Development of Novel Agents for Idiopathic Pulmonary Fibrosis

Development of Novel Agents for Idiopathic Pulmonary Fibrosis

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ONLINE FIRST This is an Online First, unedited version of this article. The final, edited version will appear in a numbered issue of CHEST and may contain substantive changes. We encourage readers to check back for the final article. Online First papers are indexed in PubMed and by search engines, but the information, including the final title and author list, may be updated on final publication. http://journal.publications.chestnet.org/

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Development of Novel Agents for Idiopathic Pulmonary Fibrosis: progress in target selection and clinical trial design Thomas O’Riordan, MD1, Victoria Smith, PhD2 and Ganesh Raghu, MD3 Gilead Sciences Inc., Seattle, WA1 Gilead Sciences Inc., Foster City, CA2 and University of Washington, Seattle, WA2 Address for correspondence: Ganesh Raghu, MD, Director: Center for Interstitial Lung Disease, University of Washington, 1959 NE Pacific Street, Seattle, WA 98185 Email: [email protected]

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Introduction Idiopathic Pulmonary Fibrosis (IPF) is a progressive fibrotic lung disease that results in loss of gas exchange units, leading to hypoxemic respiratory failure and death usually within 3-5 years of diagnosis (1). Until recently, treatment was supportive for all patients except for the minority who were eligible for lung transplant. The approval of two new specific therapies for IPF, (pirfenidone [2,3] and nintedanib (4)) that can slow the rate of decline in lung function has begun to dissipate the fatalism that had long been associated with a diagnosis of IPF. The foundation for the successful clinical trials that supported these approvals was based in part on the clinical experience gained in a number of large clinical trials undertaken over the preceding decade. Even though, these trials did not demonstrate efficacy, they yielded invaluable information on endpoint and patient selection (5, 6, 7, 8). However, despite the advent of the two approved drugs, there is consensus that the development of novel therapies that can modify the long-term course of IPF is urgently needed (8,9,10). In this review, we focus on the process for establishing a rationale for novel targets and on how clinical efficacy can be evaluated more efficiently. Establishing a plausible rationale for a novel target Drug discovery programs in IPF seek to inhibit inappropriate fibrotic processes without disrupting healthy connective tissue or interfering with wound healing. Even though the exuberant laying down of quantities of cross-linked collagen is characteristic of IPF, fibroblast activation has to be placed in the context of relationships with other processes in the microenvironment namely, epithelial injury, inflammatory cell and fibroblast/matrix interactions (9-13). Respiratory epithelial cells in IPF appear to have an increased susceptibility to apoptosis, presumably due to low-grade and recurrent “idiopathic” injury (9-13). Unfolded protein responses, abnormal surfactant, abnormal mucus, increased oxidative stress, aspirated gastric acid and shortened telomeres are amongst factors that are being studied in an effort to understand this process. The clinical benefit of therapies designed to decrease oxidative stress (and thus mitigate epithelial injury), through extracellular or intracellular augmentation of antioxidant defense has not been established clinically (14) despite promising results in animal models (15, 16). A recent, large placebo- controlled clinical trial of the commonly prescribed antioxidant, N-acetylcysteine in IPF did not demonstrate efficacy (17). It has been suggested that the injured epithelial cells may activate transforming growth factor beta (TGF-β) perhaps through over expression of integrins such as αvβ6 (18). TGF-β is a cytokine secreted by macrophages and several other cell types, which is anti-proliferative in epithelial cells but stimulates fibroblast differentiation, hence providing a potential link between the manifestations of epithelial, myelopoietic and mesenchymal dysfunction in IPF. (18) The TGFβ pathway has been a frequent target for candidate drugs. It has been suggested that the mechanism of action of pirfenidone, the first drug approved for treatment of IPF,

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Abbreviation list: IPF:

Idiopathic Pulmonary Fibrosis

αvβ6: Alpha-v-beta-6 integrin TGF-β: Transforming Growth Factor Beta SHh: Sonic Hedgehog PDGFR: platelet-derived growth factor receptors VEGFR: vascular endothelial growth factor receptors FGFR: fibroblast growth factor receptors LPA: Lysophosphotidic acid LOXL2: Lysl oxidase-Like 2 CTGF: connective tissue growth factor PFS:

Progression-free survival

IL-13: Interleukin 13

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Introduction Idiopathic Pulmonary Fibrosis (IPF) is a progressive fibrotic lung disease that results in loss of gas exchange units, leading to hypoxemic respiratory failure and death usually within 3-5 years of diagnosis (1). Until recently, treatment was supportive for all patients except for the minority who were eligible for lung transplant. The approval of two new specific therapies for IPF, (pirfenidone [2,3] and nintedanib (4)) that can slow the rate of decline in lung function has begun to dissipate the fatalism that had long been associated with a diagnosis of IPF. The foundation for the successful clinical trials that supported these approvals was based in part on the clinical experience gained in a number of large clinical trials undertaken over the preceding decade. Even though, these trials did not demonstrate efficacy, they yielded invaluable information on endpoint and patient selection (5, 6, 7, 8). However, despite the advent of the two approved drugs, there is consensus that the development of novel therapies that can modify the long-term course of IPF is urgently needed (8,9,10). In this review, we focus on the process for establishing a rationale for novel targets and on how clinical efficacy can be evaluated more efficiently. Establishing a plausible rationale for a novel target Drug discovery programs in IPF seek to inhibit inappropriate fibrotic processes without disrupting healthy connective tissue or interfering with wound healing. Even though the exuberant laying down of quantities of cross-linked collagen is characteristic of IPF, fibroblast activation has to be placed in the context of relationships with other processes in the microenvironment namely, epithelial injury, inflammatory cell and fibroblast/matrix interactions (9-13). Respiratory epithelial cells in IPF appear to have an increased susceptibility to apoptosis, presumably due to low-grade and recurrent “idiopathic” injury (9-13). Unfolded protein responses, abnormal surfactant, abnormal mucus, increased oxidative stress, aspirated gastric acid and shortened telomeres are amongst factors that are being studied in an effort to understand this process. The clinical benefit of therapies designed to decrease oxidative stress (and thus mitigate epithelial injury), through extracellular or intracellular augmentation of antioxidant defense has not been established clinically (14) despite promising results in animal models (15, 16). A recent, large placebo- controlled clinical trial of the commonly prescribed antioxidant, N-acetylcysteine in IPF did not demonstrate efficacy (17). It has been suggested that the injured epithelial cells may activate transforming growth factor beta (TGF-β) perhaps through over expression of integrins such as αvβ6 (18). TGF-β is a cytokine secreted by macrophages and several other cell types, which is anti-proliferative in epithelial cells but stimulates fibroblast differentiation, hence providing a potential link between the manifestations of epithelial, myelopoietic and mesenchymal dysfunction in IPF. (18) The TGFβ pathway has been a frequent target for candidate drugs. It has been suggested that the mechanism of action of pirfenidone, the first drug approved for treatment of IPF,

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may include modulation of TGF-β as well as fibroblast inhibition (2). However, while preliminary data with a monoclonal antibody inhibiting TGF-β, demonstrated a lack of efficacy, possibly due to failure to adequately inhibit the target, gene deletion of TGF-β has aroused concern that complete inhibition might promote inflammation (19) hence there is interest in a more modulated inhibition of the pathway through inhibiting integrins such as αvβ6 (18). Epithelial injury in IPF is also associated with activation of developmental pathways that are quiescent in mature healthy lung tissue and these reactivated pathways are being evaluated as potential drug targets. For example the Sonic Hedgehog (SHh) pathway becomes reactivated in fibrotic diseases and promotes increased susceptibility to apoptosis of epithelial cells but increased resistance to apoptosis in fibroblasts (20). A small molecule inhibitor of the pathway has been developed (21). The Wnt/β-catenin pathway is another example of developmental pathway that becomes aberrantly activated in IPF and in the bleomycin model mouse model, blockade of this pathway with a small molecule inhibitor can reverse fibrosis (22). Investigating the role of inflammatory cells in IPF is complicated by the finding that many cytokines and growth factors are secreted by both circulating inflammatory cells, activated fibroblasts and epithelial cells (9,11,12). Nevertheless it is thought that inflammatory cells may be involved in initiating lung injury or in amplifying profibrotic pathways in response to epithelial injury. However trials of agents that decrease cellular and humeral immunity have not only failed to show efficacy but may be harmful in IPF, despite evidence of therapeutic benefit in other types of interstitial lung disease (23). Nevertheless it is hoped that newer agents with more targeted anti-inflammatory and antifibrotic properties will yield positive results. For example nintedanib, an intracellular inhibitor of tyrosine kinases, has been shown to decrease the rate of decline in lung function over 12 months of therapy in patients with idiopathic pulmonary fibrosis of mild to moderate severity (4,24). Its targets include platelet-derived growth factor receptors (PDGFR), vascular endothelial growth factor receptors (VEGFR), and fibroblast growth factor receptors (FGFR) (24, 25). Lysophosphotidic acid (LPA) is a pro-inflamatory and profibrotic mediator released by platelets during epithelial injury (26) and a specific inhibitor of the LPA1 receptor is being evaluated in patients with IPF. There is also interest in novel agents that target TH2 inflammatory pathways. such as anti-IL13 monoclonal antibodies. Elevated levels of TH2 inflammation in blood of subjects with IPF are associated with accelerated decline in lung function and mortality (27). Periostin is a protein whose expression is associated with TH2 driven inflammation and remodeling. Elevated serum levels are associated with accelerated clinical decline in IPF (28). These findings provide a rationale for using monoclonal antibodies against IL13 as a potential therapy for IPF to inhibit fibrosis that mediated through TH2 pathways.

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There are other novel approaches. One approach aims to decrease the pulmonary accumulation of profibrotic (M2) macrophages by using a protein called pentraxin3 (29). Another program uses oral administration of collagen V with the objective of inducing tolerance to a T cell mediated profibrotic pathway (30). Fibroblasts and myofibroblasts not only secrete collagen but also may themselves contribute to a positive feedback loop by secreting profibrotic mediators (31). The secretory activity and differentiation of fibroblasts is influenced by the matrix on which they reside (32). For example a stiffened (i.e., fibrotic) matrix might provide a self-perpetuating stimulus to collagen production and worsening fibrosis. Lysl oxidase-Like 2, (LOXL2) is a matrix-associated enzyme that crosslinks collagen. Simtuzumab is a monoclonal antibody that allosterically inhibits this enzyme (33). In animal models treatment with a murine antibody against LOXL2, decreases fibrosis. Treatment with the anti LOXL2 antibody decreases TGF−β in a mouse model, presumably by decreasing matrix tension, a stimulus for TGF-β activation. Other investigators have studied the role of secreted macromolecules in the pathophysiology of IPF that are currently being evaluated in preclinical models (34). In vitro investigations of how mechanosensitive signaling regulates myofibroblast activation complement data from animal models in establishing a rationale for therapeutic targets such as αvβ6 (32) and rho-kinase (35). The origin of the increased fibroblast population in fibrotic lung disease is not known (36,37) but includes the proliferation of lung fibroblasts, and more controversially, the transformation of other cell types (epithelium, endothelium, pericytes) into fibroblasts and implantation of circulating fibroblasts of myeloid origin. In view of the potential for multiplicity of origins of activated fibroblasts, an agent that can potentially impact collagen formation independent of fibroblast origin may offer some advantages. Advances in understanding the pathophysiology of fibrosis when combined with recent interest in the application in regenerative and stem cell medicine (37,38) to chronic lung disease, offer hope of an alternative to lung transplant for patients with advanced fibrosis. Furthermore, while the objective of current therapies for IPF is to decrease the rate of decline in lung function, it hoped that this goal will be superceded by the objective of restoring function as novel therapies emerge. Application of an understanding of pathophysiology to the evaluation of targets Novel target pathways in IPF are usually evaluated by demonstrating increased expression of the target in biopsies from patients with IPF or in cell cultures of human fibroblasts. Candidate molecules for that target are usually evaluated in an animal model.

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Evaluation of expression of target in human disease. Examination of specimens from patients with IPF can provide evidence that the target of interest is associated with pathological fibrosis. The genomic, gene expression, and proteomic profiles of biological specimens (peripheral blood, bronchoalveolar lavage, lung tissue) obtained from subjects with IPF, can be compared to data from other lung diseases and healthy controls (39) . The demonstration of increased gene expression relevant to target pathways is of considerable probative value (26,27). Similarly, data from bronchoalveolar lavage and exhaled breath condensates in IPF can be used to support a novel target (40). An alternative technique to elucidate the role of novel targets in the pathogenesis of IPF involves isolation of fibroblasts from patients with the disease and comparing mediator release to fibroblasts from healthy subjects. In this process cells are exposed to pharmacologic agonists and antagonists. The fibroblasts can be imbedded and cultured in 3 dimensional matrices and co-cultured with other cell types (41). These harvested cells are believed to provide more clinically relevant readouts than immortalized fibroblast cultures. Yet another complex translational model is the implantation of fibroblasts from patients with IPF into immunodeficient mice and the demonstration that these fibroblasts are more fibrogenic than those implanted from healthy subjects and this model was used as rationale for the potential role of tralokinumab (a monoclonal antibody against IL-13) in IPF (42). Animal models. Animal models of disease are useful to characterize the in vitro pharmacology of novel agents thus help to establishing the case for efficacy (43). While there is no true model for IPF, the most common model for the assessment of candidate drugs and elucidation of fibrotic pathways is the bleomycin murine model, in which mice are pretreated with either the candidate drug or inactive vehicle prior to intratracheal or systemic administration of bleomycin. The low positive predictive value for subsequent human trials is a significant disincentive to the advancement of novel candidates to clinical development. It has been suggested that giving the candidate drug in a “therapeutic” mode rather than the “prophylactic” mode is preferable (i.e., one should administer the candidate drug after lung injury has been initiated as opposed to administering the candidate drug before administration of the bleomycin). The therapeutic mode allows some of the intense inflammatory response to bleomycin to subside and gives time for the fibrotic process to begin before drug is administered. For example, an inhibitor of multiple kinases (BIBF-1000) was shown to prevent the development of bleomycininduced lung fibrosis when it was administered during the fibrotic phase of the model and thus provided some of the pre-clinical rationale for another similar kinase inhibitor, the nintendanib clinical program (24). Fibrotic phase bleomycin data were also generated to support the rationale for other clinical candidates (29,33).

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Nevertheless the plausible hypothesis that the therapeutic bleomycin model should be superior to the prophylactic model in predicting subsequent efficacy in clinical trials, should be treated with caution. For example, ambrisentan, an endothelin receptor antagonist that was ineffective in a randomized clinical trial (8), was effective ameliorating the fibroproliferative stage of the bleomycin murine model (44). The tendency of the animals to recover spontaneously, the multiplicity of potential efficacy endpoints in the model and the translation of dose selection across species, are potential confounding variables that should encourage caution in extrapolation from the model to subsequent clinical development. It has been proposed that adding analysis of changes in genomic and proteomic profiles may enhance the value of the bleomycin model (45) , but further study is needed to assess the incremental value of these techniques. Gene knockout models when combined with challenges such as bleomycin help characterize fibrotic processes as well as the physiological role of the target. For example, periostin deficient mice are protected from bleomycin-induced fibrosis relative to wild type (28). Further, lack of evidence of activity in normal homeostasis or data from gene knockout murine models would provide additional evidence that candidate is likely to be safe. However gene knockouts may also reflect processes that may the critical in the developing lung but may be less critical in the adult lung and as a result more complex techniques have been developed where by the gene deletions in murine models can be restricted to certain cell types (46). Conversely, genetic augmentation using viral vectors can also be used in combination with bleomycin (47). For example part of the rationale for advancing an inhibitor of connective tissue growth factor (CTGF) is that transient overexpression in a murine model of CTGF, mediated by an adenoviral vector, led to more severe bleomycin fibrosis in a mouse (Bal/c) that had hitherto been relatively resistant to bleomycin induced fibrosis. Another approach to incorporating animal model data is to supplement the data from a bleomycin model with data from a complementary animal model of lung fibrosis. (43). The rationale for alternatives to the bleomycin model includes a need for a model that has less intense inflammation preceding the fibrosis. While persistent inflammation can cause subsequent fibrosis, the histology of stable IPF does not usually show intense inflammation. A second objective is to develop a model that is self-perpetuating after the initial injury rather than have a tendency to spontaneous resolution, and thus be more analogous to chronic pathological fibrosis rather than normal wound healing. For example, in the evaluation of an inhibitor of integrin αvβ6, radiation-induced lung fibrosis was used to supplement the bleomycin model because the former is believed to be less influenced by acute inflammation and be more reflective of subacute fibrosis (18). Alternatively, a mouse model of an adenovector mediated gene transfer of active TGFβ produced pulmonary fibrosis 7 Downloaded From: http://journal.publications.chestnet.org/ by a University of Birmingham User on 05/31/2015

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that appears to be self-perpetuating (48). A model that uses diphtheria toxin to activate apoptosis has the advantage of producing fibrosis with minimal inflammation but has not been extensively used (49). A silica exposure mouse model is associated with fibrosis. However it differs from IPF because it has a known persistent stimulus due to silica and is characterized by granulomata (50). At this time it has not been shown if these other models, which are more expensive and less accessible than the bleomycin model, have greater predictive value in clinical studies. The majority of published studies of experimental lung fibrosis have used murine models. In most cases the animals have been young adults. However there is evidence that the lungs of aged mice may demonstrate a more fibrotic response to bleomycin, viral infections and other insults than younger animals (43). Because IPF is a disease of elderly patients, the use of aged animals may have greater clinical relevance. Despite the greater access to genetically modified mice and murine antibodies, rat models may result in a more robust fibrotic reaction than mice models to certain insults. There has also been a recent increase in interest in comparative pathobiology of the spontaneous fibrosis that occurs in domestic animals including dogs, donkeys and horses, and collaboration has been initiated between investigators of human and domestic animal disease (51).

Initial clinical evaluation of candidate drugs Once preliminary safety and pharmacokinetic data have been obtained in small cohorts of healthy volunteers and subjects with IPF (“phase1”) , the next step in drug development is usually a phase 2 trial that provides initial proof of efficacy and guides dose selection for the subsequent larger “Phase 3” studies (52). The latter provide the pivotal data that support approval of new therapies by national regulatory authorities (“registration studies”). Unfortunately for IPF drug development, there is an unmet need for clinical trial designs to establish clinical proof of efficacy for novel agents in small Phase 2 studies of brief duration. For example, the TOMORROW trial was a Phase 2 trial that provided dose ranging efficacy and safety data for nintedanib and thus informed the design of the Phase 3 studies for that agent. The study enrolled over 400 subjects in 5 treatment groups for 12 months (24). The TOMORROW data can be used as a Phase 2 benchmark study in IPF. To have an adequately powered study the treatment arms may need at least 80 subjects per arm with treatment duration for 12 months if the primary endpoint is to slow the rate of decline in lung function. While retrospective analyses of prior studies suggest that treatment differences may be apparent at 6 months (53), this has yet to be validated prospectively. The most realistic hope for decreasing the size of Phase 2 studies is to develop a biomarker that is relevant to the mechanism of action of the novel agent. Potential biomarkers include cytokine profiles, molecular signatures and quantitative radiology (54). Imaging techniques that are being evaluated include quantifying the degree of fibrosis on serial HRCT (55), the evaluation of regional lung mechanics by 8 Downloaded From: http://journal.publications.chestnet.org/ by a University of Birmingham User on 05/31/2015

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54. Maher TM. PROFILEing idiopathic pulmonary fibrosis: rethinking biomarker discovery Eur Respir Rev. 2013;22(128):148-52. 55. Best AC, Meng J, Lynch AM, Bozic CM, Miller D, Grunwald GK, Lynch DA. Idiopathic pulmonary fibrosis: physiologic tests, quantitative CT indexes, and CT visual scores as predictors of mortality Radiology. 2008; 246(3):935-40 56. Kaushik SS , Heacock T, Freeman M, Kelly KT, Rackley CR, Stiles J, Foster WM, H. P. McAdams HP, Driehuys B. Hyperpolarized 129Xe Spectroscopy As A Biomarker For Gas-Transfer Impairment In Idiopathic Pulmonary Fibrosis ATS, May 1, 2014, A5422-A5422 57. De Backer J, Vos W, Smaldone GC, Skaria S, Condos, R. Disease Progression In IPF Assessed Using Pulmonary Function Tests And Functional Respiratory Imaging (FRI) - A Pilot Study ATS, May 1, 2014, A2383-A2383 58. John AE, Luckett JC, Tatler AL, Awais RO, Desai A, Habgood A, Ludbrook S, Blanchard AD, Perkins AC, Jenkins RG, Marshall JF. Preclinical SPECT/CT imaging of αvβ6 integrins for molecular stratification of idiopathic pulmonary fibrosis. J Nucl Med. 2013;54(12):2146-52. 59. Chien JW, Richards TJ, Gibson KF, Zhang Y, Lindell KO, Shao L, Lyman SK, Adamkewicz JI, Smith V, Kaminski N, O'Riordan T. Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression. Eur Respir J. 2014; 43:14308. 60. Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Stat Med. 2012;31(25):2973-84 61. Liu,S , Kurzrock R. Toxicity of targeted therapy: Implications for response and impact of genetic polymorphisms Cancer Treatment Reviews, 2014, 40: 883–891 62. Diaz KT, Skaria S, Harris K, Solomita M, Lau S, Bauer K, Smaldone GC, Condos R. Delivery and safety of inhaled interferon-γ in idiopathic pulmonary fibrosis. J Aerosol Med Pulm Drug Deliv. 2012; 25:79-87 63. Mackinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ, Delaine T, Simpson AJ, Forbes SJ, Hirani N, Gauldie J, Sethi T. Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3. Am J Respir Crit Care Med. 2012;185: 537-46. 64. Raghu G, Selman M. Nintedanib and pirfenidone. New antifibrotic treatments indicated for idiopathic pulmonary fibrosis offer hopes and raises questions. Am J Respir Crit Care Med. 2015;191(3):252-4

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Figure 1 Schematic diagram of concepts in the pathogenesis of Idiopathic pulmonary fibrosis (IPF)and potential targets to modulate fibroblast proliferation and extracellular matrix deposition in the alveolar wall. IPF is characterized by excessive deposition of collagen synthesized by myofibroblasts (that may have resulted as a transformation of epithelial cells, activated residential fibroblast-like mesenchymal cells within the alveolar wall and/or more controversially, recruited from bone marrow as circulating ‘fibrocytes’ ). Injury to the respiratory epithelium directly promotes fibrosis through activation of several mediators/growth factors and indirectly through activation of circulatory inflammatory cells. Macrophages have a complex role with subsets promoting fibrosis and others down regulating fibrosis. The increasing stiffness of the extracellular matrix may act as positive feedback to further fibroblast activation. Blocking the activation of the fibroproliferative process are likely to lead to remodulation of the fibrotic milieu and restoration to quiescent status of the cellular and soluble components of the milieu. Abbreviations TGF-β: transforming growth factor –beta CTGF: connective tissue growth factor IL-13: Interleukin 13 LPA1: Lysophosphatidic acid receptor 1 LOXL2: Lysl-oxidase like 2 αvβ6: Alpha-v-beta-6 integrin SHh: Sonic hedgehog

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blind adjudication of clinical data (69). Diagnostic criteria for an acute exacerbation includes worsening gas exchange, increased ground glass opacities and the absence of evidence of infection. Patients in clinical trials who develop acute exacerbations of IPF are often managed acutely by physicians who not affiliated with that trial and the absence standardized investigational, treatment, and data collection protocols for acute exacerbations poses challenges to the use of this endpoint in global multicenter studies. Acute exacerbations occur with greater frequency in patients with more advanced disease. Thus, in studies that are enriched for baseline severity, exacerbations may become a valuable endpoint. Demonstration of an increase in overall survival would be the most clinically probative endpoint (66). However, the natural history of IPF would require either very large and prolonged studies or enrichment for patients with more advanced disease relative to the populations enrolled in recent registration trials (66, 67). There is no standard methodology for incorporating lung transplant events into clinical trial data analysis. Phenotyping clinical trial subjects. There are ongoing efforts to increase the efficiency of clinical trials in IPF. Central reading of HRCT and biopsy samples to ensure enrollment leads to a more well defined and homogenous patient population. The diagnostic criteria used by central readers in two recent clinical trials (ASCEND and INPULSIS ) had subtle differences with former using a narrower interpretation of ATS/ERS HRCT guidelines (3) and the latter adopting a more inclusive approach that led to a lower screen failure rate (4). There is likely to be further discussion of the importance of honeycombing on HRCT in relation to diagnostic accuracy (4,70) and natural history. Another approach to increase efficiency of clinical trials is to narrow the range of physiological impairment that is required to enter the study. The aim is to enrich the study with subjects that are more likely to decline rapidly. A study enriched for “rapid progressors” would be expected to demonstrate a larger treatment response. Lowering the maximum FVC will increase the rate of death and acute exacerbations that are likely to occur in the study. However, the impact of baseline FVC on subsequent rate of decline in FVC (the primary endpoint for most studies) is less clear. Decreasing the maximum permitted baseline FVC to 90% in studies of pirfenidone seemed to be associated with more rapid decline in FVC in the ASCEND trial (3) compared to the earlier CAPACITY trials (2) where there was no upper limit for FVC. In contrast, in the INPULSIS trials, the absolute rate of decline in FVC over 12 months was similar for subjects with baseline FVC greater than or less than 70% predicted (71). The minimum baseline FVC for inclusion in most studies has been 5O% predicted but some ongoing studies registered on clintrials.gov have lowered that limit. Decreasing the minimum permitted baseline DLCO from 35% of predicted to 2530% of predicted is likely to increase rates of disease progression including mortality (72). It has also been reported that an acute respiratory hospitalization in the 24 weeks prior to enrollment in a clinical trial is associated with increased mortality in that trial (72). The role of baseline oxygen saturation and exercise 11 Downloaded From: http://journal.publications.chestnet.org/ by a University of Birmingham User on 05/31/2015

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desaturation as a baseline predictor in clinical trials is unclear, in part because these may be difficult criteria to define precisely in retrospective analyses. Many studies have excluded subjects with prominent emphysema on HRCT as well as those subjects with hyperinflation (a residual volume of >120% predicted) or a decreased FEV1/FVC ratio (less than 0.7-0.8) (2,3). There has been concern that prominent concomitant emphysema could be a confounding factor and a suggestion that its exclusion could be a potential source of enrichment for more rapid decline lung function (3). However, the consensus on the impact of concomitant emphysema on long outcome in IPF has not yet been achieved (4, 73). Patients with IPF and pulmonary hypertension have worse outcomes than those without PH (1). However trials of drugs approved for primary pulmonary hypertension (bosentan (7), ambrisentan (8), macitentan (74), iloprost (75) and sildenafil (76) have been unsuccessful in IPF. Ambrisentan is contraindicated in IPF. A post hoc analysis of the sildenafil data suggested that a subset of patients with both severe IPF and baseline documentation of right ventricular dysfunction may be worthy of additional study (77). Another strategy to increase efficiency is the use of standardized spirometry equipment with centralized quality control. Daily home spirometry has also be considered as a potential option (78). Conclusions The increased understanding of the pathophysiology of IPF will facilitate more rational selection of therapeutic targets and more efficient clinical trial design. Results of these trends combined with a committed partnership between clinical investigators, clinical and basic scientists, funding agencies and industry, and patients herald a more hopeful era for patients with IPF. REFERENCES 1. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE Jr, Kondoh Y, Myers J, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann HJ; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. 2. Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE Jr, Lancaster L, Sahn SA, Szwarcberg J, Valeyre D, du Bois RM; CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760-9. 12 Downloaded From: http://journal.publications.chestnet.org/ by a University of Birmingham User on 05/31/2015

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3. King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-92. 4. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-82. 5. Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE Jr; Idiopathic Pulmonary Fibrosis Study Group. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2004;350(2):125-33. 6. King TE Jr, Albera C, Bradford WZ, Costabel U, Hormel P, Lancaster L, Noble PW, Sahn SA, Szwarcberg J, Thomeer M, Valeyre D, du Bois RM; INSPIRE Study Group. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet. 2009;374(9685):222-8. 7. King TE Jr, Brown KK, Raghu G, du Bois RM, Lynch DA, Martinez F, Valeyre D, Leconte I, Morganti A, Roux S, Behr J. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011 Jul 1;184(1):92-9. 8. Raghu G, Behr J, Brown KK, Egan JJ, Kawut SM, Flaherty KR, Martinez FJ, Nathan SD, Wells AU, Collard HR, Costabel U, Richeldi L, de Andrade J, Khalil N, Morrison LD, Lederer DJ, Shao L, Li X, Pedersen PS, Montgomery AB, Chien JW, O'Riordan TG and the ARTEMIS-IPF investigators. Ann Intern Med.2013;158(9):641-9. 9. Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med. 2013;5(167): 10. Lota HK, Wells AU. The evolving pharmacotherapy of pulmonary fibrosis. Expert Opin Pharmacother. 2013(1):79-89. 11. Steele MP, Schwartz DA. Molecular mechanisms in progressive idiopathic pulmonary fibrosis. Annu Rev Med. 2013;64:265-76 12. Fernandez IE, Eickelberg O. New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis. Lancet. 2012;;380(9842):680-8.

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24. Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, Brown KK, Flaherty KR, Noble PW, Raghu G, Brun M, Gupta A, Juhel N, Klüglich M, du Bois RM. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365(12):1079-87 25. Chaudhary NI, Roth GJ, Hilberg F, Müller-Quernheim J, Prasse A, Zissel G, Schnapp A, Park JE. E Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis. Respir J. 2007;29(5):976-85. 26. Funke M, Zhao Z, Xu Y, Chun J, Tager AM. The lysophosphatidic acid receptor LPA1 promotes epithelial cell apoptosis after lung injury. Am J Respir Cell Mol Biol. 2012;46(3):355-64. 27. Herazo-Maya JD, Noth I, Duncan SR, Kim S, Ma SF, Tseng GC, Feingold E, JuanGuardela BM, Richards TJ, Lussier Y, Huang Y, Vij R, Lindell KO, Xue J, Gibson KF, Shapiro SD, Garcia JG, Kaminski N. Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis. Sci Transl Med. 2013;5(205):205ra136. 28. Naik PK, Bozyk PD, Bentley JK, Popova AP, Birch CM, Wilke CA, Fry CD, White ES, Sisson TH, Tayob N, Carnemolla B, Orecchia P, Flaherty KR, Hershenson MB, Murray S, Martinez FJ, Moore BB; the COMET Investigators. Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis.Am J Physiol Lung Cell Mol Physiol. 2012;303(12):L1046-L1056. 29. Murray LA, Rosada R, Moreira AP, Joshi A, Kramer MS, Hesson DP, Argentieri RL, Mathai S, Gulati M, Herzog EL, Hogaboam CM. Serum amyloid P therapeutically attenuates murine bleomycin-induced pulmonary fibrosis via its effects on macrophages. PLoS One. 2010;5(3): e9683. 30. Vittal R, Mickler EA, Fisher AJ, Zhang C, Rothhaar K, Gu H, Brown KM, Emtiazdjoo A, Lott JM, Frye SB, Smith GN, Sandusky GE, Cummings OW, Wilkes DS. Type V collagen induced tolerance suppresses collagen deposition, TGF-β and associated transcripts in pulmonary fibrosis. PLoS One. 2013;8(10):e76451 31. Marinkovic A, Liu F, Tschumperlin DJ. Matrices of physiologic stiffness potently inactivate IPF fibroblasts. Am J Respir Cell Mol Biol. 2013;48(4):422-30 32. Klingberg F, Chow ML, Koehler A, Boo S, Buscemi L, Quinn TM, Costell M, Alman BA, Genot E, Hinz B Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation. J Cell Biol. 2014;207(2):283-97 33. Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM, Oyasu M, Mikels A, Vaysberg M, Ghermazien H, Wai C, Garcia CA, Velayo AC, Jorgensen B, Biermann D, Tsai D, Green J, Zaffryar-Eilot S, Holzer A, Ogg S, Thai D, Neufeld G, Van

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44. Henderson WR, Ye X, Tien Y, Wright CD. Anti-fibrogenic effects of the endothelin-A receptor antagonist ambrisentan in a mouse pulmonary fibrosis model. European Respiratory Society Congress. 2010: A5642. 45. Peng R, Sridhar S, Tyagi G, Phillips JE, Garrido R, Harris P, Burns L, Renteria L, Woods J, Chen L, Allard J, Ravindran P, Bitter H, Liang Z, Hogaboam CM, Kitson C, Budd DC, Fine JS, Bauer CM, Stevenson CS. Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease. PLoS One. 2013;8(4):e59348 46. Oikonomou N, Mouratis MA, Tzouvelekis A, Kaffe E, Valavanis C, Vilaras G, Karameris A, Prestwich GD, Bouros D, Aidinis V. Pulmonary autotaxin expression contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Cell Mol Biol. 2012;47(5):566-74. 47. Bonniaud P, Martin G, Margetts PJ, Ask K, Robertson J, Gauldie J, Kolb M. Connective tissue growth factor is crucial to inducing a profibrotic environment in "fibrosis-resistant" BALB/c mouse lungs. Am J Respir Cell Mol Biol. 2004;31(5):5106. 48. Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J Clin Invest. 1997;100(4): 768-76 49. Sisson TH, Mendez M, Choi K, Subbotina N, Courey A, Cunningham A, Dave A, Engelhardt JF, Liu X, White ES, Thannickal VJ, Moore BB, Christensen PJ, Simon RH. Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am J Respir Crit Care Med. 2010 Feb 1;181(3):254-63 50. Langley RJ, Mishra NC, Peña-Philippides JC, Hutt JA, Sopori ML. Granuloma formation induced by low-dose chronic silica inhalation is associated with an antiapoptotic response in Lewis rats. J Toxicol Environ Health A. 2010;73(10):669-83. 51. Roman J, Brown KK, Olson A, Corcoran BM, Williams KJ; ATS Comparative Biology of Lung Fibrosis Working Group.An official American thoracic society workshop report: comparative pathobiology of fibrosing lung disorders in humans and domestic animals. Ann Am Thorac Soc. 2013;10(6):S224-9. 52. Sheiner LB , Beal SL, Sambol, NC. Study designs for dose-ranging Clinical Pharmacology and Therapeutics 1989; 46: 63–77 53. du Bois RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, Lancaster L, Noble PW, Raghu G, Sahn SA, Szwarcberg J, Thomeer M, Valeyre D, King TE Jr. Ascertainment of individual risk of mortality for patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184:459-66.

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54. Maher TM. PROFILEing idiopathic pulmonary fibrosis: rethinking biomarker discovery Eur Respir Rev. 2013;22(128):148-52. 55. Best AC, Meng J, Lynch AM, Bozic CM, Miller D, Grunwald GK, Lynch DA. Idiopathic pulmonary fibrosis: physiologic tests, quantitative CT indexes, and CT visual scores as predictors of mortality Radiology. 2008; 246(3):935-40 56. Kaushik SS , Heacock T, Freeman M, Kelly KT, Rackley CR, Stiles J, Foster WM, H. P. McAdams HP, Driehuys B. Hyperpolarized 129Xe Spectroscopy As A Biomarker For Gas-Transfer Impairment In Idiopathic Pulmonary Fibrosis ATS, May 1, 2014, A5422-A5422 57. De Backer J, Vos W, Smaldone GC, Skaria S, Condos, R. Disease Progression In IPF Assessed Using Pulmonary Function Tests And Functional Respiratory Imaging (FRI) - A Pilot Study ATS, May 1, 2014, A2383-A2383 58. John AE, Luckett JC, Tatler AL, Awais RO, Desai A, Habgood A, Ludbrook S, Blanchard AD, Perkins AC, Jenkins RG, Marshall JF. Preclinical SPECT/CT imaging of αvβ6 integrins for molecular stratification of idiopathic pulmonary fibrosis. J Nucl Med. 2013;54(12):2146-52. 59. Chien JW, Richards TJ, Gibson KF, Zhang Y, Lindell KO, Shao L, Lyman SK, Adamkewicz JI, Smith V, Kaminski N, O'Riordan T. Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression. Eur Respir J. 2014; 43:14308. 60. Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Stat Med. 2012;31(25):2973-84 61. Liu,S , Kurzrock R. Toxicity of targeted therapy: Implications for response and impact of genetic polymorphisms Cancer Treatment Reviews, 2014, 40: 883–891 62. Diaz KT, Skaria S, Harris K, Solomita M, Lau S, Bauer K, Smaldone GC, Condos R. Delivery and safety of inhaled interferon-γ in idiopathic pulmonary fibrosis. J Aerosol Med Pulm Drug Deliv. 2012; 25:79-87 63. Mackinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ, Delaine T, Simpson AJ, Forbes SJ, Hirani N, Gauldie J, Sethi T. Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3. Am J Respir Crit Care Med. 2012;185: 537-46. 64. Raghu G, Selman M. Nintedanib and pirfenidone. New antifibrotic treatments indicated for idiopathic pulmonary fibrosis offer hopes and raises questions. Am J Respir Crit Care Med. 2015;191(3):252-4

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65. Fleming TR. Current issues in non-inferiority trials. Stat Med. 2008;27:317–32 66. Raghu G, Collard HR, Anstrom KJ, Flaherty KR, Fleming TR, King TE Jr, Martinez FJ, Brown KK. Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. Am J Respir Crit Care Med. 2012;185:1044-8. 67. Wells AU, Behr J, Costabel U, Cottin V, Poletti V, Richeldi L; European IPF Consensus Group. Hot of the breath: mortality as a primary end-point in IPF treatment trials: the best is the enemy of the good.Thorax. 2012 ;67:938-40. 68. Karimi-Shah BA, Chowdhury BA Forced vital capacity in idiopathic pulmonary fibrosis--FDA review of pirfenidone and nintedanib. N Engl J Med. 2015; 372(13):1189-91 69. Collard HR, Yow E, Richeldi L, Anstrom KJ, Glazer C; IPFnet investigators. Suspected acute exacerbation of idiopathic pulmonary fibrosis as an outcome measure in clinical trials. Respir Res. 2013 Jul 13;14:73. 70. Raghu G, Lynch D, Godwin JD, Webb R, Colby TV, Leslie KO, Behr J, Brown KK, Egan JJ, Flaherty KR, Martinez FJ, Wells AU, Shao L, Zhou H, Pedersen PS, Sood R, Montgomery AB, O'Riordan TG. Diagnosis of idiopathic pulmonary fibrosis with high-resolution CT in patients with little or no radiological evidence of honeycombing: secondary analysis of a randomised, controlled trial. Lancet Respir Med. 2014 Apr;2(4):277-84 71. Costabel U, Inoue, Y, Richeldi L, Collard HC, Stowasser S, Tschoepe I, Azuma, A. Effect of baseline FVC on decline in lung function with nintedanib: results from the INPULSIS™ trials. Oral presentation at ERS International Congress, 8 Sept 2014. 72. Ley B1, Bradford WZ2, Weycker D3, Vittinghoff E4, du Bois RM5, Collard HR6. Unified baseline and longitudinal mortality prediction in idiopathic pulmonary fibrosis. Eur Respir J. 2015 Jan 22. pii: ERJ-01463-2014. [Epub ahead of print] 73. Kim YJ, Shin SH, Park JW, Kyung SY, Kang SM, Lee SP, Sung YM, Kim YK, Jeong SH.Annual Change in Pulmonary Function and Clinical Characteristics of Combined Pulmonary Fibrosis and Emphysema and Idiopathic Pulmonary Fibrosis: Over a 3Year Follow-up. Tuberc Respir Dis (Seoul). 2014;77(1):18-23. 74. Raghu G, Million-Rousseau R, Morganti A, Perchenet L, Behr J; MUSIC Study Group. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J. 2013 Dec;42(6):1622-32.. 75. Krowka MJ, Ahmad S, de Andrade JA, et al. A randomized, double-blind, placebocontrolled study to evaluate the safety and efficacy of iloprost inhalation in adults with abnormal pulmonary arterial pressure and exercise limitation associated with idiopathic pulmonary fibrosis. Chest 2007; 132: Suppl., 633S 19 Downloaded From: http://journal.publications.chestnet.org/ by a University of Birmingham User on 05/31/2015

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76. Idiopathic Pulmonary Fibrosis Clinical Research Network, Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010 Aug 12;363(7):620-8. 77. Han MK, Bach DS, Hagan PG, Yow E, Flaherty KR, Toews GB, Anstrom KJ, Martinez FJ; IPFnet Investigators Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. Chest. 2013;143(6):1699-708. 78. Molyneaux L, Lukey PT, Fraser UH, Renzoni EA, Wells A, and Maher TM. Daily Hand-Held Spirometry For The Monitoring Of Patients With Idiopathic Pulmonary Fibrosis Disclosures Dr. O’Riordan and Dr. Smith are employees of Gilead Sciences which owns simtuzumab and ambrisentan Dr. Raghu is a consultant for companies whose are involved in research in IPF (Gilead, Boehringer-Ingelheim , Biogen, Fibrogen)

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Figure 1 Schematic diagram of concepts in the pathogenesis of Idiopathic pulmonary fibrosis (IPF)and potential targets to modulate fibroblast proliferation and extracellular matrix deposition in the alveolar wall. IPF is characterized by excessive deposition of collagen synthesized by myofibroblasts (that may have resulted as a transformation of epithelial cells, activated residential fibroblast-like mesenchymal cells within the alveolar wall and/or more controversially, recruited from bone marrow as circulating ‘fibrocytes’ ). Injury to the respiratory epithelium directly promotes fibrosis through activation of several mediators/growth factors and indirectly through activation of circulatory inflammatory cells. Macrophages have a complex role with subsets promoting fibrosis and others down regulating fibrosis. The increasing stiffness of the extracellular matrix may act as positive feedback to further fibroblast activation. Blocking the activation of the fibroproliferative process are likely to lead to remodulation of the fibrotic milieu and restoration to quiescent status of the cellular and soluble components of the milieu. Abbreviations TGF-β: transforming growth factor –beta CTGF: connective tissue growth factor IL-13: Interleukin 13 LPA1: Lysophosphatidic acid receptor 1 LOXL2: Lysl-oxidase like 2 αvβ6: Alpha-v-beta-6 integrin SHh: Sonic hedgehog

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Figure 1

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