Challenges in the development of new therapies for bronchiectasis.

Review

Challenges in the development of new therapies for bronchiectasis

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Kainan University on 04/03/15 For personal use only.

James D Chalmers†, Michael Loebinger & Stefano Aliberti †

1.

Introduction

2.

Bronchiectasis clinical trials

3.

Successful Phase II trials

4.

Macrolides

5.

Anti-inflammatories

6.

Mucoactive therapies

7.

Challenges to drug development in bronchiectasis -- which populations and outcomes to use?

8.

Clinical trial end points

9.

Possible new end points

10.

Expert opinion

University of Dundee and Ninewells Hospital and Medical School, Tayside Respiratory Research Group, Dundee, UK

Introduction: Bronchiectasis is a neglected condition for which there are no licensed therapies. Increasing recognition of the disease has led to a surge in interest over recent years, with a number of active drug development programmes. Areas covered: Disappointing results with therapies successful in cystic fibrosis (CF) have forced a re-evaluation of how we develop new treatments for bronchiectasis. Bronchiectasis presents a unique array of challenges. These include a heterogeneous and poorly characterized patient population, a lack of agreed standards of care and a lack of understanding of the natural history. Pre-clinical development is limited by the lack of an adequate animal model of disease, and by our limited understanding of pathogenesis. There is no agreement on how to define key clinical trials end points including exacerbations and quality of life. The difficulty in translating positive Phase II data into successful Phase III trials suggests the need for better early phase trial end points. Expert opinion: Extrapolating from CF and chronic obstructive pulmonary disease has been a necessity but now risks holding back development if we do not recognize the unique challenges in bronchiectasis. This article comprehensively reviews the barriers to new drug development for bronchiectasis. Keywords: antibiotics, bronchiectasis, clinical trials, Pseudomonas Expert Opin. Pharmacother. (2015) 16(6):833-850

1.

Introduction

There are no therapies approved by regulatory authorities in Europe or the USA for the treatment of non-cystic fibrosis (CF) bronchiectasis (hereafter referred to as bronchiectasis). A historic lack of research and drug development has led to bronchiectasis being described as an ‘orphan’ or ‘Cinderella’ condition for many years. Improvements in diagnosis and recognition, however, have led to an increased interest in the disease and a number of academic and industry programmes are now seeking to develop new therapies [1]. These include new oral and inhaled antibiotics, anti-inflammatory drugs, mucoactive therapies and targeted anti-pseudomonal compounds [1]. The incidence of bronchiectasis is increasing with data from the US Medicare outpatient claims database (2000 -- 2007) showing an increase in claims of 8.7% per year [2]. In Europe, a study of 125 million hospitalizations in Germany (2005 -- 2011) reported a 39% increase in admissions for bronchiectasis as a primary diagnosis [3]. Bronchiectasis is increasingly recognized in association with chronic obstructive pulmonary disease (COPD), which is likely to further increase its reported incidence [4]. New therapeutic development in bronchiectasis is critical given this increasing burden, high economic impact and the impact on patients [5]. Patients experience exacerbations with an average frequency ranging from 1.5 to 6 per year [6-8]. 10.1517/14656566.2015.1019863 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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J. D. Chalmers et al.

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Article highlights. . .

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Bronchiectasis patients urgently need new therapies to reduce exacerbations and improve quality of life. A series of ‘negative’ clinical trials have forced a re-evaluation of how we develop treatments for this disease. In this article, the authors review recent clinical trials in bronchiectasis and identify the key challenges in conducting trials in this population. Key recommendations for future success in bronchiectasis trials include reducing the heterogeneity of populations, stratifying disease severity, careful definition of trial end points and realistic estimates of statistical power and feasibility. The development of international registry initiatives and development programmes for early phase clinical trials end points are needed.

Bronchiectasis clinical trials

Inhaled antibiotics Chronic bacterial infection is a feature of bronchiectasis and inhaled antibiotics are targeted towards the suppression of chronic infection. They are well established in the management of CF, where tobramycin, tobramycin dry powder, aztreonam, colistimethate sodium and the dry powder ‘Colobreathe’ are all licensed for treatment in the USA or Europe having demonstrated efficacy in randomized controlled trials [21]. Given certain similarities in the clinical characteristics of patients with bronchiectasis and CF, and the important of Pseudomonas aeruginosa in both, it seemed logical to evaluate these therapies in bronchiectasis not due to CF. The results have been mixed and largely unsuccessful to date. 2.1

This box summarizes key points contained in the article.

b-Lactams Small open-label studies of inhaled b-lactams in the 1980s demonstrated reductions in sputum purulence, reduced sputum volume and reductions in airway inflammation [22]. Treatments were well tolerated, but did not progress to large-scale placebo-controlled trials. 2.2

In specialist care populations in Europe, 20 -- 40% of patients will be hospitalized for severe exacerbations over 2-year follow-up [8]. Quality of life (QoL) is greatly impaired, with reported scores on the St. Georges Respiratory Questionnaire (SGRQ) of 39 -- 48 [9-12], which is equivalent to levels of QoL impairment seen in severe asthma, severe COPD or idiopathic pulmonary fibrosis [13-16]. Mortality in specialist care populations is high. A cohort enrolled at the Royal Brompton Hospital in 1994 was followed-up for 14 years after which 29.7% of patients had died [17]. This was more than double the expected mortality rate based on the UK life expectancy data [17]. Short-term studies in the UK and Belgium found mortality rates of 10.2--16.6% over 4 years [6,8]. Approximately 50% of deaths were related to respiratory disease directly, with cardiovascular disease as the second most frequent cause [6,8,17]. Roberts and Hubbard showed that in the UK, bronchiectasis deaths increased by 3% per year [18]. The development of new therapies follows our understanding of the pathophysiology of bronchiectasis based on Cole’s vicious cycle hypothesis [19]. The majority of therapies are therefore targeted at control of bronchial infection, neutrophilic inflammation or impaired mucociliary clearance (Figure 1). Unfortunately, a series of clinical trials of antibiotics, antiinflammatories and mucolytic therapies have given disappointing or unexpected results [20]. These have included a number of therapies previously successful in clinical trials in CF, including recombinant DNase, tobramycin, aztreonam and inhaled mannitol. This article reviews the key data on therapeutic development in bronchiectasis and considers some of the possible reasons why trials have proven so challenging. Finally, we review current and future initiatives that are needed to address these challenges. 834

Tobramycin A Phase II multicenter trial conducted at 16 sites in the USA evaluated tobramycin solution for inhalation in bronchiectasis [23]. Thirty-seven patients were randomized to tobramycin and 37 patients received placebo. Microbiological efficacy was demonstrated with a 4.54 log10 cfu/g reduction in P. aeruginosa in the active treatment group and no significant change in the placebo group. Thirteen patients in the treatment group had complete eradication of P. aeruginosa. This correlated with some subjective clinical improvement over the 4-week treatment period. There were no significant changes in lung function [23]. These apparently encouraging results were tempered by a significant increase in adverse events including dyspnea (32 vs 8%; p = 0.01), chest pain (19 vs 0%; p = 0.01) and wheezing (16 vs 0%; p = 0.01). There was also an increase in antibiotic-resistant pathogens in the tobramycin-treated group with 11% of isolates in the tobramycin group exceeding the ‘resistant’ minimum inhibitory concentration breakpoint [23]. Drobnic et al. evaluated 300 mg inhaled tobramycin versus placebo in a 6-month randomized crossover study including 30 patients with P. aeruginosa infection [24]. Tobramycin reduced sputum bacterial load and the number of hospital admissions but did not reduce exacerbations or improve QoL. Bronchospasm was reported in 10% [24]. A shorter open-label study by Scheinberg and Shore using 3 14-day treatment cycles similarly showed microbiological efficacy and some clinical benefits but showed more intolerance with 22% stopping treatment due to respiratory symptoms [25]. Possibly as a result of the tolerance issues, tobramycin has not progressed to Phase III studies. 2.3

Expert Opin. Pharmacother. (2015) 16(6)


Tobramycin Aztreonam Colistin Ciprofloxacin*

Amikacin Specific anti-pseudomonals Gentamicin Macrolides‡


Bacterial colonisation

Impaired mucociliary clearance

Airway inflammation

Inhaled mannitol Hypertonic saline rDNase N-acetylcysteine

CXCR2 antagonists Neutrophil elastase inhibitors PDE4 inhibitors Inhaled corticosteroids Statins

Figure 1. Therapies for bronchiectasis subject to randomized controlled trials (identified through a review of registered trials on Clinicaltrials.gov) according to the vicious cycle hypothesis. *Dual release (liposomal) and dry power formulations are currently under evaluation in independent trial programmes. z Macrolides are included as anti-infectives but have also been shown in in vitro studies to have effects on airway inflammation and mucociliary clearance. PDE: Protocol-defined exacerbation.

2.4

Colistin

The first Phase III study of an inhaled antibiotic to be published in bronchiectasis was a randomized trial of colistin delivered via the i-neb device in 144 patients with bronchiectasis [26]. This was a 6-month study with a primary outcome of the time to next exacerbation. The study was powered to detect a 75% difference in median time to next exacerbation assuming a median time in the placebo group of 60 days. Unfortunately, the trial narrowly failed to meet its primary end point, with a difference in time to next exacerbation of 165 days in the colistin group compared with 111 days in the placebo group (p = 0.11). The almost doubling of the expected time to next exacerbation in the placebo group resulted in the trial being underpowered. The i-neb device records patient compliance with treatment, and in a preplanned sub-analysis the authors were able to demonstrate an improved time to next exacerbation in compliant patients [26]. There was also a dramatic improvement in QoL, with an improvement in the SGRQ score of --10.5 points at 26 weeks (4 points is clinically significant). Therefore, this trial suggests a treatment that is effective and greatly improved QoL in patients with bronchiectasis and P. aeruginosa, but which failed to reach its primary end point perhaps partly because it was underpowered [26]. The trial also had difficulties with recruitment which has been a feature of bronchiectasis trials to date, requiring an extension of the completion date by over 12 months and extension of the study to Ukraine and the Russian Federation. The original

recruitment target of the study was 260, which had to be greatly revised in light of the recruitment problems [27]. Aztreonam This study was followed by the publication of another unsuccessful Phase III inhaled antibiotic programme in bronchiectasis. Inhaled aztreonam when used in CF has been shown to reduce P. aeruginosa density, improve forced expiratory volume in 1 s (FEV1) and to reduce exacerbations [28]. Aztreonam was studied in two identical double-blind placebocontrolled trials, testing the effectiveness of two 28-day courses compared with placebo [28]. The primary outcome was the newly developed QoL-Bronchiectasis (QoL-B) questionnaire. The study revealed again the difficulties among some bronchiectasis patients in tolerating inhaled antibiotics. Twenty-two percent (29 out of 134) discontinued treatment because of intolerance in the first study (AIR-BX1) compared with 3% (4 out of 132) in the placebo group. Tolerance was better in the second study (AIR-BX2), but still 8% (11 of 135) patients discontinued aztreonam as compared with 3% (4 out of 137) in the placebo group [29]. The primary symptoms causing withdrawal were worsening of respiratory symptoms such as dyspnea and cough, similar to the effects observed in the tobramycin trial [23]. The primary outcome was not met, with no improvement in QoL at either 4 or 12 weeks in AIR-BX1, and a statistically significant improvement at 4 weeks in AIR-BX2 (difference 4.6 points, p = 0.011), which did not reach the minimally important 2.5


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difference of the QoL-B, reported to be 8 points [29]. There was no difference at 12 weeks (difference 1.1, p = 0.56). The study had little power to detect a difference in exacerbations as the population had a relatively low rate of exacerbations prior to the study. Nevertheless, the data did not support an effect on exacerbations, with 38/134 patients (28%) having a protocol-defined exacerbation in the aztreonam group versus 35/132 patients (27%) in the placebo group in AIR-BX1, with 43/136 patients (32%) in the aztreonam group and 38/138 patients (28%) in the placebo group having exacerbations in AIR-BX2 [29]. The authors conducted extensive sub-group analyses according to severity of disease, co-morbidities and concomitant medications but could not identify a clear responder population. This was a disappointingly negative study for bronchiectasis, although in hindsight it is likely that changes to the choice of end point and study design may have been made. This was the first study to use the QoL-B as a primary end point. The patient population included a heterogenous group of patients including those with a history of COPD and non-tuberculosis mycobacterial. The majority of patients had P. aeruginosa but ~ 20% of patients in both studies were colonized with other Gram-negative pathogens and these patients had a numerically, but not significantly, poorer response to treatment in terms of QoL. It is also intriguing that the greatest intolerance and poorer response was observed in AIR-BX1, which was conducted predominantly in the USA, while results were more favorable in AIR-BX2, where 55% were recruited in Europe. There were major differences between the USA and Europe in terms of the etiology of bronchiectasis, the structure of healthcare systems, concomitant medications, physiotherapy practices and experience with inhaled antibiotic therapies. None of these can be clearly linked to the differences observed in this trial. 3.

Successful Phase II trials

These difficulties in Phase III contrast with several successful Phase II trials of inhaled antibiotics in bronchiectasis. Inhaled gentamicin 80 mg twice daily (n = 27) was compared with 0.9% saline (n = 30) in a single-blind randomized controlled trial over 12 months [29]. At 12 months, the primary outcome of a reduction in bacterial load was achieved (mean difference 4.7 log10cfu/ml), and this was associated with an improvement in QoL (SGRQ), cough symptoms, exercise capacity and reduced exacerbations. Lung function did not change; 30.8% of patients with P. aeruginosa at baseline did not have this organism in sputum at 12 months [30]; 21.9% of patients experienced bronchospasm with gentamicin and 2 patients had to withdraw, but it was generally better tolerated than reported with tobramycin or later with aztreonam [30]. Two preparations of inhaled ciprofloxacin have also been tested in Phase II double-blind placebo-controlled studies. Dry powder ciprofloxacin for 28 days (n = 60 receiving ciprofloxacin dry powder inhaler and 64 receiving placebo) resulted 836

in a significant reduction in bacterial load, with no significant difference in adverse events between the two groups [31]. Clinical benefits were not evident, but were not expected in a short-term study. Nebulized dual release liposomal ciprofloxacin tested over three 28-day treatment cycles similarly reduced bacterial load (n = 20 ciprofloxacin, n = 22 placebo), and even showed a reduction in time to next exacerbation in the per-protocol population (134 vs 58 days; p = 0.046) [32]. Again, this preparation was well tolerated in this small study. Both ciprofloxacin preparations are currently the subject of Phase III studies. To date, there have been no larger studies of gentamicin. There have so far been no large trials of inhaled antibiotics in the context of P. aeruginosa eradication or treatment of exacerbations, which are also key unmet needs in this area. An international multicenter study including 53 patients failed to show a clinical benefit of adding inhaled tobramycin to ciprofloxacin treatment for exacerbations [33]. 4.

Macrolides

The major success story in clinical trials in bronchiectasis has been with oral macrolide therapy. Three small but conclusive clinical trials reported in 2012/2013 showing that continuous treatment with macrolides for 6 -- 12 months was associated with reduced exacerbations [34-37]. The EMBRACE trial, conducted in New Zealand randomized 71 patients to azithromycin 500 mg three times per week or placebo for 6 months. The treatment resulted in a significant reduction in exacerbations (mean per patient per year 1.54 vs 2.54, p < 0.001) and the treatment was well tolerated [34]. These results were replicated in the Bronchiectasis Azithromycin Trial (BAT), conducted in the Netherlands, which randomized 43 patients to azithromycin 250 mg once daily and 40 patients to placebo. This study observed a difference in exacerbations favoring azithromycin of 0.91 versus 1.95 (p < 0.001). There was also a large improvement in QoL (the SGRQ reduced by --12.2 in the azithromycin group). There were more tolerability issues in this study with diarrhea occurring in 21% and abdominal pain in 19%. Other side effects were similar in frequency between the azithromycin and placebo groups [35]. Alongside these two studies of azithromycin, Serisier et al. performed the Bronchiectasis and Low Dose Erythromycin Study (BLESS) trial randomizing 59 patients to erythromycin ethylsuccinate 400 mg twice daily and 58 patients to placebo in a double-blind study [36]. Again, in this study, the macrolide group had a lower frequency of exacerbations after 12 months (mean 1.27 vs 1.97; p < 0.05). Figure 2 shows the impact on exacerbations in each of these trials [34-36]. Several meta-analyses of these trials have subsequently been published demonstrating a pooled effect of macrolides that is equivalent to preventing 1 exacerbation per patient per year


Azithromycin group Placebo group

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Log-rank p < 0.001

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Number of exacerbations Azithromycin group Placebo group

Number at risk Azithromycin group Placebo group

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Figure 2. (A) The EMBRACE trial, Kaplain--Meier analysis of time to event-based exacerbations -- shaded area indicates 95% confidence intervals. (B) BAT trial Kaplain--Meier curves demonstrating proportion of patients free from exacerbations. (C) BLESS trial, cumulative incidence of protocol-defined exacerbations. In this case, each dot represents an exacerbation and patients could account for more than one exacerbation.PDPE: Protocol-defined pulmonary exacerbation. Reproduced with permission from [39]. Expert Opin. Pharmacother. (2015) 16(6)

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(95% CI: 0.67 -- 1.35), with a clinically significance reduction in the SGRQ total score compared with placebo of --5.39 (95% CI: --0.88 to --9.89) [37]. It is hard to answer why these trials were so successful given the difficulties of other agents. A reasonable explanation is that macrolides are simply a very effective therapy and this overcomes any possible difficulties in study design. Other key factors in the authors’ opinion may be that these small studies could be conducted in single countries with the same healthcare system and high standard of care. Oral therapies may be better complied with than inhaled therapies [38]. Nevertheless, even these trials highlighted some surprising challenges. The placebo groups each showed large reductions in expected exacerbation frequency from baseline to end of study. In the EMBRACE trial, this reduced from a mean of 3.93 per patient per year to 2.54 per patient per year [34]. In the BAT trial, the placebo group’s exacerbation frequency reduced from a median of 4 to a mean of only 1.95 during the study, despite treatment only with placebo [35]. The mean pre-trial exacerbation frequency in the BLESS trial was 4.98, reducing to 1.97 following the trial [36]. This is a remarkable reduction in exacerbations without intervention. It is a reflection of the large benefit associated with macrolides that the studies still achieved their end point, but such behavior in the placebo groups makes powering future studies extremely difficult. For macrolides, the optimal patients to benefit from the treatment are unclear, as none of the trials was large enough to identify the best ‘responder’ population [39]. Patients with P. aeruginosa had the highest frequency of exacerbations in BLESS, and therefore had the greater reduction in exacerbations after treatment [36]. The trials were also not large enough or long enough to conclusively reassure regarding the potential adverse effects of macrolides including hearing loss, antimicrobial resistance and cardiovascular toxicity [39-41]. The optimal dose and agent is unclear and there remains uncertainty over how long to continue macrolides. 5.

Anti-inflammatories

Anti-inflammatory drugs do not yet have an established place in bronchiectasis management. Inhaled corticosteroids are widely used, probably as a result of extrapolating their benefits in COPD and asthma. Some small studies suggest that highdose inhaled steroids can reduce 24 h sputum volume and improve QoL; however, there are no large randomized studies [41,42]. Safety issues identified in COPD, such as the risk of pneumonia, or non-tuberculous mycobacterial infection need to be taken seriously in bronchiectasis [43,44]. These considerations led the British Thoracic Society to advise against the routine use of inhaled steroids in bronchiectasis while awaiting further evidence [45]. Experimental anti-inflammatory therapies focus on reducing either the number of neutrophils transmigrating into the airway, or limiting neutrophil-induced damage [46]. 838

Neutrophil elastase has been linked with the pathogenesis and progression of bronchiectasis for decades, and recently trials of oral neutrophil elastase inhibitors have completed [12]. These suggest the ability to inhibit neutrophil elastase in vivo and improve FEV1 but have not yet been powered to show convincing clinical benefit. A recent study of a CXCR2 antagonist, which reduces neutrophil recruitment to the airway, has reported in abstract form. This agent reduced neutrophil counts by 69% compared with placebo, but this was associated with surprising increase in airway inflammation also with an increase in adverse effects, including cases of pneumonia [47]. Neutrophils are essential to control bacterial infection, and reducing neutrophil numbers could theoretically lead to uncontrolled bacterial infection. Previous anti-inflammatory trials in other neutrophilic airway diseases have demonstrated this, such as a trial of a leukotriene B4 receptor antagonist in CF [48,49] and a study of TNF-a antagonism in COPD [50], which also led to an increase in pneumonia. These fascinating findings, if replicated in other studies may indicate that the concept of reducing neutrophil recruitment is the wrong approach in bronchiectasis. A lack of fundamental understanding of how neutrophilic inflammation contributes to outcomes in bronchiectasis makes designing appropriate anti-inflammatory drugs challenging. It is notable that no exclusively anti-inflammatory drugs are in regular use for CF. 6.

Mucoactive therapies

Inhaled dry powder mannitol has been shown to improve mucous clearance and improve FEV1 in patients with CF [51,52]. Mannitol draws fluid into the airway lumen across an osmotic gradient, therefore, changing the physicochemical properties of mucus and making it easier to clear. This drug therefore appeared an excellent candidate for translation into bronchiectasis, but has found difficulty in achieving trial end points. In a Phase III double-blind placebo-controlled study comparing mannitol (320 mg twice daily) against placebo for 12 weeks, the primary outcomes were absolute change in wet sputum weight and change in SGRQ score from baseline [53]. The study inclusion criteria were broad and the study was large, requiring age 15 -- 80 years, FEV1 ‡ 50% predicted (and ‡ 1 l), clinically stable and chronic sputum production > 10 ml/day on the majority of days. All etiologies were accepted with the exception of severe asthma. Two hundred and forty-one patients were randomized to mannitol and 121 to placebo [53]. The results were mixed. There was a significant difference at 12 weeks in sputum weight, but surprisingly the mannitol group sputum weight remained stable while the placebo group sputum weight fell, possibly due to increased antibiotic use in the placebo group. The SGRQ score at 12 weeks improved in both groups with no statistically significant difference between them. A further study was therefore designed focusing specifically on exacerbations [53].




This follow-up 52-week Phase III study randomized 233 patients to 400 mg inhaled mannitol twice daily or placebo [52]. Patients were required to have two or more exacerbations in the previous 12 months, impaired QoL and sputum production. The trial again failed to meet its end point. The primary outcome of exacerbation rate was not significantly different between the two arms (rate ratio 0.92, p = 0.3). There was, however, a difference in time to first exacerbation favoring mannitol and a small improvement in QoL [54]. Some previously mentioned features were evident, including a surprising reduction in exacerbations from baseline in the placebo group. Patients had a mean frequency of 3.25 exacerbations per year prior to the study, reducing to 1.84 without any apparent treatment [54]. This consistent finding across several studies requires investigation, and may have impacted the studies power to show a difference in the primary outcome. It is now unlikely that further studies of mannitol will now be attempted. Hypertonic saline is also widely used in CF but has not been tested in large randomized trials in bronchiectasis. A parallel group study for 12 months of 40 patients, however, showed no difference in outcome between the groups [55]. This treatment requires evaluation in a large multicenter study. The most famous example of the failure to translate a therapy from CF to bronchiectasis is the case of recombinant DNase [56]. Three hundred and forty-nine patients were randomized to either inhaled recombinant DNase or placebo for 24 weeks. The population appeared representative of ‘typical’ bronchiectasis with a mean age of 60 years and predominantly female [56]. A slightly higher frequency (30 vs 19%) of the group randomized to DNase had P. aeruginosa colonization. The outcome was that DNase increased the frequency of exacerbations and resulted in a reduction in FEV1. No clear responder population could be identified. There has been much speculation as to why this drug failed to work in bronchiectasis. A common hypothesis is that CF tends to affect the upper lobes while bronchiectasis is often basal, therefore, using DNase to reduce the viscosity of sputum may aid clearance by gravity in CF but impair it in bronchiectasis [56]. There are no data to support this contention. Another explanation is the less frequent use of continuous antibiotics in bronchiectasis. DNA is also part of the host defense against infection and also acts as a natural antiproteinase [57,58]. Therefore, use of DNase without antimicrobial therapy may lead to impaired host defense and increase the risk of exacerbations. These are speculations and serve to illustrate how little we know about the pathophysiology of bronchiectasis and its comparison with CF. The challenge of translating therapies from CF to bronchiectasis is summarized in Table 1, which compares trial evidence to date in both conditions for various therapies.

The mucolytics, particularly carbocisteine are widely used in some countries as evidenced by the British Thoracic Society audit, but there are no controlled trials to demonstrate if they are of any benefit [59].

Challenges to drug development in bronchiectasis -- which populations and outcomes to use?

7.

Having reviewed some of the clinical trial data available in bronchiectasis, we will now discuss possible reasons why conducting randomized controlled trials in bronchiectasis have been so challenging by reviewing some of the issues and the end points used. Defining populations according to etiology A key challenge in bronchiectasis is the heterogeneity of the population. Bronchiectasis is the final common pathway of diverse etiologies including some with a very different prognosis [7]. It is clear that in addition to the classically described etiologies, bronchiectasis is associated with COPD in 10 -- 20% of cases, and may also be a feature of severe asthma [60,61]. Multiple studies now suggest that bronchiectasis associated with COPD has a worse prognosis than idiopathic bronchiectasis [6]. Rheumatoid arthritis has also been associated with a more severe prognosis [62] and immunomodulatory drugs that these and other patients take may also influence the bronchiectasis prognosis and clinical course. Patients with non-tuberculous mycobacteria and bronchiectasis have particular characteristics and possibly a unique genetic, immunological and morphological phenotype [63]. Other bronchiectasis etiologies may also have specific therapies relating to the underlying disease such as inflammatory bowel disease, ABPA and immunodeficiencies such as common variable immunodeficiency. Unfortunately, to date we have no data on how these various issues affect the nature of bacterial colonization, airway inflammation or drug response, but it is highly likely that they do. In addition, standardized testing for etiologies of bronchiectasis are not necessarily available worldwide. A clear balance has to be struck between limiting drug development to idiopathic and/or post-infective bronchiectasis, and making drug treatments available to a broader population of patients. Nevertheless, until more data are available, it seems unwise to include those etiologies known to be associated with different prognoses. An important study by McShane et al. demonstrated a significantly higher frequency of P. aeruginosa colonization in Hispanic Americans along with significant ethnic differences in etiology [64]. A high frequency of bronchiectasis has been reported in indigenous populations, including Australia and Alaska [65]. We are in the very early stages of understanding the impact of these major population differences on treatment response and clinical trials design. 7.1


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Table 1. Comparison of results of inhaled antibiotic and mucolytic trials in bronchiectasis and cystic fibrosis. Therapy

Tobramycin


Aztreonam

Liposomal amikacin Colistin

Evidence in cystic fibrosis

Improved FEV1 and other lung function parameters [89,90] Improved QoL [89,90] 26% reduction in hospital admissions, 36% reduction in intravenous antibiotic use [89,90] Reduced time to next exacerbation (21 days, p = 0.007) [28] Improvement in symptoms (CFQ-R) 10% improvement in FEV1 (95% CI: 6 -- 14%) [28]

Reduced PA density [23] Subjective improvement in symptoms Other benefits in small crossover studies but no large studies. 10 -- 40% rate of intolerance and adverse events [23,24] No improvement in QoL (QoL-B) [29] No reduction in exacerbations [29] No improvement in FEV1 [29] Poorly tolerated

Improvement in FEV1 (p = 0.033) and reduced Pseudomonas aeruginosa bacterial load in Phase II studies [91] Small studies showed improved symptoms and slower deterioration in lung function. Bronchoconstriction in up to 17.7%

Antimicrobial efficacy in Phase II studies Published studies awaited [92] No reduction in time to next exacerbation (165 vs 111 days, p = 0.11) [26] Improved time to next exacerbation in compliant patients Improved health-related QoL (SGRQ --10.51 points, p = 0.006) Well tolerated [26] Reduced frequency of exacerbations Relative risk 0.70 (95% CI: 0.60 -- 0.82, p < 0.0001) [36] Improved health-related QoL SGRQ weight mean difference --5.39, 95% CI: --9.89 -- 0.88, p = 0.02. Increased incidence of gastrointestinal side effects in some studies [36]

[93,94]

Azithromycin

DNAse

Hypertonic saline

Mannitol

Evidence in bronchiectasis

94 ml improvement in FEV1 compared with placebo in patients with P. aeruginosa infection. No significant difference with placebo in patients without P. aeruginosa [95,96] Reduced frequency of exacerbations (HR: 0.65; 95% CI: 0.44 -- 0.95; p = 0.03). Increased gastrointestinal side effects [95,96] Reduced risk of exacerbations and improved FEV1 across the spectrum of cystic fibrosis severity Well tolerated [97,98]

No significant difference in the rate of change in lung function (p = 0.8). Higher absolute values of FVC and FEV1 in the hypertonic saline group. 56% reduction in pulmonary exacerbations (p = 0.02) [99,100] Improved FEV1 from baseline in one Phase III trial but no significant improvement in the second Phase III trial [49,50]. 29% reduction in exacerbations in pooled analysis of both studies (p = 0.039) No statistically significant improvement in health-related QoL [49,50]

Reduced FEV1 (--3.6% in DNase group vs --1.7% in placebo group, p < 0.05) Increased frequency of exacerbations (relative risk: 1.35; 95% CI: 1.01 -- 1.79 combining PDEs and NPDEs) [56] Improved FEV1 in two crossover studies No different in terms of FEV1, QoL or exacerbations compared with isotonic saline in a 12-month parallel group study [55] Failed to meet primary end point of mean exacerbation frequency (rate ratio: 0.92, p = 0.3) [54] Improved time to first exacerbation (HR: 0.78; p = 0.22) [54] Improved QoL (SGRQ -- mean difference --2.4 units; p = 0.046) [54] Greater sputum weight compared with placebo

Summary of status in bronchiectasis Widely used but concerns regarding tolerability and limited data on efficacy

Studies failed to meet primary end point and identified safety and tolerability issues. Cannot be recommended for use Larger studies awaited

Widely used in clinical practice Study failed to meet primary end point but some positive findings

Widely used in clinical practice with good data on efficacy and safety from existing studies

Not recommended for use by existing national bronchiectasis guidelines

Equivocal data from existing studies Large randomized controlled trials are needed

Failed to meet primary end point in two large Phase III studies

FEV1: Forced expiratory volume in 1 s; FVC: Forced vital capacity; HR: Hazard ratio; NPDE: Non-protocol-defined exacerbation; OR: Odds ratio, PDE: Protocoldefined exacerbation; QoL: Quality of life; SGRQ: St. Georges Respiratory Questionnaire.

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Defining populations according to disease severity


7.2

The optimal populations to benefit from therapies in bronchiectasis have not yet been defined. While there is a degree of logic in suggesting that patients with more severe disease, more frequent exacerbations and more impaired QoL may have the greatest to gain from new therapies, there is a counter argument that the most severe disease may be largely irreversible and that targeting the most severe populations, often colonized with P. aeruginosa, may lead to unsuccessful clinical trials. Up until now there has been no accurate means of defining disease severity in bronchiectasis. Again, extrapolating from COPD and CF, FEV1 has been primarily used to define disease severity in randomized trials, along with frequency of exacerbations. It is clear that while both of these variables correlate with mortality and other adverse outcomes, they give an incomplete picture of bronchiectasis disease impact. A recent European observational study of 1310 patients in 4 countries identified multiple risk factors for both mortality and hospital admissions, including age, prior hospitalizations, Medical Research Council (MRC) dyspnea score, exacerbations, FEV1, radiological extent of bronchiectasis and bacterial colonization with pathogens or P. aeruginosa [8]. These variables were combined into a clinical prediction tool which, when applied to a derivation cohort and 4 validation cohorts, predicted future mortality with an accuracy (AUC) of 80% in the derivation cohort and 81 -- 84% in the validation cohorts and hospitalization risk with an accuracy of 88% in the derivation cohort and 80 -- 88% in the validation cohorts [8]. The Bronchiectasis Severity Index (BSI) is the only method of disease severity classification that has been externally validated. It has limitations as some variables such as age are not modifiable and are unlikely to influence decisions, for example, to prescribe specific treatments. Nevertheless, it represents a tool that will allow more robust comparisons between cohorts and potentially the targeting of therapies to populations most likely to benefit. An alternative scoring system, the FACED score, was recently published. It is reassuring that the five predictors identified in this study (FEV1, age, P. aeruginosa colonization, radiological extent and MRC dyspnea score) are also included in the BSI. The score has not yet undergone external validation [66]. ‘Standard of care’ In the absence of any licensed therapies for bronchiectasis and few randomized controlled trials, there is the perception of great heterogeneity in the management of bronchiectasis internationally. The effectiveness of a new therapy can be greatly impacted by patient’s concomitant medications and there are large variations in the use of anti-inflammatory therapies (particularly inhaled corticosteroids), macrolides, mucoactive therapies and even variation in physiotherapy regimes. Interaction between therapies can be direct, as has 7.3

been reported for antagonism between azithromycin and tobramycin, or more subtle [67]. National and international initiatives, such as the British Thoracic Society guidelines, recently published guidelines from Australia and New Zealand and the European Respiratory Society guidelines for bronchiectasis (planned for publication in 2016) should help to define the best standard of care and therefore work towards a more harmonized approach to treatment based on evidence [43,68]. Nevertheless, increasingly as macrolides are viewed as standard of care, the interaction of drug treatments with macrolides, which have diverse effects on inflammatory pathways, bacterial pathogens and mucociliary clearance, will be important to understand. 8.

Clinical trial end points

Exacerbations There is consensus that exacerbations are a key outcome measure. Nevertheless, variations of the end point are used, including the mean frequency of exacerbations during follow-up, the time to first exacerbation or even severity of exacerbations. The mean annual frequency of exacerbations are likely to be the most clinically relevant, in the authors’ opinion, as frequent exacerbations are associated with reduced survival, worse health-related QoL and a more rapid decline in pulmonary function [8,11,17,66]. Less data are available regarding the time to first exacerbation. Exacerbations have been the primary outcome for the majority of Phase III trials in bronchiectasis to date [26,29]. For such a key end point, it is perhaps surprising that little progress has been made in agreeing how to define an exacerbation. Identifying the optimal definition is limited by the lack of a gold standard, since physician-treated exacerbation is inevitably a subjective and variable standard. Extrapolating definitions from CF is challenging as responses are not identical. In particular, several definitions include changes in pulmonary function, but pulmonary function is much less dynamic in bronchiectasis compared with CF [69]. Evidence from COPD suggests that many exacerbations are unreported and if the same were true for bronchiectasis this would have important implications for trials [70]. There is little evidence as yet that difficulties with definition of exacerbation have impacted trial outcomes. A sample of the many varied definitions used in studies in bronchiectasis to date is shown in Table 2. 8.1

QoL and symptoms The most frequently used patient-reported outcome (PRO) in bronchiectasis has been the SGRQ, a 50-item selfadministered PRO originally designed for asthma and COPD [71]. It contains 76 weighted responses divided into symptoms, activities and impacts domains. It was originally validated for use in bronchiectasis in 1997 by the Royal Brompton group, showing good repeatability and internal 8.2


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Table 2. Selected definitions of exacerbations in bronchiectasis clinical trials. Study


Definition

Study

Anthonisen criteria [52]

2 symptoms: Increased sputum purulence Increased sputum volume Increase dyspnea

Wong [32]

Bilton criteria [33]

At least two of the following MAJOR symptoms Increased cough Increased sputum volume Increased sputum purulence Increased dyspnea and wheeze And at least one of the following MINOR symptoms Fever > 38 C Malaise Increased WBC count > 10 109 cells/µl Increased CRP or ESR above screening value Event based [33,34]

Modified Bilton/O’Donnell criteria [28] At least three major criteria or two major and at least two minor criteria MAJOR Increased sputum production Change in sputum color Increased dyspnea Increased cough MINOR Fever > 38 C Increased malaise Fatigue Fall of at least 10% in FEV1 or FVC New or increased hemoptysis

Modified Fuchs criteria [31,56]

Definition

Increase or new onset of one or more of the following symptoms and treated with antibiotic therapy Sputum purulence Sputum volume Dyspnea OR ‡ 1 point increase in the mean of three symptom scores from daily diary cards on 2 consecutive days

An increase in antibiotic therapy requiring antibiotic treatment/ event based

Deterioration in at least 4 of 9 features: Sputum production Dyspnea Cough Fever Wheezing Exercise tolerance Fall of at least 10% in FEV1 or FVC New changes on chest radiograph Changes in chest signs on auscultation

References indicate examples of studies using these particular definitions. CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; FEV1: Forced expiratory volume in 1 s; FVC: Forced vital capacity; WBC: White blood cells.

consistency and importantly, a good correlation with other markers of disease severity such as breathlessness, wheeze and frequency of exacerbations [71]. This score has been widely used, demonstrating important improvements in studies of inhaled antibiotics, oral antibiotics and non-antibiotic therapies such as airway clearance. This scoring system is therefore, to some extent, the goldstandard PRO for bronchiectasis despite not being ‘disease specific’. Recently, Quittner et al. have developed the first diseasespecific PRO for bronchiectasis, the OOL-B questionnaire [72]. It differs from the SGRQ, being composed of 37 items on 8 scales (respiratory symptoms, physical, role, emotional and social functioning, vitality, health perceptions and treatment burden). It was developed in close co-operation with the US FDA and was developed as part of the programme of development of aztreonam, where the symptom scale was the trial’s primary end point [29]. As mentioned in Section 2.1, this trial failed to meet its primary end point. As with SRGQ, the validation of the QoL-B showed good psychometric values and responsiveness, the scores worsening during exacerbations [72]. In contrast to the wide use of the SGRQ as a secondary end 842

point in clinical trials, there have been no clinical trials using the QoL-B outwith or outside its development programme and so further clinical trial data are desirable. Two large inhaled antibiotic trial programmes are currently using both scales as secondary end points that will provide excellent data to determine which is the optimal PRO in a clinical trial context. Additional symptom scales include the Leicester Cough Questionnaire, which has been validated in bronchiectasis and used as the primary end point in studies evaluating the impact of co-morbidities and therapies on cough [73].

Colony-forming units per gram (quantitative bacterial load)

8.3

Evaluation of inhaled antibiotics has typically used the quantitative bacterial load, expressed as colony-forming units per gram (cfu/g) of sputum, as their end point in Phase II studies [23,31,32]. Recent failures to translate successful Phase II results with inhaled antibiotics into successful Phase III studies has led some to question the value of cfu/g as a Phase II end point [29].




In a study of 385 patients, a clear relationship was demonstrated between airway bacterial load and airway inflammation markers such as neutrophil elastase, myeloperoxidase and IL-1b. There was also a weak correlation between bacterial load and systemic inflammation, and both could be reduced by short-term intravenous antibiotic treatment, or long-term treatment with nebulized gentamicin [74]. This study also demonstrated a correlation between high bacterial loads (> 107 cfu/ml) and future exacerbation frequency and poorer bacterial loads [74]. While these data suggest that reducing bacterial load will result in benefits for patients, this has not been shown in recent studies. There is a clear disconnect between microbiological efficacy and PROs, with the study reporting the smallest reduction in cfu/g (inhaled colistin) and reporting the largest improvement in health-related QoL and other studies with large improvements in cfu/g showing no benefit on exacerbations or QoL (Table 3). These analyses are limited by the different study designs, in particular the end point that the studies are powered to detect and the durations of treatment in each study, in addition to the variable reporting of the studies. Individual patient data methods would be required to determine if reductions in cfu/ml at a patient level (rather than at the study level) correlated with patient benefit. The only trial to investigate this was in the tobramycin trial, where there was a clear relationship between subjective assessment of improvement and decreases in cfu/g after 2 weeks of inhaled antibiotics compared with placebo (< 0.01) that persisted 2 weeks after treatment was discontinued [23]. If cfu/g have only a limited correlation with clinical important end points, this would suggest we need more reliable Phase II end points for antimicrobials, or that investigators should not rely entirely on cfu/g data to determine whether to progress to Phase III trials.

Spirometry The majority of clinical trials in bronchiectasis suggest that FEV1 is insensitive as a marker of treatment response in bronchiectasis. Two weeks of intravenous antibiotic therapy in 32 patients resulted in large reductions in 24 h sputum volume, improved exercise capacity and reductions in systemic inflammation, but only improved FEV1 by 70 ml, a difference that was not statistically significant [66]. Similarly, while macrolides produced excellent improvements in most clinical end points, the meta-analysis by Wu concluded they improve FEV1 by an average of only 20 ml [37]. The lack of responsiveness of FEV1 is a major contrast between bronchiectasis and CF. Therefore, alternative markers of pulmonary function that are more responsive and more reflective of other clinical improvements would be valuable. 8.4

9.

Possible new end points

Lung clearance index Lung clearance index (LCI) is a measure of ventilation heterogeneity and is measured by multiple breath washout. It has been extensively studied in CF, where its advantage over spirometry in young children has made it an attractive tool, and it has subsequently been shown to be a sensitive marker of early lung disease [75]. Rowan et al. evaluated LCI in 60 patients with bronchiectasis, having previously demonstrated the repeatability of LCI in a cohort of 30 patients [76]. LCI was found to be superior to FEV1 or mid-expiratory flows in identifying the severity of lung disease on high-resolution CT, being strongly correlated with degree of bronchiectasis, mucus plugging and parenchymal abnormalities [76]. There was also a correlation between LCI and QoL using the LCQ. Both Rowan et al. and Gonem et al. have demonstrated that LCI can discriminate between patients with bronchiectasis and healthy controls with a high degree of accuracy (90 -- 96%) [76,77]. The next step in development of LCI would be demonstrating the relationship with clinical parameters beyond radiology and QoL, and to determine whether LCI is more responsive to treatment than existing lung function markers. 9.1

Sputum biomarkers Despite the obvious importance of inflammation in the pathophysiology and progression of bronchiectasis, there have been relatively few studies evaluating sputum biomarkers in bronchiectasis. Particularly for the development of antiinflammatory therapies, it would be attractive to identify markers to correlate with clinically important outcomes. Elastase accounts for the overwhelming majority of proteolytic activity in bronchiectasis sputum and has been linked with disease progression. The majority of such data comes from CF, but in vitro and animal studies clearly link elastase with promoting airway neutrophilic inflammation, mucous secretion, goblet cell meta-plasia and remodeling [44]. Tsang et al. demonstrated in 30 patients with bronchiectasis a strong correlation between 24 h sputum elastase and FEV1, forced vital capacity, number of bronchiectatic lobes involved and 24 h sputum volume [78]. Subsequent work has demonstrated a clear relationship with sputum color, and with airway bacterial load [74]. Therefore, elastase represents one of the few markers that have been tested in more than one study in bronchiectasis, but still requires validation in a large study. Individual markers testing in single studies include cytokines, LL-37, vitamin-D binding protein, matrix metalloproteinase-9, nitric oxide and trace metals [74,79,80]. It is too early to know if sputum biomarkers will have potential as early phase end points in trials. Difficulties in standardizing sputum processing and testing, as well as the heterogeneous methods used to measure different analytes make implementing biomarkers in clinical practice challenging. There has been 9.2


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Table 3. Colony-forming units per gram and clinically relevant end points in bronchiectasis clinical trials.


Trial

Treatment duration

Dcfu/g

D QoL

Exacerbations

Tobramycin [22]

4 weeks

--4.54 log (10) cfu/g

Aztreonam

2 28 day cycles*

--2.5 (2.9) and --2.7 (3.2) cfu/g

OR 5.6 (95% CI: 0.62 -- 50.7) HR 1.26 (0.79 -- 1.99) and HR 1.23 (0.80 -- 1.91)

Not reported

Mean difference in QoL-B 0.8 (p = 0.6) and 4.6 (p = 0.011) 6 monthsz --1.7 (2.2) vs --0.3 (1.9) log Median time to exacerbation Mean difference --10.51, Colistin [25] (10) cfu/g of 165 days vs 111 days p = 0.006 (p = 0.11) 28 days --3.62 vs --0.27 log (10) cfu/g HR 0.80 (95% CI: Mean difference in SGRQ Dry powder 0.44 -- 1.45; p = 0.6) --3.56 (p = 0.059) ciprofloxacin [30] 3 28 day treatment --4.2 (3.7) vs 0.08 (3.8) log OR 0.20 (95% CI: Active --1.3 (7.2) vs Liposomal (10) cfu/g 0.04 -- 0.89; p = --0.027) placebo --6.4 (9.8), ciprofloxacin [31] cycles p = 0.08 Median 2.96 in gentamicin Median 0 (0 -- 1) in 87.5% significant Gentamicin [29] 12 months group vs 7.67 log (10) cfu/g gentamicin group vs improvement vs 19.2% in in placebo group 1.5 (1 -- 2), p < 0.0001 the placebo group 28 days (280 and 560 mg --1.01 log (10) cfu/g (560 mg OR 0.2 (0.02 -- 2.38), --9.28 (560 mg dose), Liposomal doses compared with dose), --0.094 (280 mg p = 0.2 (pooling both --7.94 (280 mg dose), amikacin [92] placebo) dose), 0.006 (placebo) amikacin groups together) --5.01 (placebo) *Data shown for first 28-day cycle as this was the primary outcome. z cfu/g data are reported at 12 weeks. OR: Odds ratio; HR: Hazard ratio; QoL: Quality of life; QoL-B: Quality of life bronchiectasis; SGRQ: St. George Respiratory Questionnaire.

limited application of new technologies in proteomics and metabolomics in bronchiectasis and future work should aim to identify clinically important and responsive biomarkers or protein signatures.

CT scanning Imaging has been proposed as a potential end point in clinical studies in a number of respiratory diseases including CF and COPD [81]. In bronchiectasis, radiological features predict prognosis to a certain extent. The modified Reiff score forms part of the BSI and independently predicted mortality [8]. In addition, Loebinger et al. showed that the radiological factors most associated with prognosis were bronchial wall thickening, mucous plugging, mosaic attenuation and emphysema [17]. At least some of these parameters can be reversed with therapy. To date, there are limited studies of CT scanning as an outcome in bronchiectasis. In the Phase III study of dry powder mannitol, a sub-study of 82 patients was conducted [51]. Mannitol did not produce any changes in extent of bronchiectasis, severity of bronchial dilatation, bronchial wall thickening or mucus plugging of large airways. There was, however, a difference in small airways plugging at 12 weeks (p = 0.048). This exploratory study suggests that CT scanning could become a useful end point in the future [51]. Enthusiasm for this end point is limited by the risks of ionizing radiation, although influential editorials and reviews in CF have recently argued that these risks are overstated [82]. 9.3

844

MRI MRI overcomes issues related to the use of ionizing radiation in clinical trials, but there have been limited studies in bronchiectasis. Studies in CF show that MRI can reliably demonstrate bronchial dilatation, bronchial wall thickening, mucus plugging and hypoperfusion, and that changes in MRI can be demonstrated during exacerbations. This requires further evaluation in specific studies in non-CF bronchiectasis, and demonstration of treatment effects before it can be considered for use as a trial end point [83]. 9.4

Microbiome characterization Our traditional view of microbiology in bronchiectasis has been transformed by molecular techniques, which now provide a comprehensive review of the diverse bacterial populations present in the bronchiectasis airway. Recent data show conclusively that bronchiectasis patients host diverse polymicrobial communities and recent data have started to define the implications of this from a clinical perspective [84-86]. Given the limitations of traditional microbiology, could microbiome characterization become a clinical trial end point? Much work would be required before this could be said with certain. Tunney et al. demonstrated remarkable stability in bacterial load in patients before and after intravenous antibiotics, suggesting at least for short-term treatment, microbiome characterization would not give information about treatment success [84]. Studies using long-term treatments (such as inhaled antibiotics) would be valuable to determine if treatment was effective at modifying the microbiome. Rogers et al. performed a study of 96 patients using 9.5



Table 4. Possible solutions and speculations for the improved development of therapies in bronchiectasis. Challenges to treatment developments in BE Stratification of optimal study populations


Improved tolerability and compliance for inhaled antibiotics and inhaled agents

Anti-inflammatory therapies

Early efficacy end points for Phase II trials

Adequate powering of trials

Consistency of standard of care Discovery of new and repurposed therapies

Better safety monitoring

Standardization of end points across clinical trials

Possible solutions currently in development or proposed Bronchiectasis severity scores Standardized etiology testing internationally through registries and guidelines Detailed patient phenotyping Slow-release liposomal formulations of inhaled antibiotics Analysis of RCTs for responder and intolerant populations Dry powder formulations encouraging greater compliance Increase in basic drug development Development of experimental models of bronchiectasis Phase III studies of new therapies (e.g., elastase inhibitors, CXCR2 antagonists) Lung clearance index Microbiome Imaging Sputum biomarkers Better understanding of natural history from international registries Experience from previous trials particularly with regard to placebo effects International evidence-based guidelines Quality improvement initiatives Improved pre-clinical models Tools for translational research including biobanks of serum, DNA and sputum linked to registries Improved understanding of the link between COPD and bronchiectasis Pharmacovigilence embedded within international registries Microbiome studies as sensitive indicators of new pathogen emergency Agreed consensus definition of exacerbations Agreed optimal quality of life instrument Validation of novel end points Consultation with regulators

Five-year view

Personalized medicine with therapies based on patients unique inflammatory, microbiological and genetic parameters

Well-tolerated inhaled antibiotic therapies licensed for bronchiectasis Specific dose-ranging studies in bronchiectasis

The role of these agents remains unclear Immunomodulatory rather than immunosuppressive therapies likely to be beneficial

Phase II antibiotic studies no longer using cfu/g as end point. Lung clearance index currently appears most likely to be suited to Phase II studies Successful trials and therapies licensed by FDA and EMA for bronchiectasis

Improved standard of care across Europe and beyond New drug development including specific drugs for bronchiectasis, rather than repurposing from cystic fibrosis and COPD Repurposing of therapies used in other conditions for bronchiectasis Better understanding of long-term risks and benefits of therapies leading to better international guidelines

Allows greater confidence for clinicians and regulators in trial results, and comparative data across trial programmes

COPD: Chronic obstructive pulmonary disease; EMA: European Medicines Agency; RCT: Randomized controlled trial.

pyrosequencing and demonstrated a clear relationship between dominance of P. aeruginosa and Haemophilus influenzae with airway inflammation and worse lung function, suggesting the dominant bacterial taxa may be useful in future studies [85]. Interestingly, there is a message emerging from some studies that species diversity is associated with better lung function, symptoms and reduced exacerbations. This presents a challenge for the design of treatments in bronchiectasis, since antibiotics would tend to reduce diversity which may be undesirable [84-86]. This concern has recently been strengthened by a secondary analysis of the BLESS trial of erythromycin. An analysis of paired samples before and after treatment of 44 patients given erythromycin and 42 patients

treated with placebo found substantial changes in the microbiome in the erythromycin group, mainly reduced H. influenzae abundance. There was a small increase in the abundance of P. aeruginosa in the macrolide-treated group suggesting the possibility that long-term macrolide might predispose to acquisition of P. aeruginosa. No patients became culture positive, so the clinical relevance is unclear [86]. These data suggest that microbiota composition may have a potential application to stratify patients for inclusion in trials, to monitor the microbiological response to long-term therapies or to act as a very sensitive method of monitoring for the emergence of new pathogens, an important safety consideration with long-term antibiotic therapies. A large amount of


845


additional work is required before this can be viewed as a viable end point or guide to therapy in bronchiectasis.


10.

Expert opinion

There is currently great momentum in the development of new therapies for bronchiectasis driven by enthusiasm and interest from academic researchers and industry. Disappointing results with recent clinical trials does not seem to have suppressed this enthusiasm and a number of new therapies are now in, or preparing for, late phase clinical trials. Table 4 illustrates possible solutions to the current challenges in drug development for bronchiectasis. The scale of the work required should not be underestimated. Extrapolation of drugs and end points from COPD and CF to bronchiectasis has been necessary despite significant limitations, but may now hold back clinical development in bronchiectasis if the unique challenges in this disease are not rectified. Understanding the natural history of bronchiectasis is essential to designing better clinical trials. Large international datasets can start to define differences in disease prognosis, including less common etiologies that cannot be studied with adequate power in single-center studies. Disease registries have made a major contribution to driving research and improving clinical care and we hope that bronchiectasis registries will provide equal benefits. The European Respiratory Society have supported the establishment of a Europeanwide prospective bronchiectasis registry, EMBARC, which at the time of writing has united > 150 centers in 40 countries including major networks in the UK, Germany, Italy and France [87]. The US registry has been active since 2007 and has successfully recruited several thousand patients [88]. Registries have made a major contribution to understanding the natural history of CF as well as highlighting variations in care and encouraging international collaborations, and it is hoped the same can be achieved in bronchiectasis. Early development of therapies in bronchiectasis is greatly limited by the lack of an adequate animal model of bronchiectasis. The cause of bronchiectasis in the majority of cases remains unknown with 30 -- 50% of patients classified as idiopathic, and a similar proportion classified as ‘post-infective’.

846

In the latter group, even where there is a clear temporal relationship between infection like pneumonia and the development of bronchiectasis, it is unclear why tiny minority of patients should develop this complication of common infections [7]. It is likely that a number of patients with idiopathic or post-infective bronchiectasis have previously unrecognized immune defects. Genetic studies to date have been small single-center studies and it will be essential to link national and international registry initiatives to biobanks to provide the platform for translational research, including genomewide association studies [10]. Even in single gene disorders such as CF, the phenotype can be dramatically altered by epistatic mutations. There is likely to be great variation in bronchiectasis that may impact treatment response. Tolerability issues of inhaled therapies can be addressed to some extent by improved formulations and most importantly by performing dose-ranging studies specifically in bronchiectasis rather than extrapolating doses from CF [28,31]. End points are key to the success of trials, and a major programme of work to develop new trial end points particularly for Phase II, and to standardize the major end points such as exacerbations and QoL measures is required. In conclusion, bronchiectasis is a common, disabling disease with no approved therapies. Changing this will require close collaboration between clinicians, academics, industry and regulators, and we hope current initiatives are beginning to overcome a number of important challenges to therapeutic development.

Declaration of interest JD Chalmers declares grant support to the European Bronchiectasis Registry from the European Respiratory Society and Bayer HealthCare and also declares membership of advisory boards of Bayer Healthcare and AstraZeneca. S Aliberti declares personal fees for lectures or advisory boards from Bayer Healthcare, Zambon, Novartis and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.



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Affiliation

James D Chalmers†1, Michael Loebinger2,3 & Stefano Aliberti4 † Author for correspondence 1 University of Dundee and Ninewells Hospital and Medical School, Tayside Respiratory Research Group, Dundee, DD1 9SY, UK Tel: +01382386131; E-mail: [email protected] 2 Royal Brompton and Harefield NHS Foundation Trust, London, SW3 6NP, UK 3 National Heart and Lung Institute, Imperial College, London, UK 4 University of Milan Bicocca, Clinica Pneumologica, Department of Health Science, AO San Gerardo, Via Pergolesi 33, Monza, Italy

The development of new therapies for human herpesvirus 6.

Challenges and promises in the development of neurotrophic factor-based therapies for Parkinson's disease.

Biofilm Forming Lactobacillus: New Challenges for the Development of Probiotics.

Strategies for the development of animal models for bipolar disorder: new opportunities and new challenges.

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