europe recommend the use of anti-staphylococcal antibiotics (such as flucloxacillin) from the point of diagnosis until ~3 years of age. This regimen has been shown to reduce the incidence of MSSA although improvement in clinical outcomes has not been confirmed [Mogayzal et al., 2013, www.cysticfibrosis.org.uk/media/82010/CD_Antibiotic_treatment_for_CF_May_09.pdf]

However current recommendations in the USA are against the use of prophylactic anti-staphylococcal antibiotics [Mogayzel et al., 2013], in part based on one trial of a cephalosporin reporting an increased rate of pseudomonas infection [Stutman et al., 2002]. Good quality clinical trial data remain a need in resolving this issue.

Eradication of early infection

Whilst clinicians will often treat an early bacterial infection with a view to both managing symptoms and decreasing the likelihood of chronic infection, the organism for which evidence supports the latter most strongly is P. aeruginosa [Langton Hewer et al., 2014] . If not detected and treated aggressively, this gram negative, opportunistic bacterium will become chronic; the resulting inflammatory response is closely linked to decline in lung function. Eradication strategies vary between countries and even between sites but comprise inhaled +/- systemic antibiotics. In North America, inhaled tobramycin is first line [Mogayzel et al., 2014, whereas in Europe, a multicentre trial is currently assessing whether intravenous or oral antibiotics are superior, when administered with nebulised colomycin (http://www.torpedo-cf.org.uk/).

Suppression of chronic infection

Once bacterial infection has become chronic, emphasis switches from eradication to chronic suppression in the hope of reducing the inflammatory response. Systemically delivered antibiotics carry with them the potential for side effects (such as renal/ hearing impairment with aminoglycosides) and may lead to suboptimal sputum concentrations [Waters et al., 2014]. Therefore much research has focused on inhalation as a route of antimicrobial delivery, which by delivering of the drug directly to the site of infection and in high concentrations can enhance bacterial killing whilst limiting side effects [Hewer, 2012]. Disadvantages include in some cases an unpleasant taste, the potential for bronchospasm, particularly with the dry powder formulations, and the time required both to administer the drug and care for the equipment, which may impact adherence. The most commonly used nebulised antibiotics against P.aeruginosa are tobramycin, colistin and more recently, aztreonam; in many cases, a cycling approach is used, administering on a month on/ month off basis or alternating drugs.

In an attempt to reduce the time needed to deliver the drug to the airway and the preparation/ cleaning required, dry powder formulations have been developed for both colistin and tobramycin. Colistimethate sodium and tobramycin were delivered using a dry powder inhaler (DPI) and short term results showed they were non-inferior to the nebulised versions of the drug. There was no evidence of increased adherence, although this is a difficult outcome to measure. It appeared there was an increase in the reporting of a cough in the DPI group [Uttley et al., 2013]. Further research needs to be carried out looking at the long term outcomes of using a DPI rather than the more traditional nebulised medicines [Trappenden et al., 2013].

Aztreonam for inhalation solution (AZLI) has been trialled in patients with chronic P.aeruginosa infection 6 years of age and older; over a period of 18 months on alternating monthly treatment, an improvement in FEV1 and reduction in bacteria burden was seen. Interestingly, significant weight gain was also noted and sustained during the 18 months. The best results were achieved using a three times daily regimen which may be challenging for patients [Oermann et al., 2010]. A modest improvement in FEV1 and reduction in bacterial burden was also noted in patients who only had mild lung impairment, possibly suggesting a role of earlier intervention and treatment in relatively well patients [Wainwright et al., 2011]. A recent open label, parallel group international trial compared the use of tobramycin (nebulised) with AZLI. The results showed a significant improvement in lung function in the AZLI group when compared to the tobramycin group and a reduction in pulmonary exacerbations over 3 treatment courses. AZLI was well tolerated and showed an equal decrease in P.aeruginosa density when compared to tobramycin. It should be noted that only a small number of their study group were aged 6-11 therefore care needs to be taken extrapolating their results to children with chronic P.aeruginosa infection [Assael et al., 2013].

Several newer agents are currently under investigation. A liposomal formulation of amikacin is being trialled as a new once a day alternative. An attractive feature of the liposome is its breakdown by bacterial rhamnolipids, effectively meaning the drug becomes activated at the site of need. In both phase 2 and phase 3 trials similar increases in FEV1 were seen as for tobramycin [Clancy et al., 2013, Ehsan et al., 2014,]. Levofloxacin inhalation solution (MP-376) has recently been shown safe and non-inferior to tobramycin [Stuart Elborn et al., 2015]. Finally, a double-blind, placebo controlled multicentre trial compared a combination antibiotic fosfomycin/tobramycin to a placebo after a 28 day open label run in course of aztreonam and showed maintenance of the substantial improvement in FEV1 in patients after the aztreonam course [Trapnell et al., 2012]. This suggests that alternating antibiotics but using continuous treatment may be an appealing future to the treatment of P.aeruginosa infection, although debate remains regarding which combination of antibiotics that should include.

Acute exacerbations

Pulmonary exacerbations (PEx) are constellations of symptoms and worsening lung function; their mechanism is poorly understood. In childhood, it is common for viruses to be detected in airway secretions at the time of PEx and on occasions, a new bacterial organism might be isolated, but much more commonly, neither the type of organisms isolated nor their numbers appear to have changed significantly. This raises the possibility that it is bacterial behaviours, for example the production of virulence factors, or the host response which has changed. PEx are treated with oral or intravenous (IV) antibiotics depending on severity. Traditionally patients receive a 14 day course of IV antibiotics however one study has shown that after 10 days of IV treatment maximal lung function is achieved and no further benefit is obtained thereafter [Waters et al., 2014]. This is the focus of a large, multicentre research programme led by the CF Foundation in the USA (NCT02109822)

Mycobacterial disease

Non-tuberculous mycobacteria (NTM) are commonly found in the environment and frequently cultured from the respiratory tract of CF patients. A recent Cochrane review reported a lack of randomised controlled trials addressing the treatment of NTM pulmonary infections [Waters et al,. 2014]. Patients tend to be treated by local or national protocols of multiple agents for long periods of time. There is a current multicentre randomised double blind control trial investigating Arikace in the treatment of NTM [Olivier et al., 2014].

Fungal disease and Allergic bronchopulmonary aspergillosis (ABPA)

Infection can occur with a number of fungal organisms, most commonly, Aspergillus fumigatus (Af); this can lead to chronic infection or an allergic response, ABPA, manifest by wheeze, infiltrates on chest radiograph, eosinophilia and raised total and specific IgE. Anti fungal agents include Itraconazole, Voriconazole, Posaconazole, Ketoconazole, Nystatin and Amphotericin B. In a systematic review, oral azoles were associated with improvements in symptoms and a decrease in the frequency of exacerbations however adverse effects were also common [Moreira et al., 2014] Optimal treatment of fungal bronchitis is unclear, and systemic anti-fungals of the azole class have significant side effects including hepatotoxicity and photosensitive skin reactions [Sheu et al., 2015]. A recent Cochrane review highlighted the lack of evidence for treatments of ABPA also [Elphick et al., 2014]; therapy is usually based around systemic corticosteroids in combination with anti-fungal agents. More recently, since the recombinant Anti-IgE monoclonal antibody, Omalizumab, has become established for the treatment of severe asthma, [Lehmann et al., 2014], there have been several reported case studies in CF patients, some reporting success, although there is a lack of good quality clinical trial data. [Lehmann et al., 2014]. [Tanou et al., 2014, Zicari et al., 2014 ].

Non-antibiotic approaches to bacterial infection

Azithromycin

The macrolide antibiotic, Azithromycin has shown benefit in CF patients with and without chronic P.aeruginosa [Southern et al., 2012]. Its mechanism is incompletely understood, although it appears to possess anti-biofilm properties and may also be modulating the inflammatory system. It is used widely in patients, although recent data describing apparent antagonism with the nebulised aminoglycoside, tobramycin, have raised concern [Nick et al., 2014] and require further study. There have also been some concerns raised about the emergence of non-tuberculous mycobacteria, although reports are inconsistent [Renna et al., 2011, Coolen et al. 2015].

OligoG

Chronic P.aeruginosa grows in the CF airways in a biofilm. This consists of the bacteria itself embedded in a complex matrix of neutrophil DNA, exopolysaccharide and airway mucins, which makes them highly resistant to antibiotic therapy. OligoG, a dry powder formulation of seaweed-derived alginate oligosaccharide, appears to possess both anti-biofilm and mucolytic properties and is currently in phase 2 trials (NCT02157922).

IgY antibodies

A small clinical trial has previously suggested that IgY derived from immunised hens’ eggs could offer protection from P. aeruginosa infection [Kollberg et al., 2003]. A multicentre trial is currently exploring the benefits of this antibody administered as a gargle solution (clinicaltrials.gov NCT01455675)

Anti-inflammatory agents

As mentioned earlier, inflammation plays a significant role in the progression of CF related lung disease.

Early trials of systemic corticosteroids showed some benefit, but at the expense of significant side effects [Auerbach et al., 1985]. This led to trials of the non-steroidal anti-inflammatory agent, ibuprofen, which showed some benefit particularly in younger patients with milder disease [Konstan et al., 1995] . There are issues however related to dosing. Low dose ibuprofen has been shown to be pro-inflammatory and high dose has associated side effects [Lands et al., 2013] although Lahiri et al showed no significant correlation between high dose ibuprofen and biomarkers of kidney injury. A recent Cochrane review concluded that high dose ibuprofen slowed the decline in lung function and decreased the number of days spent in hospital. However, long term side effects have not been examined, care should be taken when treating with IV aminoglycosides and concomitant gastric cover should be prescribed [Lands et al., 2013]. These drugs are not in widespread use in the majority of European countries. A topical, rather than systemic, approach could reduce side effects, whilst directly targeting the organ of interest. However, in a multicentre randomised double blind control withdrawal trial, inhaled corticosteroids were shown to have little effect [Balfour-Lynn et al., 2006]. Leukotriene B4 (LTB4) is produced by both macrophages and polymorphonuclear neutrophils (PMNs) in response to infection and plays a significant role in the CF inflammatory response. It was therefore postulated that a LTB4 receptor antagonist could be a beneficial treatment. However, a phase 2 clinical trial was halted prematurely base on a significant increase in side effects including pulmonary exacerbations in the actively treated group [Konstan et al., 2014]. This highlights the potential protective effects of inflammation, perhaps by localising infection in the lungs, and suggests that for an anti-inflammatory agent to be safe and effective, a balance needs to be achievable. There are currently a small number of clinical trials exploring anti-inflammatory agents in the CF Foundation Therapeutic Development Network drug pipeline (https://tools.cff.org/research/drugdevelopmentpipeline/).

Therapies targeting the basic defect

CFTR modulators

There are five main classes of CFTR mutations based on their consequences on function (figure 1). Class I mutations cause a total or partial lack of production of a functional CFTR, most commonly as a result of a premature termination codon (PTC). Class II mutations lead to misfolding of the protein and failure of trafficking to the cell surface. Class III are mainly gating mutations, which fail to open in response to intracellular signals and Class IV mutations demonstrate reduced ion conductance. Class V are splicing mutations resulting in reduced amounts of CFTR protein. Also described are Class VI mutations which possess a shortened half life. Novel therapies are being developed which target these various classes of mutation [Sawczak et al., 2105]

[Figure 1 near here]

Figure 1: Classification of CF mutations based on CFTR structure and function [Reproduced with permission from Fanen et al., 2014].

Current research and treatment is focussed on three groups of drugs: potentiators, correctors or read-through agents. Potentiators enhance the activity of the CFTR channel if it is correctly located. Correctors aim to correct defects such as protein misfolding in F508del allowing trafficking to the cell surface. Read-through agents allow the ribosome to ‘ignore’ a premature termination codon and produce full length protein. Over the last few years, drugs in all of these groups have progressed into, and in some cases through, clinical trials.

Potentiators

The most significant advance in the treatment of CF over the last few years has been the development of ivacaftor (Kalydeco). Trials have confirmed efficacy in Asp551Gly (G551D) the commonest mutation in this class [Ramsey et al., 2011 Davies et al., 2013] and also more recently in rarer gating mutations [De Boeck et al., 2014] . Significant improvements in lung function (~10% absolute improvement), exacerbation rate, weight and health-related quality of life led to ivacaftor being licensed for use in these patients aged 6 years and above. A clinical trial has been conducted in children aged 2-5 years in which the drug was found to be safe and lead to similar improvements in the CFTR biomarker, sweat chloride; regulatory approval has been granted by the FDA and is currently being sought in Europe. A trial in patients with the class IV conductance defect, arg 117His (R117H) failed to confirm efficacy over all but did show an effect in adult patients [Moss et al., 2015] ; the drug is currently approved for patients with this mutation in the US.

Correctors and combination therapy

F508del is the commonest CF mutation globally. Lumacaftor (VX-809) restored CFTR function to around 15% of wild type CFTR levels in vitro, but did not lead to significant clinical changes in F508del patients [Clancy et al., 2012]. Similarly, single agent ivacaftor had shown little effect in this patient group, likely as there is insufficient CFTR available at the cell surface for potentiation [Flume et al., 2012]. Therefore the benefit of combined Lumicaftor/Ivacaftor treatment has been investigated. The phase 3 TRAFFIC and TRANSPORT trials showed significant improvements in FEV1, although this was of a lower magnitude (3-4%) than seen in class III patients with ivacaftor [Wainwright et al., 2015] and there was a substantial decrease in the number of pulmonary exacerbations, in particular those leading to the requirement of IV antibioitics. Some recent work has demonstrated an adverse impact of ivacaftor on the stability of corrected CFTR [Cholon et al., 2014] which may explain the limited efficacy. The newer corrector, VX-661 is currently undergoing large, phase III clinical trial testing in combination with ivacaftor in patients with a range of mutations (NCT02565914, NCT02392234, NCT02516410), and several other pharmaceutical companies are also active in this space, providing encouragement that wider coverage may be available in the near future. There is however, a significant issue of cost; whilst insurance based health care systems may be able to support the relatively small number of patients with CF suitable for these drugs, this is likely to pose a significant problem for nationalised health care systems. Strategies to tackle this, and the inevitable global inequalities which will arise, are urgently needed.

Read-through agents

Ataluren promotes ribosomal read-through of premature termination codons resulting in the production of a full length CFTR . No statistically significant difference was seen in the ataluren treatment group when compared to the placebo group in a large phase 3 trial, although intriguingly, significant benefits were seen in patients not receiving inhaled aminoglycoside antibiotics; these drugs also act on the ribosome, so inhibition is highly plausible [Kerem et al., 2014]. A second phase 3 trial is currently underway in patients 6 years and older not receiving these drugs (NCT02139306) .Read through agents also have potential for a range of other inherited diseases caused by stop mutations; conditional approval has recently been granted for certain types of Duchenne muscular dystrophy.

CFTR Gene Therapy

Since the CFTR gene was first discovered, over 20 clinical trials have been conducted but these have largely been single dose and focussed on correction of molecular or electrophysiological defects [Armstrong et al., 2014] . The UK CF Gene Therapy Consortium (GTC) has recently conducted a large, phase 2b, clinical trial of liposomal CFTR gene therapy [Alton et al., 2015]. Patients received monthly nebulised doses for a year, or placebo. The primary outcome was met, in that treated patients had stabilisation of FEV1 whereas the placebo group declined, with a statistically significant difference of 3.7%. Greater effects were seen in patients with more severe baseline lung disease, which may reflect more proximal deposition. Trials are planned to explore whether improvements can be further amplified by higher or more frequent dosing. In parallel, the GTC has developed a pseudotyped lentivirus (modified to bind to respiratory epithelial cells), which is showing promise as a repeatable, long-duration vector [Griesenbach et al., 2012]. Further preclinical work is underway to explore safety prior to a proposed first in man trial in the near future.

Lung transplantation

All of the above are non-invasive treatments intended to maintain pulmonary health for as long as possible and improve quality of life. However, currently, the majority of patients will ultimately progress to end-stage respiratory failure, the only treatment for which is lung transplantation. Approximately 16% of lung transplants globally are carried out in adults with CF. Timing to listing is crucial as up to 41% of patients can die while awaiting transplant. Although the survival rate post transplant tends to be better in CF patients than other indications, it is still associated with significant morbidity and mortality. Complications include graft failure (acute and chronic), opportunistic infections those related to immunosuppression [Lynch et al., 2015]. New approaches include the use of extracorporeal membrane oxygenation (ECMO) as a bridge to transplant in severely sick patients and ex-vivo conditioning strategies which may significantly increase the availability of suitable organs [Corris 2013].

Summary

The prognosis for patients with CF has improved dramatically over the last few decades. Multiple therapies are currently available targeting the downstream symptoms of the disease and we now have the first drugs in the new classes of CFTR modulators. The research field is currently extremely active, providing encouragement that further novel therapies, with perhaps genuinely transformative potential, will become available for larger numbers of patients in the near future.

Declaration of Interests

CE has no interests to declare

JCD has served on advisory boards, undertaken educational activities and lead clinical trials for which Imperial College London has received fees, for the following companies relevant to this review: Vertex, PTC, AlgiPharma, Novartis, Chiesi. She is part of the UK CF Gene Therapy Consortium which has received funding from the Cystic Fibrosis Trust and the NIHR.

Acknowledgements

Work conducted by JCD is supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.

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