Considerations for the Conduct of Clinical Trials with Antiinflammatory Agents in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report.

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ANNALSATS Articles in Press. Published on 06-July-2015 as 10.1513/AnnalsATS.201506-361OT

Considerations for the Conduct of Clinical Trials with Anti-inflammatory Agents in Cystic Fibrosis: A Cystic Fibrosis Foundation Workshop Report Theodore J. Torphy1, Janet Allen2, André M. Cantin3, Michael W. Konstan4, Frank J. Accurso5, Elizabeth Joseloff1, Felix A. Ratjen6, James F. Chmiel4 on behalf of the Anti-Inflammatory Therapy Working Group Author Affiliations: 1Cystic Fibrosis Foundation, Bethesda, MD; 2United Kingdom Cystic Fibrosis Trust, London, United Kingdom; 3Pulmonary Research Unit, Department of Anatomy and Cellular Biology, Faculty of Medicine University of Sherbrooke, Sherbrooke, Quebec, Canada; 4 Case Western Reserve University School of Medicine, Rainbow Babies and Children’s Hospital, Cleveland, OH; 5Department of Pediatrics, University of Colorado Denver School of Medicine, Children’s Hospital Colorado, Aurora, CO; 6Division of Respiratory Medicine, Department of Paediatrics and University of Toronto, Hospital for Sick Children, Toronto, Canada Corresponding Author: James F. Chmiel, MD, MPH Case Western Reserve University School of Medicine Rainbow Babies and Children’s Hospital 11100 Euclid Ave Cleveland, OH 44106 Telephone: (216) 844-3267 Facsimile: (216) 844-5916 Email: [email protected] Author Contributions: All authors were members of the Cystic Fibrosis Anti-inflammatory Strategy group, which served as the genesis for this manuscript. Each author contributed to the recommendations and overall conclusions of the Strategy group. Each author took the lead in writing one of the manuscript’s major sections. Sources of Support: The Cystic Fibrosis Foundation provided travel expenses for F.J.A., J.A., A.C., M.W.K., J.F.C., and F.R. Running Head: Anti-inflammatory Agents in Cystic Fibrosis Descriptor: Cystic Fibrosis: Translational & Clinical Studies Key Words: Cystic fibrosis, lung, airway inflammation, anti-inflammatory drugs, clinical trials Word Count: 4100

Copyright © 2015 by the American Thoracic Society


Abstract Inflammation leads to lung destruction and loss of pulmonary function in patients with cystic fibrosis (CF). Drugs that modulate cystic fibrosis transmembrane conductance regulator (CFTR) have recently been approved. While the impact of CFTR modulators on sweat chloride and lung function are exciting, they have not yet demonstrated an effect on inflammation. Therefore, CF anti-inflammatory drug development must continue. Unfortunately, the lack of clarity with this process has left investigators and industry sponsors frustrated. The Cystic Fibrosis Foundation established a working group in early 2014 to address this issue. There are many inflammatory processes disrupted in CF, and therefore, there are many potential targets amenable to antiinflammatory therapy. Regardless of a drug’s specific mechanism of action, it must ultimately affect the neutrophil or its products to impact CF. The working group concluded that prior to bringing new anti-inflammatory drugs to clinical trial, pre-clinical safety studies must be conducted in disease relevant models to assuage safety concerns. Furthermore, while studies of anti-inflammatory therapies must first establish safety in adults, subsequent studies must involve children as they are most likely to reap the most benefit. The working group also recommended that pharmacokinetic-pharmacodynamic studies and early phase safety studies be performed before proceeding to larger studies of longer duration. In addition, innovative study designs may improve the likelihood of adequately assessing treatment response and mitigating risk before conducting multi-year studies. Learning from past experiences and incorporating this knowledge into new drug development programs will be instrumental in bringing new anti-inflammatory therapies to patients.


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Cystic fibrosis (CF) pulmonary inflammation leads to lung destruction and an inexorable decline in lung function. Consequently, anti-inflammatory therapy is an important component of CF treatment (1, 2). The introduction of new therapies that target the fundamental defect, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) hold great promise. By targeting the disease process early in the pathophysiologic cascade, it is hoped that CFTR modulators will also address downstream consequences like the excessive host inflammatory response. However, the ability of CFTR modulators to ameliorate inflammation has not been demonstrated. Therefore, until that time when a cure is found, development of new anti-inflammatory drugs must continue. One of the issues with clinical trials of anti-inflammatory drugs is that they often take 24 years and require more than a hundred study subjects when lung function decline is used as an outcome measure. This has caused investigators and industry sponsors to seek a quicker path for approval of anti-inflammatory drugs for CF. Multiple approaches have been suggested and even attempted when designing anti-inflammatory clinical trials. This has led to confusion regarding the best approach for developing anti-inflammatory drugs for CF. In early 2014, the CF Foundation convened a working group to address this issue and to develop a strategic plan for anti-inflammatory drug development. The working group convened in March 2014. At the first meeting, working group members summarized the current state of knowledge pertaining to inflammation and antiinflammatory drug development in CF, identified knowledge gaps, and created six overarching questions. Anti-inflammatory drugs being used to treat other inflammatory conditions were



also reviewed to determine their applicability to CF. The working group was then subdivided into teams to address each question. Over the next three months, each team engaged content experts outside of the working group, performed an exhaustive literature review on the team’s overarching question, and wrote a 4 page research report for their assigned question. A second face-to-face meeting was held in June 2014 where the research reports were reviewed by the working group. The research reports were revised, and the working group leader (TJT) summarized the reports into this document with input from all working group members. This workshop report represents the cumulative effort of all working group members and was approved by all working group members. The purpose of this document is to provide guidance to investigators and potential industry sponsors on the development of antiinflammatory drugs for CF.

What Are the Causes of Inflammation? CF is characterized by early, persistent bacterial airway infection and a pronounced increase in inflammatory cells and mediators. Airway inflammation occurs in young infants even in the absence of detectable bacterial or viral infection (3). Structural airways changes, due to both developmental changes caused by dysfunctional CFTR and ongoing inflammation, are observed in young children with CF (4). Once infection occurs, the inflammatory response to pathogens is excessive relative to the infectious burden (5). The inflammatory response is dominated by neutrophil infiltration with massive quantities of free neutrophil elastase (NE) that overwhelms the ability of endogenous anti-proteases to neutralize proteolytic activity and leads to lung destruction and loss of pulmonary function (6, 7).


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The exaggerated neutrophilic response is likely the consequence of several abnormalities stemming from dysfunctional CFTR activity (4). Although changes in myeloid and lymphoid cells have been demonstrated in vitro (8, 9), systemic immune function in CF is largely normal. This implies that the unique CF airway environment plays a major role in the excessive inflammatory response. Leading hypotheses focus on the abnormal airway surface liquid (ASL) and mucus in the CF lung. Recent work has provided insights into how ASL is dysregulated in CF (10). Normally, tethered mucins on airway epithelial cell cilia form a mesh network that attracts water from the adjacent ASL and ensures that the water content between cilia is constant (Fig. 1). In the absence of CFTR function, ASL hydration is inadequate as a consequence of unopposed sodium reabsorption. In addition, the pH of CF ASL is lower because CFTR is unable to transport bicarbonate to the epithelial surface. Both of these factors result in an increase of mucus solids making it highly viscous and facilitating the retention of pathogens which stimulates inflammation (Fig. 2). Another major factor is the inability of the innate immune system to kill bacteria efficiently in the context of an abnormal ASL. First, the relatively acidic pH of the CF airway hampers neutrophil function (10). Second, NE promotes bacterial persistence by crippling normal host opsonophagocytotic mechanisms (11). Third, NE cleaves and inactivates CXCR1 (12) and CD14 and CD16 (13), proteins that are essential for neutrophil phagocytic activity. Fourth, NE impairs ciliary beat frequency and is a potent secretagogue, further worsening mucostasis. The failure to clear bacteria efficiently both propagates inflammatory cell infiltration and results in neutrophil death by necrosis rather than apoptosis (14). Finally, CF



neutrophils have a defect in their ability to undergo normal autophagy (15). Consequently, large quantities of NE and myeloperoxidase are released. NE itself is a pleiotropic proinflammatory agent that also increases IL-8 release from epithelial cells and generates C5a-like peptide from C5 (16). All of these factors conspire to fuel a feed-forward cycle of chronic infection accompanied by non-resolving inflammation (Fig. 3). An intriguing argument questioning the role of ASL as a central factor responsible for the abnormal CF inflammatory response comes from a Phase III clinical trial with the CFTR potentiator, ivacaftor (17). In individuals with the G551D CFTR mutation, ivacaftor improved pulmonary function, enhanced mucociliary clearance, reduced exacerbations, and lowered P. aeruginosa burden (17). However, despite evidence that CFTR activity improved in individuals receiving ivacaftor, no changes in sputum inflammatory markers were detected in a subset of the trial participants (17). Assuming that these observations are confirmed, there are two important implications. First, once the infection-inflammation cycle is fully established, improvement in ASL function may not necessarily reduce inflammation. Second, the positive impact of ivacaftor on bacterial load may stem from enhanced bactericidal activity of the neutrophil due to improved ASL composition, although other actions such as improved clearance of mucus could be involved. Another abnormality in CF that may contribute to the inflammatory response is an elevated arachidonic acid / docosahexaenoic acid (AA / DHA) ratio in CF cell membranes (18). DHA is a precursor of several anti-inflammatory lipids including the resolvins (19). The resolvins, along with lipoxins, are fatty acid metabolites that are central in the resolution of both acute and chronic inflammation, in part through promoting apoptosis (18-20). Thus, both an


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overactive inflammatory response and a failure to appropriately resolve this response are responsible for the pulmonary pathophysiology of the disease.

What Therapeutic Interventions Warrant Clinical Investigation? The complexity of CF-associated airway inflammation offers multiple targets for intervention. This discussion will be limited to approaches that are particularly attractive and have not been tested previously in CF, but where potential clinical candidates are available. As an example, NE inhibitors, which may have an important role in CF therapy, are not covered. Phosphodiesterase inhibitors. Increases in cyclic AMP broadly suppress inflammatory cell activity, both through direct actions on these cells and by reducing the generation and release of numerous mediators (21). Cyclic AMP and cyclic GMP are metabolized and inactivated by cyclic nucleotide phosphodiesterases (PDE), a superfamily of isozymes that differ with respect to substrate selectivity, cellular distribution, and sensitivity to various inhibitors (22). The primary cyclic AMP metabolizing enzyme in inflammatory cells is PDE4, and PDE4 inhibitors produce a wide range of anti-inflammatory and immunomodulatory effects (22, 23). PDE4 inhibitors reduce neutrophil trafficking to sites of inflammation, release of neutrophil products, leukotriene B4 (LTB4), IL-8 and reactive oxygen species, and promote neutrophil apoptosis (23, 24). Two PDE4 inhibitors are approved for clinical use, roflumilast for COPD (25, 26), and apremilast (27) for psoriatic arthritis and plaque psoriasis. PDE4 inhibitors in COPD reduce sputum neutrophils and markers of neutrophilic inflammation (25, 28). Similarly, a combined PDE3 / PDE4 inhibitor reduces lipopolysaccharide-induced sputum neutrophils in healthy



volunteers (29). Roflumilast improves FEV1 and reduces exacerbations in COPD patients (26). Collectively, both the preclinical and clinical profiles of PDE4 inhibitors provide support for their evaluation in CF. Lipoxins and resolvins. Lipoxins, primarily LXA4, are eicosanoids derived from arachidonic acid that resolve acute inflammation (30-33). LXA4 attenuates neutrophil chemotaxis, respiratory burst, adhesion, and transendothelial migration, facilitates neutrophil apoptosis, stimulates macrophage clearance of apoptotic cells, suppresses IL-8 production, enhances airway epithelial tight junction formation, and augments repair of the bronchial epithelia. Interestingly, concentrations of LXA4 are low in lungs of individuals with CF, which may be an important factor underpinning chronic inflammation (33, 34). The half-life of LXA4 is short, which makes it unusable as a therapeutic. However, stable agonist analogs have been generated that mimic the effects of LXA4, making clinical evaluation a possibility (35, 36). Other lipid modulators of interest are the resolvins. In particular, resolvins D1 and E1, which are derived from DHA and omega-3 eicosapentanoic acid, respectively and have antiinflammatory and proresolution activities (37). These agents inhibit neutrophil transmigration, prevent neutrophil chemotaxis and oxidative burst, down-regulate neutrophil adhesion molecules, induce apoptosis, and promote clearance of apoptotic neutrophils. Like LXA4, resolvins exert cytoprotective effects on epithelial cells. Resolvins are typically present at very low concentrations, but their production increases during latter stages of inflammatory processes. Regarding a potential therapeutic approach that leverages the beneficial effects of resolvins, aspirin stimulates resolvin D1 synthesis (38), suggesting that co-administration of aspirin and DHA may be useful in dampening inflammation in the CF airway.


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Cannabinoid receptor 2 agonists. Cannabinoid receptor 2 (CB2) is found primarily on immune cells and sensory neurons (39). Activation of CB2 receptors produces a spectrum of anti-inflammatory effects, including inhibiting the generation of pro-inflammatory cytokines and suppressing leukocyte trafficking (40, 41). CB2 receptor activation also stimulates LXA4 synthesis (42). Selective CB2 agonists have been synthesized and evaluated in in vivo models of neuropathic and inflammatory pain (43). One compound, ajulemic acid, was effective against neuropathic pain in a Phase II clinical study (44). Leukotriene modulators. Two enzymes in the leukotriene pathway are of interest. 5lipoxygenase is responsible for the conversion of arachidonic acid to 5hydroperoxyeicosatetraenoic acid, which is subsequently converted to LTA4. LTA4 is then converted to either LTB4 by LTA4 hydrolase or to LTC4 by LTC4 synthase. Zileuton, an inhibitor of 5-lipoxygenase, reduces the formation of both LTC4 and LTB4, and is effective in asthma (45). It has not been evaluated in CF. Leukotriene A4 hydrolase inhibitors reduce LTB4 synthesis without altering the production of LTC4, and have the potential advantage of increasing LXA4 formation (46, 47). CTX-4430, an orally-active LTA4 hydrolase inhibitor, was recently shown to have an attractive pharmacokinetic-pharmacodynamic profile in a Phase I trial (48). Although reasonable rationales exist for evaluating both 5-lipoxygenase inhibitors and LTA4 hydrolase inhibitors in the clinic, a caveat behind their use is that while reducing LTB4 production may be beneficial, completely eliminating its activity may be harmful (49). Th17 Cells and the mucosal immune response. A role for Th17 cells in regulating CF pulmonary inflammation has been proposed (50). Naïve Th0 cells tend to differentiate towards a Th17 phenotype in CF (51); indeed, increased numbers of Th17 and Th2 cells in lungs of CF



patients precede P. aeruginosa infection (52). IL-17, an orchestrator of mucosal host defense and key regulator of neutrophil activity, is present in elevated concentrations in neutrophils isolated from individuals with CF (53). Two anti-IL-17 monoclonal antibodies, secukinumab (54) and ixekizumab (55), are effective in a number of autoimmune disorders, including psoriasis, rheumatoid arthritis and ankylosing spondylitis. As attractive as Th17 cells and IL-17 may be as therapeutic targets in CF, IL-17 also plays an important protective role against infection, particularly at mucosal barriers. Therefore, compromising host defense in the setting of chronic infection is a concern. Administration of secukinumab to individuals with Crohn’s disease in a Phase II clinical trial was associated with adverse events, primarily infections, including local fungal infections (56).

What Preclinical Efficacy and Safety Data Are Needed to Support Clinical Studies? There are no preclinical models that recapitulate all aspects of CF airway inflammation. Consequently, while desirable, demonstrating anti-inflammatory efficacy in CFTR knockout or transgenic animals should not be considered a requirement before initiating clinical trials. Instead, preclinical data should support the proposed mechanism of action (MOA) of the agent in question. The largest concern in conducting clinical trials with anti-inflammatory agents in CF is the potential that they will compromise host defense and exacerbate infections. Indeed, experience with the LTB4 receptor antagonist, BIIL 284 BS, provides a cautionary tale (49). Despite strong circumstantial evidence that LTB4 is an important mediator of neutrophil infiltration and activation in the CF airway, this trial was terminated early due to an increase in


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pulmonary-related serious adverse events in adults, but not children. The reason for the increased number of exacerbations is not clear. However, in a murine P. aeruginosa pulmonary infection model, BIIL 284 BS treatment decreased pulmonary neutrophils, but increased bacteremia rates and overall lung inflammation (57). This suggests that LTB4 may be an important component of host defense in the CF lung, and that abolishing its activity may be deleterious. If safety information on the drug of interest in CF patients is not available, it is recommended that the activity of any anti-inflammatory agent destined for CF trials be assessed in the murine agarose bead model of chronic lung infection using an appropriate bacterium, typically P. aeruginosa (58, 59). This model involves instilling intratracheally agarose beads embedded with a mucoid P. aeruginosa strain isolated from a CF patient. Changes in body weight and clinical assessments are performed over the course of the infection. Animals are evaluated for local and systemic infection and inflammation. Bronchoalveolar lavage should also be conducted and evaluated for cellular differential, bacterial burden, NE, cytokines, and mediator expression. Additional measurements could be added as more is learned about new CF-associated mediators or to evaluate potential clinical biomarkers associated with the test compound’s MOA. Initial studies can be conducted in wild-type animals to define appropriate dosing regimen of test compounds. However, it is important to be mindful that abnormal CFTR results in compromised host defense. This is mimicked in the CFTR knockout mouse model, in which the animals are inefficient at resolving infections with P. aeruginosa as well as the ensuing inflammatory response (60). Consequently, in most instances candidate molecules that appear



safe and effective in wild-type studies should also be evaluated in CFTR deficient mice. Undesirable results from these studies should not necessarily prevent an agent from entering a clinical study, but great care should be taken to incorporate safety monitoring in early trials.

What Target Population(s) Will Benefit Most from Anti-inflammatory Therapy? Anti-inflammatory drugs are likely to be most effective if initiated prior to the development of bronchiectasis. Thus, children may benefit most from anti-inflammatory therapy. Recent data demonstrate that free elastase in bronchoalveolar lavage fluid obtained at three months of age is associated with the development of bronchiectasis at three years (61). This suggests that inflammation begins early in life and results in structural damage. Clinical trials of ibuprofen and dornase alfa also indicate that children with minimal lung disease receive significant benefit from the administration of anti-inflammatory drugs (62, 63). The goal of initiating therapy early is to prevent inflammation from becoming established and halt the progression of lung disease. However, it will be difficult to initiate Phase II studies in children without substantial safety data in adults. Therefore, studies of anti-inflammatory agents will have to be conducted in adults first. Patients who do not have a significant amount of inflammation are less likely to benefit from the administration of anti-inflammatory drugs. However, defining what constitutes a significant amount of inflammation and at what point anti-inflammatory drugs should be initiated is difficult. In addition, patients with more advanced lung disease are not likely to benefit as much from routine use of anti-inflammatory agents as those patients with an earlier stage of lung disease. Another consideration is that the nature of the inflammatory process may


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differ among patients, and even vary over time in individual patients. The components of inflammation during periods of stable disease may differ from those present during exacerbations. Such scenarios imply that in real-world practice, the use of broad spectrum antiinflammatory drugs might be more practical than agents targeted toward single mediators.

What Have We Learned From Past Successes and Failures? The major challenge facing the advancement of new anti-inflammatory drugs is that the standard clinical outcome measures explored in Phase II trials, an acute change in FEV1 or time to pulmonary exacerbation, may not be impacted during the typical length of a Phase II study (e.g. 2-3 months) (64). On the other hand, it is not wise to conduct a large Phase IIb/III trial without sufficient safety information as demonstrated by the clinical trial of the LTB4 receptor antagonist BIIL 284 BS. The BIIL 284 BS clinical development program in CF consisted of single-dose and 14-day multi-dose safety and pharmacokinetic studies with a small number of patients, followed by a 6-month 600 patient Phase IIb/III trial in adults and children. The latter trial was terminated after 420 patients were enrolled because of pulmonary-related serious adverse events in adults (49). After the clinical trial was completed, the deleterious effects of BIIL 284 BS in the mouse model of P. aeruginosa lung infection was shown (57). Conducting this study prior to BIIL 284 BS entering the clinic could have informed a better trial design or perhaps, led to a decision not to conduct the trial. Given the experience with BIIL 284 BS, a conservative approach in conducting CF clinical trials for anti-inflammatory drugs is warranted. Because anti-inflammatory agents have



potential to suppress the host immune response, safety indices should include some measure of change in the burden of bacteria in the lung (e.g. CFU of P. aeruginosa in expectorated or induced sputum) and monitoring for emergence of new organisms. Another important consideration in the development of new anti-inflammatory therapies is ensuring that adequate pharmacokinetic-pharmacodynamic studies have been conducted. Without such information, potentially valuable new drug targets could be eliminated inappropriately. For example, studies in CF patients using SB-656933, a CXCR2 antagonist, demonstrated only modest trends for improvement in sputum inflammatory biomarkers (65). However, plasma concentrations of SB-656933 were unexpectedly low in this study compared to previous results, and probably did not reach and maintain concentrations adequate to demonstrate a robust pharmacological effect. Previous experience with clinical trials indicates that the safety and efficacy of antiinflammatory agents may differ in adults versus children. The increase in pulmonary exacerbations in the BIIL 284 BS trial was observed in adults, not in children (49). Moreover, the effect of ibuprofen on slowing FEV1 decline in a four-year trial, although significant for the entire study group age 5-41 years, was mostly attributed to children (62). Consequently, the effect of age on the response to anti-inflammatory agents needs to be considered in trial design. In reviewing past experience with anti-inflammatory therapies in CF, we also recognized that the failure to employ standardized preclinical models (e.g. the mouse P. aeruginosa model), clinical biomarkers, and Phase II trial design has prevented iterative learning, using


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results from previous studies to understand success factors and inform the selection of future candidates. A final lesson learned is that a rigorous drug safety monitoring process can appropriately identify if and when a study needs to be terminated for safety reasons (e.g. the BIIL 284 BS trial).

What Factors Should Be Considered in the Design of Clinical Trials? The study design and outcome measures used to assess response will vary with the development phase as well as the MOA of the drug. Anti-inflammatory therapy may or may not result in short term improvements in lung function. Here, we describe conventional concepts for study design in different phases of development and make suggestions for novel approaches to assess therapeutic utility in more efficient and practical ways. Phase I/II studies. While safety is the main outcome measure in most early Phase studies, the balance of safety versus efficacy is particularly relevant for anti-inflammatory therapy as the lung that is commonly chronically infected with pathogens requires a high degree of caution because of the risk of compromising host defense. As previous studies of anti-inflammatory drugs have not shown short term improvements in FEV1, Phase II programs will likely require both a Phase IIa and Phase IIb study, with the Phase IIa study covering four to eight weeks to assess safety without the expectation of an efficacy signal for established outcome measures. Trends in pulmonary function or exacerbations are unlikely to be seen in a Phase II study of two or three month’s duration. Consequently, consideration should be given to demonstrating some beneficial effect on a biomarker pertinent to inflammation. These might



include favorable changes in mediators of inflammation (e.g., cytokine or chemokine levels), products of inflammation (e.g., neutrophil counts, NE and oxidants), or general plasma markers such as C-reactive protein and calprotectin (66). Phase IIb studies will require a three to six month duration with numbers of patients exceeding those of phase II trials for drugs addressing CF lung disease to demonstrate trends in the time to or rate of pulmonary exacerbations, as shorter trials will unlikely have a high enough event rate for this outcome measure (67). Enrichment strategies can be used to reduce patient numbers for these trials by limiting recruitment to individuals with a recent history of exacerbations as this has high predictive value for future events (68). Phase III studies. Pulmonary exacerbations are the outcome measure of choice for Phase III. The longer the study, the more likely it is that treatment effects can be conclusively demonstrated, but six months is the minimal duration of such a study with 12 months being preferred. Studies assessing lung function decline, a desirable goal, take multiple years and large numbers of subjects (69), and are generally more suitable for post-marketing studies using databases such as the CF Foundation Patient Registry. Alternative study designs. Standard study designs akin to those described above in which trial phases are initiated serially with traditional outcome measurements as endpoints are costly and fraught with risk. New approaches are needed that incorporate different endpoints, to make early go/no-go decision points, or both. Consideration should be given to adaptive trial designs that combine both Phase IIa and IIb into a single study, with biomarkers incorporated into the first stage, and exploration of trends in clinical endpoints (pulmonary exacerbation and FEV1) in the second stage. An interim


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analysis could inform whether subjects can move on to the second part of the study allowing for efficiency with regards to start-up and site and subject participation. An alternative approach to following outcomes in patients with stable disease is to initiate treatment during pulmonary exacerbations. Exacerbations are a major driver of lung function decline with approximately half of lung function decline being caused by these events (70). Cohort analyses of the CF Foundation Patient Registry indicate that in 25% of patients who experience an exacerbation, FEV1 does not return to pre-exacerbation values despite treatment with antibiotics (71, 72). It is tempting to speculate that the failure of pulmonary function to recover is linked to the fulminant inflammatory process that takes place during an exacerbation. If this is the case, initiating anti-inflammatory therapy during an exacerbation may help to recover lung function. Time to next pulmonary exacerbation after recovery could be added to this study paradigm for further evidence of beneficial effect. If such studies are conducted, patients should be monitored closely to ensure that treatment is not compromising host defense. Another approach is to study anti-inflammatory therapy as an early intervention strategy. These studies would likely need to be conducted in young children and would require bronchoalveolar lavage based markers of neutrophil inflammation, sensitive markers of lung function such as lung clearance index as well as radiological methods to assess bronchiectasis as outcome measures. A high degree of safety information for a given compound would be needed to consider such a study design.



Conclusions Extraordinary advances in the pharmacotherapy of CF have been made in the last decade, perhaps the most exciting of which is the CFTR potentiator, ivacaftor. However, the development of better therapies directed toward downstream pathological consequences is likely to continue for decades. In particular, better means to treat the CF inflammatory response will be required to slow lung destruction. In realizing this goal, innovative science and medicine will be required as will creative approaches toward trial design and clinical outcomes. Taking advantage of previous experience and incorporating a more cohesive approach toward evaluating new therapies will be instrumental in achieving ultimate success.

Acknowledgments The authors wish to acknowledge the thought leaders who provided comments and advice to the Anti-Inflammatory Therapy Working Group including Tracey L. Bonfield, Ph.D., Case Western Reserve University School of Medicine, Cleveland, OH, USA; J. Stuart Elborn, M.D., Queens University Belfast and Belfast City Hospital, Belfast, Northern Ireland, UK; Dominik Hartl, M.D., Children’s Hospital of the University of Tübingen, Tübingen, Germany; Noel G. McElvaney, M.D., Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland; and Scott D. Sagel, M.D., Ph.D. University of Colorado, Children’s Hospital of Colorado, Denver, CO, USA.


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Anti-Inflammatory Therapy Working Group: Frank J. Accurso, M.D., University of Colorado Denver School of Medicine, Children’s Hospital Colorado, Aurora, CO, USA; Janet Allen, Ph.D., United Kingdom Cystic Fibrosis Trust, London, United Kingdom; Robert J. Beall, Ph.D., Cystic Fibrosis Foundation, Bethesda, MD, USA; Preston W. Campbell, III, M.D., Cystic Fibrosis Foundation, Bethesda, MD, USA; André M. Cantin, M.D., University of Sherbrooke, Sherbrooke, Quebec, Canada; James F. Chmiel, M.D., M.P.H., (Working Group Co-leader), Case Western Reserve University School of Medicine, Rainbow Babies and Children’s Hospital, Cleveland, OH, USA; Elizabeth Joseloff, Ph.D., Cystic Fibrosis Foundation, Bethesda, MD, USA; Michael W. Konstan, M.D., Case Western Reserve University School of Medicine, Rainbow Babies and Children’s Hospital, Cleveland, OH, USA; Bruce C. Marshall, M.D., Cystic Fibrosis Foundation, Bethesda, MD, USA; Felix A. Ratjen, M.D., Ph.D., University of Toronto Hospital for Sick Children, Toronto, Ontario, Canada; Theodore J. Torphy, Ph.D., (Working Group Leader), Cystic Fibrosis Foundation, Bethesda, MD, USA; Katherine L. Tuggle, Ph.D., Cystic Fibrosis Foundation, Bethesda, MD, USA.



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Figure Legends

Figure 1. Role of CFTR in maintaining a healthy mucosal environment. The presence of CFTR in the healthy airway is essential to ensure appropriate hydration of the airway surface fluid (ASL) and mucus layer, proper ciliary beating and to prevent acidification of the extracellular compartment. Not shown are the submucosal glands, which also are rich in CFTR and produce secretions that must have adequate water content and pH for host defenses.

Figure 2. Mechanisms that initiate severe airway inflammation in cystic fibrosis (CF). In CF, the primary defect is a lack of CFTR at the apical membrane, which markedly decreases chloride and bicarbonate secretion. Sodium absorption is increased, and water is depleted from the ASL in the periciliary compartment. Mucus (purple layer) is secreted by submucosal glands and goblet cells, which are increased in number. The absence of adequate chloride and bicarbonate creates long polymers of mucus that are tethered to each other and are viscous.

Figure 3. Secondary defects that maintain severe airway inflammation in cystic fibrosis (CF). The lack of an appropriate ASL pH in the CF airway increases susceptibility to infection, as does the absence of ciliary beating, and defective mucociliary clearance. Severe sustained infection and neutrophil dominated inflammation render the mucus purulent (green layer) and increase extracellular DNA. Bacterial and neutrophil products accumulate in the extracellular space where proteins essential to host defenses are cleaved, thus creating secondary defects in opsono-phagocytosis, autophagy and efferocytosis, all of which fuel further inflammation. Lack


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of CFTR also favors an airway Th17 lymphocyte response, which accentuates inflammation. Not illustrated are several defects directly related to CFTR deficiency, which also contribute to inflammation and infection. These include, but are not limited to docosahexaenoic acid (DHA) deficiency in cell membranes, increased IL-8 release by airway epithelial cells, abnormal ceramide metabolism, abnormal redox homeostasis and altered immune cell regulation. Please see text for details.



Table 1. Key Implications for Cystic Fibrosis Clinical Trials and Clinical Care What are the causes of inflammation? •

Abnormal airway surface liquid (ASL) and mucociliary clearance play a central role in CF pulmonary inflammation.

•

Persistent airway inflammation in CF is related to the inability of the innate immune system to kill bacteria in the context of the altered ASL, the failure to resolve inflammation appropriately, or both.

•

The neutrophil and its products, especially neutrophil elastase, are major factors responsible for the chronic inflammation and damage to the CF lung, suggesting that inhibiting the trafficking or activity of neutrophils would have beneficial effects.

What therapeutic interventions warrant clinical investigation? •

There are several anti-inflammatory and pro-resolving drugs for which there is a strong rationale to evaluate their activity in CF.

•

To mitigate the risk of compromising host defense, the most promising agents may be those that modulate rather than abolish the activity of one or more targets or pathways.

What preclinical efficacy and safety data are needed to support clinical studies? •

To test for potential deleterious effects of anti-inflammatory agents on host defense in the context of an active infection, candidate molecules should be evaluated in an animal model of airway infection such as the agarose bead model of P. aeruginosa lung infection before entering CF clinical trials.

What target population(s) will benefit most from anti-inflammatory therapy? •

Inclusion and exclusion criteria must be carefully defined: -What is the youngest age at which an anti-inflammatory drug should be administered? -Will an anti-inflammatory drug impact a patient’s ability to mount a response to certain infections? -Should an anti-inflammatory drug not be administered to particular patients, especially those with certain co-existing infections?

•

Initial studies of anti-inflammatory therapies must first establish safety in adults; subsequent studies will necessarily involve children, in whom long-term treatment with anti-inflammatory drugs may provide the greatest benefit.

•

Individuals experiencing exacerbations might also benefit from anti-inflammatory therapy.

What have we learned from past successes and failures? •

Adequate Phase I/II safety and pharmacokinetic-pharmacodynamic studies in CF patients with sufficient subject number and duration are essential before moving to larger, longer duration trials.


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•

Sputum and serum biomarkers of inflammation, as well as bacterial counts in sputum should be included in clinical trials to demonstrate safety, target engagement, and for comparison with results from other clinical and preclinical studies.

•

Because children with early lung disease are a target population for anti-inflammatory therapy and different clinical responses have been observed in adults versus children, children should be included in all phases of a clinical development program once safety is first established in adults.

What factors should be considered in the design of clinical trials? •

Traditional study designs for anti-inflammatory therapy using standard outcome measures are complex and require trials of long duration or large numbers of participants.

•

Pulmonary exacerbations are likely the best patient-relevant outcome measure for clinical trials involving anti-inflammatory drugs; ultimately, a benefit on lung function decline should be demonstrated.

•

Innovative study designs may help to improve the likelihood of adequately assessing treatment response and mitigating risk before conducting multi-year trials.



254x190mm (96 x 96 DPI)


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254x190mm (96 x 96 DPI)



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Cystic Fibrosis Foundation and European Cystic Fibrosis Society Survey of cystic fibrosis mental health care delivery.

US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis.

US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis: executive summary.

Minorities Are Underrepresented in Clinical Trials of Pharmaceutical Agents for Cystic Fibrosis.

Point: does the risk of cross infection warrant exclusion of adults with cystic fibrosis from cystic fibrosis foundation events? Yes.

Counterpoint: does the risk of cross infection warrant exclusion of adults with cystic fibrosis from cystic fibrosis foundation events? No.

International Committee on Mental Health in Cystic Fibrosis: Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus statements for screening and treating depression and anxiety.

Cystic fibrosis. 7. Management of cystic fibrosis in different countries. Cystic fibrosis in Leeds.

Cystic fibrosis and non-cystic fibrosis bronchiectasis.

Practice guidelines, clinical trials, and unexpected results in cystic fibrosis.

Cystic fibrosis. 7. Management of cystic fibrosis in different countries. Cystic fibrosis in Melbourne.

Cystic fibrosis. 7. Management of cystic fibrosis in different countries. Cystic fibrosis in Copenhagen.

Cystic fibrosis. 2. Lung injury in cystic fibrosis.

Screening for cystic fibrosis.

Screening for cystic fibrosis.

Screening for cystic fibrosis.

Fungi in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Nontuberculous mycobacteria in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Imaging in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Cystic fibrosis.

Cystic fibrosis.

Cystic fibrosis.

Cystic fibrosis and myocardial fibrosis.

Cystic Fibrosis.