Emerging drugs for cystic fibrosis.

Review

Emerging drugs for cystic fibrosis Reshma Amin† & Felix Ratjen University of Toronto,The Hospital for Sick Children, Division of Respiratory Medicine, Department of Pediatrics, Physiology and Experimental Medicine, Toronto, ON, Canada 1.

Background

2.

Existing treatment and medical need

3.

Market review and current

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research goal 4.

Scientific rationale

5.

Competitive environment

6.

Conclusion

7.

Expert opinion

Introduction: Cystic fibrosis is an autosomal recessive disease, which is the result of a genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Pulmonary disease accounts for over 90% of the morbidity and mortality associated with the disease. Conventionally, CF treatment has focused on symptomatic therapy. Areas covered: In the past, the emphasis for the development of CF therapeutics has previously been on addressing complications of the manifestations rather than on the underlying disease process. However, in the past few decades there has been a paradigm shift with new attention on the underlying biological mechanisms and therapies targeted at curing the disease rather than simply controlling it. This review summarizes the current CF therapeutics pipeline. These developing therapies include CFTR gene therapy, CFTR pharmacotherapeutics, osmotically active agents and anti-inflammatory therapies, as well as novel inhaled antibiotics. Expert opinion: The CF therapeutics pipeline currently holds great promise both for novel therapies directly targeting the underlying biological mechanisms of CFTR dysfunction and new symptomatic therapies. While CFTRdirected therapy has the highest potential to improve patients’ outcome, it is important to continue to develop better treatment options for all aspects of CF lung disease. Keywords: clinical trials, cystic fibrosis, cystic fibrosis transmembrane conductance regulator pharmacotherapy, pulmonary treatment Expert Opin. Emerging Drugs (2014) 19(1):143-155

1.

Background

Pulmonary manifestations are the main cause of morbidity and mortality in cystic fibrosis patients, an autosomal recessive disease that occurs as a result of a genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common CFTR gene mutation worldwide is a deletion of phenylalanine in position 508 (F508del), but almost 2000 different CFTR mutations have been described to date [1]. CFTR mutations can be classified according to their functional consequences: absence of CFTR protein synthesis (class I), inadequate processing (class II), defective regulation (class III), abnormal conductance (class IV), reduced quantity of CFTR (class V) or increased turnover of the protein (class VI) [2]. In general, classes I -- III mutations are associated with a more severe phenotype and pancreatic insufficiency, whereas classes IV and V mutations are associated with a better prognosis and pancreatic sufficiency. Understanding the cellular consequences of a genetic mutation is essential for the development of new therapies aimed to correct specific aspects of CFTR dysfunction [3]. The most common mutation, F508del is a class II trafficking mutation, and also shows abnormal conductance and increased turnover of the misfolded protein. All of these aspects of CFTR dysfunction can be a therapeutic target and, as outlined below, addressing more than one aspect of CFTR dysfunction may be required to optimize therapeutic response. A lack of CFTR activity leads to decreased chloride secretion as well as sodium hyperabsorption, since one of the physiological functions of CFTR is to inhibit 10.1517/14728214.2014.882316 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

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Table 1. Competitive environment. Compound

Company

Stage of development

Mechanism of action

VX-809 VX-661 Ataluren (PTC 124) Bronchitol (mannitol) Aeroquin

Vertex Pharmaceuticals Vertex Pharmaceuticals PTC Therapeutics Pharmaxis Aptalis Pharma, Inc.

CFTR corrector CFTR corrector Suppressor of premature stop codons Osmotic agent Suppression of Pseudomonas aeruginosa

Arikace Tobramycin Inhalation Powder Colobreathe dry powder for inhalation Fosfomycin/tobramycin

Insmed Novartis Forest Laboratories

Phase III trials underway Phase II trial completed Phase III trial ongoing Phase III trials completed Phase III completed, results pending Phase III trial ongoing Phase III trial completed and a vailable for clinical use Phase III trial completed

Gilead Sciences

Phase II trial completed

Savera CSL Behring Grifols Therapeutics, Inc.

Phase IIa trial ongoing Phase II trial completed Phase II trial ongoing

Suppression of P. aeruginosa and Gram-positive organisms Suppression of MRSA Inhibit neutrophil elastase Inhibit neutrophil elastase

Kalobios Pharmaceuticals

Phase I trial recently completed

AeroVanc a1-antitryspin a1-hydrophobic chromatography process KB001

Suppression of P. aeruginosa Suppression of P. aeruginosa Suppression of P. aeruginosa

Decrease type III secretion of P. aeruginosa

CFTR: Cystic fibrosis transmembrane conductance regulator.

the epithelial sodium channel [4]. However, recent evidence has challenged the concept whether this is a primary or secondary event in CFTR-related pathophysiology [5]. The result of CFTR function is a decreased airway surface liquid (ASL) volume, which leads to collapse of respiratory cilia, impaired mucociliary clearance (MCC) and mucus retention in the lower airways. Inhaled microorganisms cannot be efficiently cleared from the cystic fibrosis (CF) airway, which results in the vicious cycle of chronic bacterial infection, inflammation and pulmonary exacerbations. 2.

Existing treatment and medical need

Historically, conventional CF treatment has focused on symptomatic therapy. Therefore, the focus has previously been on addressing complications of the manifestations rather than on the underlying disease process. The mainstay of current CF therapy is chronic suppressive antibiotics therapy delivered by inhalation in conjunction with intravenous antibiotics to treat acute pulmonary exacerbations. The limitation of this approach is that pulmonary disease inevitably continues to progress resulting in a significant shortening of lifespan despite aggressive antibiotic therapy. Therefore, in the past decade there has been a shift toward developing medical treatments that address the underlying genetic defect -- essentially, a preventative rather than a reactionary approach.

cure to all CF patients, regardless of mutation. However, novel symptomatic treatments, especially inhaled antiinfective therapies continue to be essential in managing CF pulmonary disease, while patients are awaiting specific biological therapies with a promise to make a major difference in the long-term prognosis of patients with CF (see Table 1, for a list of the compounds being reviewed in this article). 4.

In the past few decades, there has been a paradigm shift with new attention on the underlying biological mechanisms and therapies targeted at addressing the underlying genetic defect rather than simply controlling its sequelae. At present, treatment of CF lung disease can be divided into categories based on the primary target within the cascade of CF pathophysiology (Figure 1): i) gene therapy aimed at correcting the gene defect; ii) CFTR pharmacotherapy which targets defective ion transport; iii) airway surface fluid hydration; iv) agents that improve mucus clearance; v) anti-infective therapy; and vi) anti-inflammatory therapy. However, the readers must be aware that a therapeutic agent may affect more than one step in the pathophysiology cascade. Furthermore, some pathophysiological targets such as anti-inflammatory therapies continue to remain poorly developed. 5.

3.

Scientific rationale

Competitive environment

Market review and current research goal Gene therapy Gene therapy seeks to introduce a normal copy of the CFTR gene into the cells of the conducting airways [6]. However, finding an ideal vector for gene therapy has proven to be challenging. Adenovirus was initially thought to be promising [7]. 5.1

Current and future CF therapeutics need to address the earlier steps in the CF pathophysiology cascade. CFTR pharmacotherapies have yielded exciting results for the CF community in the past 18 months. CF gene therapy offers the hope of a 144

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Emerging drugs for cystic fibrosis

CF Pathophysiology CFTR gene defect

Defective ion transport Airway surface liquid depletion


Defective mucociliary clearance

Mucus obstruction

Infection

Inflammation

Figure 1. The cascade of cystic fibrosis pathophysiology.

However, immunogenicity, chronic infection and the vector’s transfection inefficiency after repeated dosing have been significant hurdles. Currently, the most advanced program is led by the UK Cystic Fibrosis Gene Therapy Consortium which was formed over a decade ago and has been working collaboratively to develop a structured approach to gene therapy. The consortium has recently launched a Phase IIb clinical trial of a non-viral, lipid-based vector complexed with a CFTRexpressing plasmid [6]. Clinical benefit will be assessed by assessing numerous outcome measures throughout one year of therapy [8]. Newer vector models such as lentivirus and modified adenovirus vectors are currently being tested in murine and porcine models, but are still in the preclinical stage [9,10]. Although, gene therapy is not an imminently available therapy, it still holds promise as a treatment option for all CF patients independent of CFTR genotype. Mutation-specific CFTR pharmacotherapy Unlike other pulmonary therapeutics for CF, which are ‘onesize-fits all’, these therapies are CFTR mutation class-specific. There have been major advances in this class of pulmonary therapeutics in the past decade which has resulted in significant excitement in the CF community. Candidate drugs can be further divided into three therapeutic categories: i) CFTR potentiators; ii) CFTR correctors; and iii) agents that promote ribosomal read-through of nonsense mutations. 5.2

CFTR potentiators The year 2012 was a landmark year for CF therapeutics as ivacaftor became the first available treatment to directly address the underlying defect in CF. Although the market approval of ivacaftor has significantly changed treatment for patients carrying the G551D mutation, this pertains to only 5.2.1

4% of the CF population. Ivacaftor is an oral CFTR potentiator which increases chloride transport by CFTR molecules that are already on the epithelial cell surface [11]. The Phase III trial randomized 167 patients older than 12 years to receive 150 mg of ivacaftor or placebo every 12 h for 48 weeks. There was a 10% absolute improvement in FEV1 that was seen at 2 weeks and sustained for 48 weeks [12]. This treatment effect exceeded what has previously been seen in any study of a CF therapeutic. There was also a significant reduction in pulmonary exacerbations (55%, p = 0.0003), and increase in weight gain (2.7 kg, p < 0.0001). There was also an increase in the score from baseline on the respiratory domain of the cystic fibrosis questionnaire-revised (CFQ-R), a quality of life questionnaire that is scored on a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient’s quality of life (CFQ-R respiratory domain: 8.6 points, p < 0.001). Furthermore, sweat chloride values were markedly reduced with treatment (-48.1 mEq/l, p < 0.0001). Notably, mean sweat chloride values in the ivacaftor group were lowered below the diagnostic threshold of 60 mEq/l. Although the ivacaftor group had a higher rate of adverse reactions that required discontinuation the drug than the placebo group (13 vs 6%), treatment was overall well tolerated. The major reason for discontinuation of ivacaftor was an increase in hepatic enzymes which was reversible after discontinuation of therapy [12]. After the completion of the Phase III trial, participants were invited to continue in an open-label study [13]. To date, 144 participants have been followed for time periods ranging from 2 to 96 weeks. The adverse events reflected those commonly observed in CF trials; the most common of which were cough, pulmonary exacerbation, hemoptysis, upper respiratory tract infection, headache and abdominal pain [13]. Treatment effects were maintained throughout week 96 showing persistence of efficacy over time. In addition to this study, a trial was conducted in children < 12 years of age [14]. The Phase III study in young children demonstrated similar results with the exception of improvements in the CFQ-R respiratory symptom scores not reaching statistical significance. Ivacaftor has shown some benefit in potentiating class IV conductance mutations such as R117H and a study is currently underway to assess its efficacy in this patient population [15]. In support of its utility beyond G551D, a recent study in patients with class II mutations other than G551D yielded similar results to those reported in G551D patients [16-18]. A Phase II study was also completed in CF patients homozygous for F508del. Not unexpectedly, as little CFTR is expressed at the cell surface in these patients, ivacaftor did not significantly reduce sweat chloride concentrations or improve lung function [19]. Based on in vitro studies, other mutations may benefit from ivacaftor monotherapy [20]. CFTR correctors Lumacaftor is a CFTR corrector which has been shown to affect the folding and processing of CFTR in F508del 5.2.2


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mutation cells and improve CFTR expression at the cell surface [21]. A Phase IIa study randomized patients to receive lumacaftor or placebo for 28 days [22]. The 89 randomized patients demonstrated similar adverse event profiles in both the lumacaftor and placebo groups. There was a significant reduction in the sweat chloride levels -- a marker of CFTR activity [22]. However, the magnitude of the change in sweat chloride (-8.21 mmol/l) was significantly less than the ivacaftor alone for G551D mutations (-47.9 mmol/l) [12]. Although, limited efficacy has been demonstrated with monotherapy of lumacaftor, CFTR functionality improves with CFTR potentiation and CFTR corrector combination therapy. A second Phase II study evaluated the safety and efficacy of 28 days of lumacaftor, 600 mg/day monotherapy followed by 28 days of combination therapy with lumacaftor, 600 mg/ day and ivacaftor, 250 mg twice daily (b.i.d.), in homozygous F508del adults [23,24]. After 28 days of monotherapy with lumacaftor, FEV1 declined 2% relative to placebo. However, after 28 days of combination therapy, there was a relative change in FEV1% predicted which was 8.6% greater than placebo; this improvement was only seen with the highest combination dose. Based on these results, two Phase III studies are currently underway which will include > 1000 CF patients [14,25]. VX-661 is another potential CFTR corrector of protein misfolding and trafficking [26]. A Phase II dose-escalation study of VX-661 monotherapy (dose 10, 30, 100, 150 mg) alone and in combination with ivacaftor (150 mg b.i.d.) has been completed in 128 adults homozygous for F508del [27]. Preliminary results from the trial demonstrated that patients in the 100 and 150 mg combination groups had significant mean relative improvements in FEV1% predicted as compared to placebo, of 9.0% (p = 0.01) and 7.5% (p = 0.02), respectively, at day 28 [28]. Even if one of these two drugs will succeed in Phase III trials, this is only the first step toward finding therapies controlling CF-related pathology. As pointed out above, Phase II study results, while promising, were less impressive compared to the effect of ivacaftor in G511D. Correction of CFTR trafficking is more complex and involves multiple cellular processes. Recent evidence suggests that a combination of drugs targeting different aspects of CFTR processing may be more efficacious and thus multiple drugs may be needed to achieve CFTR correction sufficient to normalize CFTR function [29]. Read through of nonsense mutations Ataluren is an oral drug that targets CF nonsense mutations. It allows ribosomes to read through mRNA premature stop codons, resulting in the production of functional CFTR protein [30]. Although nonsense mutations account for only 5 -- 10% of all CF mutations worldwide, they account for > 60% of CF in Israel [31]. Ataluren was first studied in a mouse model, where it restored chloride transport to approximately 25% of normal levels in mice with CF and a 5.2.3

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G542X mutation [32]. After the promising animal studies, dose-finding studies were performed in healthy adults with doses being well tolerated up until 150 mg/kg [33]. Ataluren was then studied in a Phase II study in adults which looked at the effects of two different daily dosing regimens each for 14 days [34]. In an open-label study, not including a placebo group, no changes were observed in sweat chloride concentrations, but chloride transport in nasal epithelium assessed by potential differences (NPD) increased significantly (p = 0.0003 for cycle 1 and p = 0.02) [34]. The Phase II study extension evaluated high and low ataluren dosing for 12 weeks [35]. The investigators demonstrated a statistically significant change of -5V in NPD in both groups (p < 0.001) [35]. The same dosing regimens were then studied in CF patients between the ages of 6 and 18 years. The pediatric study also demonstrated a significant change in NPD [36]. However, there were no significant differences in lung function in either the adult or pediatric study [35,36]. A Phase III trial in patients > 6 years of age studied patients who received ataluren 10 mg/kg in the morning, 10 mg/kg at noon and 20 mg/kg in the evening or placebo for 48 weeks [37]. Neither the primary end point relative change in FEV1% predicted nor the secondary end point of pulmonary exacerbations is significant at 48 weeks [37]. However, patients not receiving inhaled antibiotics did seem to benefit -- a difference that was attributed to the potential competition of inhaled aminoglycosides and ataluren for binding to PTCs affecting the efficacy of readthrough therapy. Another study is now planned in patients not receiving inhaled aminoglycosides to clarify whether ataluren is a potential treatment option in patients with class I mutations. ASL hydration Therapies have been developed to restore the ASL, as adequate ASL hydration is needed for adequate MCC in CF patients. This can be achieved via inhibition of sodium absorption, osmotic therapy or stimulation of chloride secretion. The dependence of ASL volume for adequate MCC in CF patients has led to study osmotic substances such as inhaled hypertonic saline and mannitol. 5.3

Hypertonic saline Hypertonic saline (HS) acts as an osmotic agent to restore the ASL fluid layer and thus improves MCC. The therapeutic application of HS originated in Australia by clinician researchers who noted subjective improvement in CF patients who surfed regularly. Subsequent studies have demonstrated that HS improves MCC in a concentration-dependent fashion [38]. This effect is sustained for up to 24 h [39]. Treatment with HS was shown to significantly improve FEV1 and reduce pulmonary exacerbations as compared to controls, in a large randomized controlled trial of children and adults ‡ 6 years of age [40]. For participants who were at least 14 years old, there were significant differences between groups in favor of HS in the role domain (7.3 points, p = 0.04), the emotional 5.3.1




domain (4.8 points, p = 0.03) and the health domain (5.3 points, p = 0.01) of the CFQ for adults. For participants < 14 years of age, only the digestion domain was significantly higher. The respiratory domain was not significantly different between HS and placebo groups in either age category [40]. The Infant Study of Inhaled Saline in Cystic Fibrosis, a recent Phase III trial, studied the efficacy of HS in children £ 6 years of age [41]. A total of 321 children were enrolled to power the primary end point of pulmonary exacerbations. A difference in pulmonary exacerbations was not seen between treatment arms but, in a subgroup of participants, a treatment effect for FEV0.5 was identified. In addition, a significant treatment effect was seen for lung clearance index in the small subset of 25 patients that underwent this measure [42]. This highlights the challenges of choosing an adequate outcome measure when studying young children with limited lung disease. A further trial using functional and structural measures of lung disease is planned for the near future to clarify the utility of HS as an early intervention strategy. Mannitol Mannitol is a six-carbon monosaccharide believed to create an osmotic gradient leading to an influx of water into the CF airway. Wills et al. is credited with being the first to study the effects of mannitol on CF sputum; this group reported improvements in the tracheal mucus velocity of CF sputum placed on the bovine trachea [43]. The safety and efficacy of mannitol were assessed in a Phase II trial of mannitol versus placebo in 49 CF patients and the study demonstrated a 7% increase in FEV1% predicted and a decreased sputum viscosity in the mannitol group [44]. A second dose-finding Phase II study demonstrated that 400 mg b.i.d. of inhaled mannitol was safe and showed superior efficacy compared to lower doses [45]. Two Phase III studies have been completed for mannitol, both with similar study designs [44,46]. They were randomized, double-blind, 26 weeks studies, followed by a further 26-week open-label extension. A total of 324 subjects in the Bilton et al. study and 318 patients in the Aitken et al. study were randomized to mannitol (400 mg b.i.d.) or control. The primary end point was the change in FEV1 [44,46]. Eligible subjects were aged ‡ 6 years with baseline FEV1 of ‡ 30 and < 90% predicted [44] and FEV1 of ‡ 40 and < 90% predicted [46]. In the study by Bilton et al., there was a significant 35.4% (p = 0.045) reduction in the incidence of having a pulmonary exacerbation during the double-blind phase of the study. However, there was no statistically significant reduction in the rate of exacerbations in either Phase III study. In addition, mannitol inhalation did not result in a statistically significant improvement in quality of life in either study. Unlike the Phase II study where a nonrespirable dose of mannitol was given, both studies used a subtherapeutic (50 mg) dose of mannitol as the control. The choice of control for this study was based on the need to maintain the blinding, provide an appropriate comparator 5.3.2

and comply with scientific advice from regulatory agencies. FEV1 improved by 4% in the European trial and 3.8% in the American trial. Bilton et al. have published a pooled analysis of the Phase III study results [47]. There were several notable findings. Both the mean absolute change in FEV1 and the relative change in FEV1 (% predicted) from baseline for mannitol versus control were statistically significant (73.42 ml, 3.56%, both p < 0.001). Increases in FEV1 were observed irrespective of rhDNase use. Significant improvements in FEV1 occurred in adults but not children (aged 6 -- 11) or adolescents (aged 12 -- 17), but these differences were largely driven by differences in the control groups, whereas the response in patients receiving 400 mg mannitol was similar throughout different age groups. Furthermore, pulmonary exacerbation incidence was reduced by 29% (p = 0.039) in the mannitol (400 mg b.i.d.) group [47]. One of the concerns regarding mannitol inhalation is the potential for chronic therapy to lead to proliferation of bacteria as mannitol is a substrate that can be metabolized by bacteria such as Burkholderia cepacia [48]. Thus far, clinical trials have not shown any negative effects on sputum microbiology from mannitol inhalation [44,46,47,49]. At present, mannitol is licensed in Australia and the European Union for the treatment of CF patients ‡ 18 years. Anti-infective treatment Anti-Pseudomonas aeruginosa inhaled antibiotics

5.4

5.4.1

Chronic respiratory disease accounts for the majority of the morbidity and mortality associated with CF. Impaired MCC prevents effective clearance of organisms from the lower airways thus predisposing these patients to ongoing pulmonary infections. About 60 -- 80% of CF patients become chronically infected with Pseudomonas aeruginosa -- the prototypical CF pathogen [50,51]. Chronic infection with P. aeruginosa and its conversion to the mucoid phenotype is associated with a progressive decline in lung function, increased risk of hospital admission and reduced survival [52-56]. The chronic management of P. aeruginosa is complicated by the fact that it is inherently resistant to many classes of antibiotics and quickly develops de novo resistance upon antimicrobial exposure [57]. While some groups are still administering chronic suppressive antipseudomonal therapies using scheduled routine parenteral antibiotics [58], inhaled antibiotics have become mainstay for maintenance therapy in patients with chronic P. aeruginosa infection. Nebulized antimicrobial therapies for the lung were first proposed over 70 years ago [59]. Advantages include the ability to have high concentrations of the drug in the lungs to maximize antimicrobial killing, while reducing systemic toxicities [60]. At present, tobramycin and aztreonam are the only inhaled antibiotics recommended by the CF Foundation guidelines to treat chronic P. aeruginosa infections in patients with CF [61]. Other inhaled antibiotics


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and/or novel delivery systems for existing antibiotics are needed, given the potential for development of de novo resistance and allergy in some patients as well as the need to minimize the treatment burden of CF patients to maximize compliance. However, there are significant challenges to the assessment of the safety and efficacy of these antimicrobials in clinical trials. These include: i) difficulty in finding patients not currently on inhaled antibiotics for chronic P. aeruginosa; ii) having patients not receive standard for care to participate in placebo-controlled trials; and iii) choosing appropriate outcome measures for the short periods of study. As a result of these challenges, antimicrobial studies are now moving toward comparative effectiveness studies, whereby the new therapy is being compared to standard of care. Inhaled antibiotics targeting P. aeruginosa in the CF patient which are currently under development include: i) tobramycin inhalation powder (TIP); ii) levofloxacin; iii) amikacin; iv) colistin; and v) fosfomycin/tobramycin combination. Tobramycin inhalation solution (TIS) is the most frequently prescribed inhaled antibiotic for chronic P. aeruginosa infection in CF patients worldwide. The safety and efficacy of TIS was first demonstrated > 20 years ago [62]. However, given the length of time required for nebulization, TIP was developed to replicate the pharmacodynamics of TIS and to reduce the time required for administration, with the aim of improving compliance. The Phase I trial was an open-label, single-dose sequential cohort escalation study involving 15 CF centers across the USA [63]. Inclusion criteria included clinically stable CF patients > 6 years of age, with an FEV1% predicted ‡ 40%, who were able to expectorate sputum [63]. A total of 90 patients were randomized into the five arms as follows: TIP 28 mg (2 14 mg capsules), TIP 56 mg (2 28 mg capsules), TIP 56 mg (4 14 mg capsules), TIP 112 mg (4 28 capsules) and TIS (300 mg). TIP dosed at 112 mg most closely replicated the pharmacodynamics of TIS. In clinical studies, TIP consistently achieved higher sputum concentrations than TIS: 1979 ± 2770 versus 1074 ± 1182 µg/g [64]. Additionally, after 3- to 28-day cycles of use, 86% of patients achieved peak sputum concentrations > 30 times than that of the MIC of their P. aeruginosa species [64]. The EVOLVE trial was a Phase III trial comparing TIP to placebo through 28-day on-and-off drug cycles; cycle one was double-blind, placebo-controlled and cycles two and three were open-label, crossover extensions where the placebo group received active therapy [65]. Inclusion criteria for the trial were age 6 -- 21 years and FEV1 between 25 and 80% predicted. The study was stopped after the first interim safety analysis conducted after the first 80 patients completed cycle one [65]. This population predominantly represented TIS treatment-naı¨ve patients with only 4% having been exposed to TIS in the preceding months [65]. The final analysis was further compounded by the exclusion of a further 18 patients from certain centers with inconsistent pulmonary function tests [65]. Therefore, the intention-to-treat analysis was based on 29 patients who received TIP versus 32 patients who 148

received placebo. The primary outcome was improvement in the relative change from baseline FEV1 at day 28. This was significantly greater in the TIP group with a treatment difference of 13.3% between groups (95% CI: 5.3 -- 21.3; p = 0.0016) [65]. The second Phase III trial, the Establish a New Gold Standard Efficacy and Safety with Tobramycin in Cystic Fibrosis (EAGER) study, was defined as a noninferiority study to assess 24 weeks of TIP (4 28 mg capsule) b.i.d. versus TIS (300 mg/5 ml) b.i.d. [64]. A total of 553 CF patients, chronically infected with P. aeruginosa, age ‡ 6 years with FEV1 25 -- 75% predicted were enrolled. This population was extensively pretreated with TIS [64]. The primary end point was the change in FEV1 from baseline in each group. The increases in FEV1% predicted during the treatment cycles were comparable during the three active cycles and the declines during the ‘off months’ were also similar [64]. Sputum P. aeruginosa density fell with each treatment cycle, mirroring previous data collected with TIS, with no decline in effect across the three cycles [64]. Neither the EVOLVE nor the EAGER trial demonstrated an emergence of nonpseudomonal CF pathogens during therapy; this had been previously well established using TIS [66]. TIP then underwent some minor improvements in the manufacturing process; the droplet size of the feedstock was reduced and the design of the powder collection hardware was changed to improve the stability, consistency and yield [67]. The EDIT study evaluated the efficacy and safety of TIP manufactured by an improved process in CF subjects aged 6 -- 21 years [67]. CF patients with FEV1 ‡ 25 -- £ 80% predicted positive P. aeruginosa cultures and inhaled antipseudomonal therapy-naı¨ve (or at least for the past 4 months) were eligible. Patients were randomized to TIP or placebo for one treatment cycle (28 days on drug, 28 days off drug). The primary end point was the relative change in FEV1% predicted from baseline to day 29. A total of 62 patients were randomized. Recruitment for this study was challenging as it was difficult to find patients who fulfilled the inclusion criteria, in particular chronic P. aeruginosa infection but not receiving inhaled antibiotics targeted against the P. aeruginosa for the past 4 months. The mean treatment differences (TIP-placebo) were 5.9% (p = 0.148) and 4.4% (p < 0.05) for relative and absolute change in FEV1% predicted, respectively [67]. However, the generalizability of these results comes into question because the inhaled antibiotic treatment is considered standard of care in CF patients with chronic P. aeruginosa infection and patients off standard therapy may, therefore, not be representative of an expected effect seen in patients treated in most CT centers. Inhaled levofloxacin is a synthetic fluoroquinolone which exerts its bactericidal effects by inhibiting bacterial topoisomerase IV and indirectly affecting bacterial multiplication [68]. The four Phase I studies demonstrated the safety, tolerability and dose-dependent pharmacokinetics of levofloxacin [69-72]. A Phase IIb randomized, placebo-controlled study




demonstrated a significant reduction in sputum P. aeruginosa and improvement in lung function as compared to placebo [73]. The significant improvement in FEV1 was maintained by day 42 in the 240 mg b.i.d. group but returned to baseline by day 56. A second Phase II trial was completed in chronic obstructive pulmonary disease patients [74]. These results were less impressive than in the CF population and a reduction in exacerbation rate or time until the next exacerbation was not observed [74]. Two Phase III clinical trials have been completed. The first study compared the safety and efficacy of levofloxacin 240 mg b.i.d. versus placebo [75]. There was no significant difference between the two groups with respect to time to next pulmonary exacerbation, the primary outcome. However, the primary outcome was assessed over a relatively short period of time which may have contributed to a lack of treatment effect, and significant improvements in lung function were seen in treated patients. The second Phase III trial demonstrated that inhaled levofloxacin was not inferior to TIS. The primary end points were change in quality of life and reduction in bacterial load [76]. Amikacin is encapsulated in neutral liposomes composed of dipalmitoylphosphatidylcholine and cholesterol and delivered using a eFlow nebulizer system [77]. Upon inhalation, amikacin liposomes are able to penetrate P. aeruginosa biofilms at the site of infection, are lysed by local P. aeruginosa-derived products (targeted drug delivery) and have a prolonged lung half-life relative to liposome-free antibiotics because the liposomal preparation permits the slow, sustained release of amikacin [78,79]. This formulation reduces P. aeruginosa density in animal models, and studies in human subjects support once-daily (OD) dosing [80,81]. The preclinical studies for inhaled liposomal amikacin development provided safety and efficacy data for dosing up to 560 mg OD [82]. The Phase II program consisted of two parallel studies which were conducted in Europe (13 sites) and the USA (19 sites) [82]. The studies were randomized, double-blind and placebo-controlled. In Europe, subjects were randomized to liposomal amikacin (280 or 560 mg OD) or placebo or 28 days, followed by 28 days off of study drug. Patients in the USA were randomized to liposomal amikacin (70 or 140 mg OD initially and then the dose was increased to 560 mg) or placebo for 28 days with observation until day 56 [82]. Pooled analyses of common end points between the two studies were established a priori and included safety, adverse events, lung function, quality of life, microbiology and pharmacokinetic data [82]. Overall, liposomal amikacin was well tolerated and was a safe drug within the study period. FEV1 significantly improved in the 280 and 560 mg amikacin groups as compared to placebo at day 28; a sustained benefit of amikacin on FEV1 at day 56 was only seen at the 560 mg dose. The most striking effect on P. aeruginosa sputum density was seen at the 560 mg dose and these effects were seen at day 28 as well as at day 35 follow up. A subset of patients in the European trial were continued in an open-label

extension of the study to evaluate six repeat cycles of the 560 mg dose of amikacin (28 days on followed by 56 days off for a total of six cycles) [82]. FEV1 significantly increased by 7.9% (p < 0.0001) from baseline to the end of the 28-day treatment course as compared to placebo with each cycle. Interestingly, there was also a mean increase in FEV1 of 5.7% from baseline to the end of day 84 (56 days post treatment) across all cycles [82]. These prolonged benefits from an inhaled antibiotic are exciting and had not been previously demonstrated. There were no differences in audiologic or renal safety which is highly important for the development of chronic nebulized aminoglycosides [82]. Further, the OD dosing makes this inhaled therapeutic attractive for the CF population. The Phase III trial comparing the effectiveness, safety and tolerability of liposomal amikacin with TIS has recently been completed [83]. Enrolled patients were randomized to receive amikacin 560 mg OD or TIS 300 mg b.i.d. for 3 cycles (28 days on, 28 days off). The primary end point was the change in FEV1 from baseline to the end of the study. Amikacin was shown to be noninferior to TIS; however, the increases in lung function seen in the TIS group exceeded those previously reported in other trials [64,84]. Furthermore, the sustained benefits of amikacin on lung function during offtreatment months seen in the Phase II trials was not observed in the Phase III trial. Therefore, although a clear advantage of the liposomal formulation has not been established at present, the OD dosing may improve adherence in CF patients. Although, colistin inhalation solution is not recommended at present in the American CF guidelines for the management of chronic P. aeruginosa infection in CF patients, colistin is still utilized in many European countries. However, nebulization with standard nebulizers takes about 20 min which may have a negative effect on patients’ adherence [61,85-87]. Therefore, colistin which uses micronized colistimethate sodium administered via a handheld inhaler was developed to increase patient convenience, which may improve treatment adherence and clinical outcomes. The Freedom Study, a Phase III trial, was designed to investigate the safety and efficacy of colistin (125 mg b.i.d.) compared to TIS (300 mg/5 ml b.i.d.) for patients ‡ 6 years of age with chronic P. aeruginosa pulmonary infection for 24 weeks with 3 cycles of therapy [84]. A total of 380 patients were randomized. The adjusted mean difference between treatment groups (colistin vs TIS) in change in forced expiratory volume in 1 s (FEV1% predicted) at week 24 was 0.98% (95% CI: -2.74 -- 0.86%) in the intentionto-treat population (n = 373) and -0.56% (95% CI: -2.71 -- 1.70%) in the per protocol population (n = 261) consistent with the noninferiority of colistin as compared to TIS [84]. Therefore, although colistin was shown to be not inferior to TIS, a significant clinical improvement in FEV1 was not apparent with colistin [84]. Although this study has resulted in EMA approval of the drug, further evidence for the efficacy of colistin is needed to support its use as a treatment option for chronic P. aeruginosa infection.


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Fosfomycin/tobramycin for inhalation (FTI) is a novel, broad-spectrum inhalational antibiotic combination with therapeutic potential for patients with CF given its Grampositive and Gram-negative coverage. A recent Phase II trial evaluated the safety and efficacy of FTI (160/40 or 80/20 mg), administered b.i.d. for 28 days versus placebo, in patients ‡ 18 years of age, with CF, chronic P. aeruginosa airway infection and FEV1 ‡ 25% and £ 75% predicted [88]. The study participants received FTI or placebo after a 28-day, open-label, run-in course of aztreonam for inhalation. FTI maintained the substantial improvements in FEV1% predicted (7.5% treatment difference, p < 0.001) achieved during the aztreonam run-in and was well tolerated [88]. Lung function in the placebo group decreased toward pretreatment levels. Continuous alternating antibiotics is an appealing treatment option for chronic P. aeruginosa infection; the study design used for FTI could be a promising approach to evaluate such a strategy [88]. Other anti-P. aeruginosa therapies The type III secretion system is one of the factors responsible for the increased virulence and proinflammatory effects of P. aeruginosa [89]. KB001-A is a PEGylated, recombinant, anti-Pseudomonas-PcrV antibody Fab’ fragment that blocks the function of the type III secretion [89]. The pharmacodynamic properties of KB001-A in CF subjects with chronic P. aeruginosa infection have been studied in a recently completed Phase I trial. A total of 27 CF subjects (‡ 12 years of age, FEV1 ‡ 40% of predicted and sputum P. aeruginosa density > 105 CFU/g) received a single intravenous dose of KB001-A (3 or 10 mg/kg) or placebo. There were no significant differences between KB001-A and placebo for changes in P. aeruginosa density, symptoms or spirometry after a single dose. However, compared to baseline, at day 28, there was a trend toward a dose-dependent reduction in sputum myeloperoxidase, IL-1 and IL-8, and there were significant overall differences in change in sputum neutrophil elastase and neutrophil counts favoring the KB001-A 10 mg/kg group versus placebo. These results support targeting P. aeruginosa with KB001-A as an antibiotic adjuvant strategy to reduce airway inflammation and damage in CF patients with chronic P. aeruginosa infection but further study is needed [89]. 5.4.2

Chronic MRSA infection MRSA has become an emerging pathogen in CF patients with rates up to 40% in CF clinics in the USA. Chronic MRSA infection has been described to be associated with increased lung function decline and higher mortality [90,91]. Savera is currently conducting a Phase IIa, randomized, multicenter, double-blind, placebo-controlled, parallel group study to examine the safety and efficacy of vancomycin hydrochloride inhalation powder in the treatment of persistent MRSA lung infection in CF [92]. The study is planned to recruit 80 subjects from over 25 centers throughout the USA. Eligibility criteria include a diagnosis of CF, ‡ age 12 years, respiratory culture 5.4.3

150

positive for persistent MRSA which is also suspected to be causing health consequences. Prior to treatment, patients will be randomized to receive either inhaled vancomycin b.i.d. or placebo b.i.d. Patients will be stratified based on the presence or absence of sputum culture positivity for P. aeruginosa. The vancomycin or placebo treatment duration is 28 days, during which efficacy and safety parameters will be measured, and after which patients will be followed up for 56 days. There will be two treatment cohorts. Cohort 1 patients will be randomized to receive the 32 mg b.i.d. dose of vancomycin versus placebo b.i.d. The dose for cohort 2 (16, 32 or 64 mg b.i.d.) will be determined based on the Data Monitoring Committee’s evaluation of cohort 1. Anti-inflammatory therapy Neutrophilic inflammation plays a key role in the pathogenesis and progression of CF lung disease [93]. Neutrophilic inflammation leads to the formation of toxic oxygen free radicals and free elastase; their persistence leads to pulmonary destruction [94]. Neutrophil elastase is a potent serine protease secreted by neutrophils and is thought to be the most important protease which damages the CF lung; it upregulates IL-8, neutrophil chemoattractants and other proteases [95]. Increased neutrophil elastase release is also a risk factor for P. aeruginosa lung infection due to rendering neutrophils less efficient at killing bacteria [95]. 5.5

a1-antitrypsin a1-antitrypsin (AAT) is the main inhibitor of neutrophil elastase in the lung, therefore leading for this compound to be studied in CF patients. Patients with CF have been shown to have normal serum and lung absolute AAT levels; however, lung AAT is inactivated by proteolytic cleavage [95]. In vitro CF sputum demonstrates reduced neutrophil elastase activity, when treated with AAT [95]. Five separate clinical studies and two Phase II trials have explored the safety and efficacy of different preparations of inhaled AAT in CF patients [96-102]. The Phase II trial randomized (2:1) 21 patients to 80 mg of AAT or placebo OD. All patients completed the study without adverse effects [102]. A second Phase II trial, randomized patients to receive nebulized treatment once a day for 4 weeks, followed by 2 -- 4 weeks with no study treatment, and then a 2-week rechallenge phase. Trends toward a reduction in neutrophil elastase activity were observed in patients treated with 500 and 250 mg of AAT compared to placebo [99]. This study demonstrated that nebulized AAT is safe and well tolerated but has limited effect on neutrophil elastase (NE) activity and other markers of inflammation at the doses studied in patients with moderate-to-severe lung disease [99]. Neutrophil burden is high in patients with advanced disease; thus, the question arises as to whether patients with milder lung disease would be more likely to benefit from therapy. At present, a dry powder inhalation of AAT is in Phase II trial [103]. If the results are promising, this will hopefully proceed to a Phase III trial that can clarify the efficacy of this potentially 5.5.1



relevant treatment addressing an aspect of CF lung disease that is currently not addressed by any of the available medications.


6.

Conclusion

Pulmonary therapeutics has traditionally been focused on symptomatic management of the existing pulmonary disease. However, the past few decades in CF therapeutics has seen a paradigm shift with a new focus on gene therapy, CFTR pharmacotherapy and ASL strategies. The advances in the field of CF in the past few decades have been exciting, especially with the release of ivacaftor last year which modifies sweat chloride results, thus providing evidence for a direct effect on CFTR activity. The future for CF pulmonary therapeutics is bright and with the promising advances in CFTR pharmacotherapy and gene therapy, a cure could be just around the corner. 7.

Expert opinion

High-throughput screening for compounds that can potentially benefit patients with CF continues to be essential for maintaining momentum in the CF therapeutic pipeline. The pipeline currently holds great promise both for novel therapies directly targeting the underlying biological mechanisms of CFTR dysfunction as well as new symptomatic therapies. Traditionally, symptomatic therapies such as antibiotics, antiinflammatory agents and mucolytics have been the mainstay of CF pulmonary treatment and have contributed to significant improvements in survival in the past few decades. Novel inhaled antibiotics for chronic bacterial suppression are promising for increasing the number of antibiotics options because of concerns with bacterial resistance and because novel delivery systems provide an opportunity for decreasing the treatment burden and improve compliance. Recent developments have shifted the focus to higher up on the CF pathophysiology cascade. CFTR pharmacotherapeutics, led by ivacaftor, has

generated great excitement in the CF community in the hope that progression of CF lung disease can be halted. While a Phase IIb gene therapy study is currently underway, effective gene therapy for CF appears to be years away. Preliminary results of clinical studies of the new CFTR modulators suggest that combination therapy may be needed to improve clinical outcomes. It appears that both combinations of novel biological compounds (i.e., CFTR potentiators and correctors) as well as newer compounds for conventional therapies (i.e., inhaled antibiotics from chronic bacterial suppression) may have the potential to help slow the decline of lung function, decrease pulmonary exacerbations and improve quality of life. Therefore, symptomatic treatments will likely remain a cornerstone of CF pulmonary treatment, where as CFTR biological compounds continue to be developed. In the CF pipeline, based on the success of ivacaftor, CFTR pharmacotherapeutics seem to hold the greatest promise at present of all compounds in the pipeline. However, an important consideration in the development of these compounds is the choice of appropriate outcome measures. With the paradigm shift toward interventions targeting younger children with CF with milder disease, ensuring adequate sensitivity, validation and clinical relevance of up and coming biomarkers is essential for future clinical trials and highly needed to further advance CF care. Finding an outcome measure that is sufficiently sensitive to detect therapeutic changes in mild patients is a significant hurdle the CF clinician-researchers must overcome.

Declaration of interest R Amin states no conflict of interest. F Ratjen has acted as a consultant for Vertex, Novartis, Bayer, Talecris, CSL Behring, Roche, Gilead, Aptalis and Insmed on CF-related activities. He is the principle investigator for a grant pending from Novartis. He has given a talk with travel expenses sponsored by Pari.


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Affiliation

Reshma Amin†1 MD MSc & Felix Ratjen2 MD PhD † Author for correspondence 1 Staff Physician, University of Toronto, The Hospital for Sick Children, Division of Respiratory Medicine, Department of Pediatrics, Physiology and Experimental Medicine, 555 University Avenue, Toronto, ON, M5G 1X8, Canada Tel: +416 813 6346; Fax: +416 813 6246; E-mail: [email protected] 2 Division Head, University of Toronto,The Hospital for Sick Children, Division of Respiratory Medicine, Department of Pediatrics, Physiology and Experimental Medicine, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

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Emerging cystic fibrosis pathogens and the microbiome.

The microbiome and emerging pathogens in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Update on key emerging challenges in cystic fibrosis.

Cystic Fibrosis and Its Management Through Established and Emerging Therapies.

Cystic Fibrosis: Breakthrough Drugs at Break-the-Bank Prices.

Screening for cystic fibrosis.

Screening for cystic fibrosis.

Predicting CFTR activity with front-runner cystic fibrosis drugs.

Screening for cystic fibrosis.

Emerging drugs for acromegaly.

Emerging drugs for osteoporosis.

Cystic fibrosis and non-cystic fibrosis bronchiectasis.

Current and Emerging Therapies for the Treatment of Cystic Fibrosis or Mitigation of Its Symptoms.

Population screening for cystic fibrosis.

Lung transplantation for cystic fibrosis.

Screening for cystic fibrosis carriers.

Life tables for cystic fibrosis.

Screening for cystic fibrosis carriers.

Prenatal screening for cystic fibrosis.

New treatments for cystic fibrosis.

Carrier screening for cystic fibrosis.

Lung Transplantation for Cystic Fibrosis.

Inhaled corticosteroids for cystic fibrosis.

Letter: Screening for cystic fibrosis.