Emerging therapies for cystic fibrosis lung disease

1. Background

2. Existing treatment and medical

need

3. Market review and current

research goal

4. Competitive environment

5. Potential developmental issues

6. Conclusion

7. Expert opinion

Review

Emerging therapies for cysticfibrosis lung diseaseHartmut Grasemann & Felix Ratjen††Hospital for Sick Children, Division of Respiratory Medicine, 555 University Avenue, Toronto,

Ontario, Canada

Importance of the field: Cystic fibrosis (CF), one of the major respiratory dis-

eases, is caused by mutations in a gene encoding for a chloride channel.

Abnormal transepithelial ion transport leads to a reduced volume of the

airway surface liquid layer and reduced mucociliary clearance.

Areas covered in this review: There is currently no cure for CF and CF lung

disease remains a major contributor to morbidity and mortality. However,

most current treatments for CF lung disease do not address the underlying

pathology. We describe here new therapeutic developments aiming to iden-

tify or generate compounds that counteract the effects of cystic fibrosis

transmembrane conductance regulator (CFTR) on the airway.

What the reader will gain: This review summarizes the current state of new

developments in the treatment of CF lung disease. These drugs include nebu-

lized and inhaled osmotically active agents, but also modifiers of ion channels

other than CFTR, such as activators of alternative chloride channels or inhibi-

tors of sodium absorption, and compounds in development aim to correct or

improve impaired CFTR function directly. First clinical trials with new drugs

including ion channel modifiers and CFTR pharmacotherapeutics have

revealed very promising results.

Take home message: CF drug therapy is moving rapidly from symptomatic

therapy to treatment of the underlying pathophysiology.

Keywords: CFTR pharmacotherapy, chloride secretion, clinical trials, cystic fibrosis,

osmotic therapy

Expert Opin. Emerging Drugs (2010) 15(4):653-659

1. Background

1.1 GeneticsCystic fibrosis (CF) is an inherited autosomal recessive disease of impaired epithelialtransmembrane ion transport which is caused by mutations in the cystic fibrosistransmembrane conductance regulator (CFTR) gene. The most common CFTRgene mutation worldwide causes a deletion of phenylalanine in position508 (F508del), but since the discovery of the CF gene, > 1600 different CFTRmutations have been described [1-3]. However, the majority of these are rare andthe functional consequences of these rare CFTR mutations are poorly understood.CFTR mutations can be classified according to their functional consequences, asmutations can result in absence of CFTR protein synthesis (class I), inadequateprocessing (class II), defective regulation (class III), abnormal conductance(class IV) or partially defective production (class V) [4]. Interestingly, although pul-monary disease is responsible for most of the morbidity and mortality in CFpatients, there is no strong association between the type of CFTR mutation andseverity of lung disease. In fact, even siblings with the same CFTR genotype maydiffer significantly in pulmonary function and outcome. However, patients carrying

10.1517/14728214.2010.517746 © 2010 Informa UK, Ltd. ISSN 1472-8214 653All rights reserved: reproduction in whole or in part not permitted

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classes I -- III mutations are typically pancreatic insufficient,while the less common class IV -- V mutations are associatedwith pancreatic sufficiency. Understanding the biological con-sequences of CFTR gene mutations for translation as well asprotein expression and CFTR function is essential for thedevelopment of new therapies aiming to correct specificaspects of CFTR dysfunction [5].

1.2 CFTR functionCFTR is a glycoprotein with 1480 amino acids. The proteinconsists of five domains with two transmembrane domainsof which each has six spans of a helices. These are each con-nected to a nucleotide binding domain in the cytoplasm.CFTR functions as a cAMP-activated ATP-gated anion chan-nel for certain anions in apical membranes [6]. CFTR is oftenreferred to as a chloride (Cl-) channel but may also transportthiocyanate (SCN-) and bicarbonate (HCO3

-) as well as otherproteins, such as glutathione [7,8]. In addition to its role as ananion channel, CFTR has been shown to interact with otherintracellular proteins [9]. For instance, CFTR regulates theactivity of other membrane channels including the epithelialsodium channel (ENaC) and the outwardly rectifying chlo-ride channel [10]. This is important for the development fornew therapies as drugs that will only improve epithelial chlo-ride transport, but not other aspects of CFTR function, maynot be sufficient to correct all aspects of CFTR deficiencyand may only have limited success in the treatment of patientswith CF lung disease.

1.3 Pathophysiology, airway surface liquid and

mucociliary clearanceCF is caused by CFTR gene defects that result in no expressionof CFTR or in expression of malfunctioning CFTR protein.Reduced CFTR-related chloride secretion in association withincreased sodium and water absorption at the apical membraneof airway epithelial cells causes airway surface liquid (ASL)depletion and consequently reduced mucociliary clearancedue to loss of ciliary stability and function [11,12]. Retentionof airway secretions promotes chronic inflammation andinfection, the hallmarks of CF lung disease.

2. Existing treatment and medical need

Conventional existing treatment strategies for CF lung diseaseare predominantly symptomatic and do not address theunderlying defects. Many advances have been achievedaddressing malnutrition, sputum retention, airway infectionand inflammation. Accepted treatment options for CF lungdisease besides physiotherapy include the use of mucolyticdrugs that help improve mucociliary clearance, drugs thatreduce viscoelasticity of the sputum (e.g., dornase a) andantibiotics directed against specific bacteria identified inmicrobiology cultures from individual airway secretions. Asmost current treatment options are symptomatic or onlyaddress complications of the disease but not the underlying

mechanisms, these interventions will only help to controlbut not cure CF.

3. Market review and current research goal

Modern treatments in CF should be directed against theunderlying pathophysiology, that is, to reconstitute thereduced ASL layer. These drugs include osmotically activeagents such as hypertonic saline or mannitol [13]. A trulyemerging field in new CF therapies, however, is the develop-ment of CFTR pharmacotherapeutics. These drugs will helpcorrect or improve impaired CFTR function directly andmay soon prove as a useful alternative to what has beenthought to be the ultimate therapy in CF, that is, the replace-ment of abnormal CFTR by gene therapy. Normalization ofthe ASL may also be achieved with modifiers of ion channelsother than CFTR including activators of alternative Cl- chan-nels or inhibitors of sodium absorption, an alternativeapproach to address the basic defect in CF.

4. Competitive environment

4.1 Airway rehydrationThe clinical efficacy of hypertonic saline in CF was demon-strated in a multi-center trial conducted in Australia [14].Inhaled nebulized hypertonic saline resulted in a reductionin pulmonary exacerbation frequency in treated CF patientsand also in a small improvement in lung function [14]. Inhaledhypertonic saline was initially tested to obtain induced spu-tum samples in patients with airway diseases, but positiveeffects on mucociliary transport and lung function havealready been described in smaller studies [15]. The beneficialeffects of hypertonic saline may not only be due to its acuteeffects on mucus hydration and cough induction, as it alsohas a prolonged effect on ASL height in CF [16]. Therefore,the use of inhaled hypertonic saline may already be beneficialin young children with CF who do not yet have significantlung disease, as normalization of airway hydration may helpprevent lung damage and, therefore, have important long-term effects. In fact, inhaled hypertonic saline has been shownto improve the lung clearance index, a measure of ventilationinhomogeneity, in CF children with normal pulmonary func-tion [17] and was demonstrated to have good tolerability ininfants [18].

Mannitol is a polyol or sugar alcohol that is derived froma sugar by reduction. Mannitol is used as a sweetener butalso as an osmotic diuretic. Mannitol is currently beingtested in a dry powder formulation in CF patients and aPhase II study has demonstrated positive effects on lungfunction as well [19]. A first Phase III study has shown prom-ising results on lung function [20] and a second Phase IIIstudy has just been completed [21]. Concerns have beenraised about potential detrimental effects of inhaled Manni-tol on certain bacteria in the CF lung, as a recent studyhad revealed a link between growth conditions and

Emerging therapies for cystic fibrosis lung disease

654 Expert Opin. Emerging Drugs (2010) 15(4)

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exopolysaccharide (EPS) production in Burkholderia cepaciacomplex (Bcc), demonstrating that the carbohydrates sucrose,fructose and fructans but also the alcohol sugars glucitol andmannitol are able to induce EPS production in Bcc. EPS is aputative virulence factor of Bcc that is involved in persistenceof these bacteria in CF lungs (Table 1) [22]. So far, patientswith Bcc have been excluded from clinical trials of mannitoland the clinical relevance of these findings, therefore, ispresently unclear.

4.2 Modifiers of ion channel function4.2.1 Stimulation of alternative chloride channelsOther chloride channels than CFTR exist and a calcium-dependent chloride channel has been shown to secrete chlo-ride in epithelial cells [23]. Therefore, increasing the activityof alternative chloride channels in CF airways could poten-tially be therapeutic. Supporting evidence for this comesfrom CF-deficient mice. As the relative contribution ofCFTR to total transepithelial chloride transport is low inthese animals, mice deficient for CFTR do not develop a sig-nificant pulmonary phenotype [24]. Certain drugs can activatethis calcium-dependent chloride channel either directly orindirectly through the purinergic P2Y receptor. Two drugsthat increase alternative chloride secretion through thischannel are currently in clinical CF trials.

4.2.1.1 Lancovutide (Moli1901)Lancovutide is an antibiotic (duramycin) that was found toraise intracellular calcium levels and thereby increase alterna-tive chloride channel activity. The exact mechanism of actionremains unclear, but in a proof of concept study lancovutidewas shown to increase chloride conductance measured bynasal potential difference measurements when applied topi-cally to the nasal mucosa of CF patients [25]. Inhalation of lan-covutide was found to be safe and have a positive effect onpulmonary function in a Phase II, placebo-controlled, double-blind, single center study of aerosolized lancovutide in CFpatients [26]. A subsequent 4 week study supported these ini-tial findings and a larger multi-center study powered to assessefficacy had been conducted in Europe. Unfortunately,although this larger trial was completed > 2 years ago, nodata have been presented to date.

4.2.1.2 DenufosolSignal transduction molecules that are secreted into the ASLmay play an important role in the dynamic regulation of theASL volume [27]. ATP, for instance, has been shown to induceCFTR-independent chloride secretion by activation of P2Yreceptor in both CF and non-CF epithelial cells. The P2Yreceptor mediates chloride secretion independent of CFTRthrough an alternative calcium-dependent chloride chan-nel [28]. Binding of ATP and other purines to the P2Y receptorinduces intracellular calcium release. ATP analogs may,therefore, increase ASL volume and mucociliary clearance.Uridine triphosphate had been tested as an agent to enhance

mucociliary clearance in CF patients but its clinical usefulnesswas limited by a short biological half-life [29].

Denufosol is a P2Y receptor agonist with enhanced stabilityand prolonged activity in vitro that increases chloride transportthrough the calcium-dependent chloride channel, inhibitssodium absorption via ENaC and directly stimulates ciliarybeating, which results in increased mucociliary clearance asdemonstrated in healthy subjects [30]. Three independentplacebo-controlled Phase II studies consistently demonstrateda significantly better FEV1 in denufosol treated versus controlCF patients [30]. A first Phase III clinical study on inhaled denu-fosol tetrasodium in CF patients has recently completed the6 month placebo-controlled phase and a 6 month denufosol-only open-label extension. Results of this TIGER1 (Transportof Ions to Generate Epithelial Rehydration) study lookedpromising, as they showed a significant effect of treatment onFEV1, the primary outcome measurement [31]. Interestingly,the open-label extension data would suggest ongoing improve-ment in patients on long-term therapy. A second placebo-controlled denufosol trial with a 12 month study period(TIGER2) is currently ongoing [32]. Both studies have focusedon patients with relatively mild CF lung disease. The role ofdenufosol in patients with more advanced lung disease isstill unclear.

4.2.2 Inhibition of sodium absorptionAs the genetic mouse models of CFTR deficiency failed todevelop a CF-like lung phenotype, transgenic mice havebeen generated that overexpress the b subunit of the ENaC.This physiological CF mouse model is characterized by epi-thelial sodium hyperabsorption and shares other characteris-tics of CF lung disease, such as mucus plugging andneutrophilic inflammation [33]. Interestingly, studies in theENaC transgenic mouse model showed that the ENaCblocker amiloride could prevent the development of lung dis-ease when given early, while administration after airway dis-ease had developed failed to have a beneficial effect [34].Similarly, clinical trials in CF patients fail to demonstrateclinical efficacy but rather showed a trend towards decreasinglung function in treated patients [35]. Amiloride has a shortbiological half-life and new ENaC blockers with a longerhalf-life are being developed [36]. Compared to ion channeltherapy directed against chloride channels, these compoundsare at an earlier stage of development and both safety and effi-cacy in patients are yet to be determined. Inhalation of onecompound, GS-9411, had been tested in healthy subjectsbut a planned Phase I trial of GS 9411 in subjects with CFhas just recently been withdrawn [37].

4.3 CFTR pharmacotherapyNew drugs under development are designed to eithercorrect specific CFTR gene mutations or target certain biolog-ical consequences characteristic for classes of CFTR muta-tions. CFTR pharmacotherapy affects aspects of disturbedintracellular function including protein trafficking, CFTR

Grasemann & Ratjen

Expert Opin. Emerging Drugs (2010) 15(4) 655

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expression or function of CFTR expressed at the cell mem-brane. Some promising compounds in clinical testing arelisted below.

4.3.1 CFTR correctorsThe most common CFTR mutation, F508del, results in mis-folded protein which, when expressed at the apical epithelialcell membrane, has been shown to have some residual chlo-ride conducting activity [38]. However, the majority of theproduced F508del CFTR protein is recognized as abnormalin the endoplasmic reticulum (ER) and subsequently under-goes proteolytic degradation in the proteasome [39,40], andthe small amount of protein that does reach the plasma mem-brane has a significantly reduced half-life [41]. Therefore, res-cue from ER degradation, improving trafficking of CFTR tothe cell surface and inhibition of proteins involved in recy-cling of CFTR in the cell membrane are potential targets ofF508del and other class II directed pharmacotherapy [42].Using high-throughput assays to screen libraries of known

therapeutics, a number of drugs have been identified topotentially improve mutated CFTR processing. Screening ofchemical libraries and subsequent modifications of certaincompounds to optimize function have resulted in new drugswith potential for CFTR pharmacotherapy [43]. However,degradation of faulty protein is an important intracellularcontrol mechanism and interference with the involved path-ways may, by affecting proteins other than CFTR, have toxicand unwanted side effects. Nevertheless, testing of some com-pounds revealed promising results in preclinical studies [44]

and a Phase IIa trial of four oral doses of compoundVX-809 found that this corrector was well tolerated in CFpatients. In addition, there was a dose-dependent effect onsweat chloride levels at higher doses, suggesting an effect ofthis drug on F508del activity [45].

4.3.2 CFTR potentiatorsClass III mutations are characterized by a reduced openingprobability of the CFTR channel. VX-770 is an orally bio-available CFTR potentiator with good efficacy and safety pro-file that is currently in clinical testing. In vitro cell culturestudies had shown that VX-770 can increase CFTR channel

open probability in both the G551D gating mutation andthe F508del processing mutation and increased Cl- secretionin cultured human CF bronchial epithelia carrying theG551D mutation on one and the F508del mutation on theother allele. Furthermore, VX-770 reduced sodium (Na+)and fluid hyper-absorption from the apical surface andincreased cilia beating in epithelial cultures, suggesting thatpharmacological agents that restore or increase CFTR func-tion can rescue CF airway epithelial cell function [46]. Initialresults from clinical studies look promising, as VX-770 notonly enhanced CFTR function as demonstrated by nasalpotential difference measurements, but also normalized sweatchloride concentrations after oral administration of the drugin CF patients with the G551D mutation [47].

While class III mutations are relatively rare, compoundsthat potentiate function of mutated CFTR may have a rolebeyond this patient group. For instance, a combination ofcorrector and potentiator compounds has potential in thetreatment of patients with class II mutations, in whom thecorrector drug would improve trafficking of CFTR tothe cell membrane and the potentiator would improvefunction of the mutated but expressed CFTR protein.

A larger clinical study to evaluate the safety and efficacy ofVX-770 in subjects with G551D mutations is currentlyongoing [48]. In addition, CFTR potentiator therapy isbeing evaluated in CF patients homozygous for the F508delCFTR mutation [49]. Future studies will evaluate theeffect of combined corrector and potentiator treatment inthese patients.

4.3.3 Suppressors of premature stop codonsAminoglycosides have been shown to induce read through ofpremature termination codons (PTCs) in CF (class I) andother genetic diseases. Topical application of aminoglyco-side antibiotics to the nasal mucosa has been shown toimprove CFTR function in CF patients [50]; however, theconcentration required to achieve an effect on chloride trans-port is high and would not be suitable for clinical use due tothe well-known side effects of aminoglycosides. PTC124,now called ataluren, has been developed as a compoundsharing the action on stop codons but lacking both

Table 1. Competitive environment.

Compound Company Stage of development Mechanism of action

Bronchitol (mannitol) Pharmaxis Phase III trial ongoing Osmotic agentLancovutide (Moli1901) Lantibio Phase II trial completed,

results pendingAlternative chloride channel activator

Denufosol Inspire Pharmaceuticals First Phase III trial completed,Second Phase III trial ongoing

P2Y receptor agonist, ion channel regulator

VX-809 Vertex Pharmaceuticals Phase IIa trial completed CFTR correctorVX-770 Vertex Pharmaceuticals Phase III trials ongoing CFTR potentiatorAtaluren (PTC124) PTC Therapeutics Phase III trial ongoing Suppressor of premature stop codonsGS-9411 Gilead Phase I trial Sodium channel blocker

CFTR: Cystic fibrosis transmembrane conductance regulator.



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aminoglycoside antibiotic function and toxicity. Clinical tri-als in CF patients with class I mutations were promisingbut demonstrated variable treatment response to PTC124between patients with different CFTR genotypes, suggestingthat even CFTR class specific pharmacotherapy may not beequally effective in all CF patients within a given class ofmutations [51,52]. A larger placebo-controlled study is cur-rently under way [53]. There is evidence suggesting thatin vitro assays may help to predict in vivo efficacy of suppres-sors of premature stop codons such as ataluren, as theamount of transcript RNA was shown to predict success ofgentamicin therapy on the correction of stop codon muta-tions [54]. However, as PTCs are the cause of CF in only5% in countries other than Israel, where class I mutationsare more frequent, this potential treatment will be an optionfor only a small fraction of the CF patient population.Ataluren is also of interest for other diseases including non-sense mutation caused hemophilia type A and B as well asDuchenne and Becker muscular dystrophy [55].

4.4 CFTR replacement therapyThe current state of gene therapy trials for CF has beenrecently reviewed by others [56]. The goal of gene therapy inCF is that delivery of a normal CFTR gene to the lung wouldresult in expression and restored function of CFTR in the CFairway epithelium. Among the multiple challenges with genedelivery is the question of which vector to use for gene deliv-ery. Adenovirus, adeno-associated virus and cationic lipids arethe most commonly used vectors. Successful gene transfer intoairway epithelial cells was demonstrated for different vectorsin vitro and in vivo but CFTR expression was only transientin most studies. Viral vectors seem more efficacious, but alsomore likely to cause side effects compared to liposomal vectorswhich, however, show lower transfection efficiency. As geneexpression is short termed, successful gene therapy mayrequire repeated dosing which is especially problematic forviral vectors as they induce virus specific immune response [56].However, inhaled or oral treatment may be more convenientfor the patient than repeated gene therapy. Another interest-ing, yet unresolved question is how much CFTR functionneeds to be restored in the CF airways to result in clinicalimprovement [57].

5. Potential developmental issues

Screening assays for existing drug libraries and chemicallibraries with subsequent modifications of identified com-pounds has resulted in the identification of compounds thatcould potentially be used to treat CF [43]. Ongoing researchinto the mechanisms is needed to continue a pipeline of com-pounds with even better activity as those currently discovered.Combined therapies of for instance CFTR correctors andpotentiators will probably be needed for the best efficacy.However, testing a combination of new drugs will be a

challenge for many reasons including sample size and primaryoutcome measures of clinical trials.

6. Conclusion

Currently, none of the new therapeutic agents that target theunderlying defect in CF, that is, drugs that restore ASL, modi-fiers of ion channel function, CFTR pharmacotherapy or genereplacement, has reached the stage of licensing for clinical use.However, multiple compounds are in the advanced stage ofclinical development with the ion channel regulator denufosoltetrasodium being in the most advanced stage [58].

7. Expert opinion

The new developments in therapeutics targeting the underly-ing pathophysiology in the CF airways are all very excitingand will probably result in a change in the therapeuticapproach in the next few years. It is important to note thoughthat the continued progress in treatment of symptoms such asdecreased mucociliary clearance, infection and airways inflam-mation as well as other aspects of the disease has resulted in asignificant improvement in survival in recent years. Control ofsymptoms will remain an important component of patientcare. A better understanding of the CFTR-mutation specificabnormalities, however, will help to correct abnormalitiesearly which will hopefully result in less symptoms andreduced need for conventional therapy. New treatmentapproaches may, therefore, help reduce treatment burdenand improve outcome. The preliminary results of the presentpreclinical and clinic studies of the new compounds suggestthat a combination of different new compounds or a combi-nation of conventional and new drugs may be needed toimprove clinical outcome. However, a cure of CF by a singlecompound or intervention may be feasible; and this is the goalof ongoing research. Given the diversity of abnormalitiescaused by different CFTR gene mutations, it is unlikely thata single compound will cure all CF patients, but possibly cer-tain classes of mutations. A more realistic goal for future treat-ments, however, is the development of therapeutics that willhelp slow down the progressive decline or maintain pulmo-nary function, decrease the need for symptomatic treatmentsand hospital admissions, and improve quality of life inpatients with CF. This is an exciting era for CF research andthe advances made for the patients will serve as a positiveexample of productive collaborative efforts not only in theCF community but also for other devastating diseases.

Declaration of interest

F Ratjen acts as a consultant for Inspire, Inc.; Pharmaxis; andVertex, companies that produce compounds discussed in thisarticle. He is also the lead PI for Tiger 2, the second Phase IIIstudy of denufosol, which is sponsored by Inspire.

Grasemann & Ratjen


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research/DrugDevelopmentPipeline

AffiliationHartmut Grasemann1,2 MD &

Felix Ratjen†3,4,5 MD PhD FRCPC†Author for correspondence1Associate Professor,

Department of Paediatrics,

University of Toronto,

Division of Respiratory Medicine,

555 University Avenue,

Toronto, Ontario M5G 1X8, Canada2Associate Scientist,

SickKids Research Institute,

Program in Physiology and

Experimental Medicine and

Hospital for Sick Children,


Toronto, Ontario M5G 1X8, Canada3Professor,

Department of Peadiatrics,

University of Toronto,


Toronto, Ontario M5G 1X8, Canada4Senior Scientist,

Head,

Division of Respiratory Medicine and

Sellers Chair of Cystic Fibrosis,

Hospital for Sick Children,


Toronto, Ontario M5G 1X8, Canada

Tel: +1 416 813 6167; Fax: +1 416 813 6246;

E-mail: [email protected] Scientist,

SickKids Reserach Institute,

Program in Physiology and

Experimental Medicine,

University of Toronto, Canada

Grasemann & Ratjen


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Emerging therapies for cystic fibrosis lung disease