Accepted Manuscript Title: Pharmacological treatment of idiopathic pulmonary fibrosis: an update Author: Paolo Spagnolo Athol U. Wells Harold R. Collard PII: DOI: Reference:
S1359-6446(15)00019-7 http://dx.doi.org/doi:10.1016/j.drudis.2015.01.001 DRUDIS 1564
To appear in: Received date: Revised date: Accepted date:
1-10-2014 3-12-2014 7-1-2015
Please cite this article as: Spagnolo, P., Wells, A.U., Collard, H.R.,Pharmacological treatment of idiopathic pulmonary fibrosis: an update, Drug Discovery Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.01.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Paolo Spagnolo1,2, Athol U. Wells3, and Harold R. Collard4 1
ip t
Pharmacological treatment of idiopathic pulmonary fibrosis: an update Medical University Clinic, Canton Hospital Baselland, Liestal, Switzerland University of Basel, Liestal, Switzerland 3 Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK 4 Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine, University of California, San Francisco, CA, USA Corresponding author: Spagnolo, P. ([email protected]) Keywords: idiopathic pulmonary fibrosis; treatment; nintedanib; pirfenidone; clinical trials; interstitial lung disease. Teaser: Idiopathic pulmonary fibrosis is a chronic disease for which there is no cure. New evidence shows that two compounds (pirfenidone and nintedanib) reduce functional decline and disease progression in this devastating disorder.
us
cr
2
an
Author biographies Paolo Spagnolo
Paolo Spagnolo is an associate professor of respiratory medicine and a senior clinical research fellow at the
M
Medical University Clinic of the Canton Hospital Baselland in Liestal. Between 2010 and 2013, he was lecturer in respiratory medicine in the Department of Oncology, Hematology and Respiratory Medicine at the University of
ed
Modena and Reggio Emilia. From 2002 to 2008, Dr Spagnolo worked as a clinical research fellow at the Interstitial Lung disease Unit, Royal Brompton Hospital. In 2008, he completed his PhD at Imperial College
pt
London, with a thesis on genetic susceptibility to sarcoidosis. His main research interests are sarcoidosis and IPF, with special focus on genetic predisposition, prediction of disease behavior, and clinical trials of novel
Ac ce
therapies. Dr Spagnolo is the author or co-author of more than 50 journal articles, review articles, editorials, and book chapters.
Harold R. Collard
Harold R. Collard is an associate professor of medicine in the Division of Pulmonary and Critical Care Medicine at the University of California San Francisco (UCSF) and the director of the Interstitial Lung Disease Program at UCSF. He is a clinical and translational researcher focused on interstitial lung disease. Dr Collard is currently conducting projects investigating: (i) acute exacerbations of IPF; (ii) predicting disease progression; (ii) factors contributing to patients’ symptoms of shortness of breath and ways to improve patients’ quality of life; and (iv) clinical trials of novel therapies for patients with interstitial lung disease. He sits on the American Thoracic Society – European Respiratory Society group revising guidelines in IPF, as well as other joint groups involved in
Page 1 of 26
the definition of nonspecific interstitial pneumonia, and acute exacerbations of IPF. He is the author or co-author of approximately 150 journal articles, review articles, editorials, and book chapters. Athol U. Wells Athol U. Wells is professor of respiratory medicine in the Faculty of Medicine at Imperial College London and
ip t
head of the Interstitial Lung Disease Unit at The Royal Brompton Hospital. Dr Wells chairs the British Thoracic Society group revising guidelines in diffuse lung disease and sits on the American Thoracic Society – European
cr
Respiratory Society group revising guidelines in IPF, as well as other joint groups involved in the definition of nonspecific interstitial pneumonia, smoking-related diffuse lung disease, and acute exacerbations of IPF. His
us
research interests include prognostic evaluation in diffuse lung disease using HRCT and pulmonary function tests, definition of relations between structure and function in diffuse lung disease, definition of disease type and
an
severity in genetic and laboratory studies, and studies of new therapies in diffuse lung disease. He has authored or co-authored more than 300 journal articles, review articles, editorials, and book chapters.
M
Idiopathic pulmonary fibrosis (IPF) is a progressive and almost invariably lethal disease that affects primarily older adults. After a decade of negative (or inconsistent) results, two recent clinical trials have
ed
demonstrated that slowing disease progression with medication is possible. An improved understanding of disease pathogenesis, epidemiology, and diagnostic criteria has been key to this success. Yet, this is only the beginning. It is hoped that continuous efforts by dedicated scientists and
pt
clinicians, patient organizations, health authorities, and pharmaceutical companies will soon lead to the
Introduction
Ac ce
development of more effective and better-tolerated treatment strategies for this devastating disease.
IPF is the most common and lethal of the idiopathic interstitial pneumonias (IIPs), a heterogeneous group of disorders characterized by varying patterns of inflammation and fibrosis [1,2]. The disease, which is relentlessly progressive, is limited to the lungs and occurs primarily in older adults. Retrospective longitudinal studies suggest a median survival time of 2–3 years after diagnosis, but recent clinical trials that recruited patients with mild to moderate functional impairment reported a lower mortality rate [1,3–6]. In the USA alone, approximately 40 000 patients die of this disease annually and recent data indicate a substantially higher incidence and prevalence of IPF in patients aged 65 years and older than previously reported [7]. According to current evidence-based guidelines, the diagnosis of IPF requires the exclusion of all known causes of pulmonary fibrosis (e.g., inhalation of fibrogenic dusts or aerosolized organic antigens, collagen vascular disease, or drug
Page 2 of 26
exposure) and the presence of a usual interstitial pneumonia (UIP) pattern, which is defined radiologically by subpleural, basal-predominant reticular changes, traction bronchiectasis, and honeycombing (Figure 1) and histologically by patchy involvement of lung parenchyma (e.g., alternating areas of dense fibrosis and lessaffected or normal lung); architectural distortion with/without honeycombing; and presence of active fibroblastic
ip t
foci adjacent to areas of densely collagenized fibrosis, all in a subpleural distribution (Figure 2) [1].
Our understanding of the pathobiology of IPF has significantly evolved over the past decade. The disease
cr
appears to be driven by abnormal and/or dysfunctional alveolar epithelial cells (AECs) that promote fibroblast recruitment, proliferation, and differentiation, resulting in scarring of the lung, architectural distortion, and
us
irreversible loss of function [8]. Accordingly, more recent clinical trials have shifted their focus from antiinflammatory and immunosuppressant compounds to molecules targeting the wound-healing cascade and
an
fibrogenesis. Until recently, the results of these studies have been disappointing, probably because of the multitude of mediators, growth factors, and signaling pathways involved in the fibrotic process [9]. As such, the
M
only care options endorsed by guidelines published in 2011 were pulmonary rehabilitation, long-term oxygen therapy, lung transplantation, and enrolment in a clinical trial [1].
ed
Since the publication of the guideline document, two new drugs have consistently shown a positive effect on disease progression in IPF: pirfenidone and nintedanib [10–12]. However, at the time of publication of the guidelines, pirfenidone was already approved in Japan and the results of the Clinical Studies Assessing
Ac ce
not yet been published in full.
pt
Pirfenidone in idiopathic pulmonary fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY) trials had
Here, we provide an overview of the most recent clinical trials in IPF and discuss how their results are likely to change the clinical and clinical research landscape of this devastating disease. Pathogenesis of IPF
Over the past decade, the traditional concept of inflammation as the primary pathologic process in IPF has been discarded [13,14]. Today, most clinicians believe IPF to be a disease of aging that results most directly from dysfunctional, senescent lung epithelial cells and fibroblasts [15]. In this pathobiological model, repetitive alveolar stress (e.g., silent microaspiration, chronic low grade infection, or cigarette smoking) occurs in a susceptible lung epithelium (e.g., with genetic or epigenetic abnormalities, telomere shortening, or poor regenerative capacity), leading to the release of cytokines and growth factors [e.g., transforming growth factor
Page 3 of 26
(TGF-β), platelet-derived growth factor (PDGF), Wnts, C-X-C motif chemokine 12 (CXCL12), and chemokine (CC motif) ligand 2 (CCL2)] that activate and recruit fibroblasts and promote fibroproliferation (Figure 3). The observation that drugs with treatment effects (e.g., pirfenidone and nintedanib) are pleiotropic in their mechanism of action suggests that multiple mediators and signaling pathways are involved in disease
ip t
pathogenesis and that truly effective therapies (either single agent or combination) will need to target profibrotic signaling pathways at multiple levels.
cr
Traditional approaches to the pharmacological treatment of IPF
The management of IPF has largely been based on the recommendations of evidence-based guidelines
us
published in 2011 [1], which adopted the American Thoracic Society GRADE methodology to assess the quality of available data [16]. These guidelines did not strongly recommend any pharmacological treatments for patients
an
with IPF (Table 1). Importantly, the historical approach to therapy with prednisone or prednisone plus an immunomodulator, such as azathioprine or cyclophosphamide, was not recommended. Some treatment
M
regimens [combination of N-acetylcysteine (NAC)/prednisone/azathioprine; NAC monotherapy; warfarin; and pirfenidone] were considered unproven but reasonable therapeutic choices for a few IPF patients, based on their
ed
individual values and preferences.
Lessons learned over the past decade of IPF clinical trials The past decade has seen tremendous progress in the management of IPF, largely because of the investment
pt
of key stakeholders (patients, scientists, industry sponsors, and government agencies) in the development and
Ac ce
conduct of high-quality clinical trials (Table 2). Although these advances took longer than hoped, we learned many lessons along the way that will benefit future clinical trial design. Lesson 1: there is no good animal model for IPF Over the years, numerous agents have been shown to inhibit experimentally induced lung fibrosis in mice. Yet, almost all of these compounds have failed to demonstrate comparable antifibrotic effects in humans. One important potential explanation for this is that the bleomycin model, the most widely used animal model of pulmonary fibrosis, does not recapitulate the underlying pathobiology of IPF [17] (although a compound that is ineffective in the bleomycin model is unlikely to be developed further). Indeed, there is no known animal model for IPF. This is not to say that animal models are irrelevant to the drug development pathway (e.g., they allow for specific analyses of signaling pathways and interactions among various cell types), but relying on an animal
Page 4 of 26
model alone to argue for likely efficacy in IPF has proven unwise. Additional preclinical data from IPF patient tissues (e.g. blood or lung) is valuable. Lesson 2: IPF is a disease of abnormal fibroproliferation As previously discussed, the pathogenetic paradigm of IPF has shifted from a primarily inflammatory process to
ip t
a primarily fibroproliferative one [15], although a relative role for inflammation in the initiation and progression of the fibrotic process cannot be excluded, at least in selected disease subsets [18–20]. Several observations from
cr
epidemiologic and genetic studies suggest that IPF develops in genetically susceptible individuals as a
consequence of an aberrant wound-healing response to repetitive epithelial stress [21]. However, novel
us
pathogenetic concepts also suggest a key role for the aberrant extracellular matrix in the fibroproliferative process [22]. Accordingly, drug development in IPF has adjusted to this paradigm and focused on modulation of
an
wound-healing cascades with the intent of inhibiting the fundamental fibrogenetic mechanisms. Lesson 3: IPF is probably a disease with multiple, redundant pathways
M
IPF appears to be characterized by abnormalities in multiple pathways involved in the wound-healing process, many of which display considerable redundancy. Clinical trials of targeted therapies (e.g., bosentan and
and nintedanib) appear efficacious.
ed
etanercept) have shown no benefit, whereas drugs that are highly pleiotropic in their activity (e.g., pirfenidone
Lesson 4: there are no readily measurable tools with which to judge drug effectiveness in individual patients
pt
There has been much discussion regarding what constitutes appropriate primary endpoints in clinical trials in IPF
Ac ce
[23–25]. Using current trial designs, mortality appears prohibitive as a primary endpoint because of the number of patients and study duration required for an adequately powered study [26]. In addition, owing to the availability of two drugs with definite treatment effects (e.g., pirfenidone and nintedanib), it would be unethical to perform a mortality study in patients with mild to moderate disease. Mortality studies might be best suited for patients with end-stage disease, patients who are having an acute exacerbation [27,28], or other subsets of patients who are deemed to be at high risk of disease progression [29]. Change in forced vital capacity (FVC) is considered a marker of disease progression in IPF and is a widely used primary endpoint, given its efficiency, reliability, and regulatory precedent [30]. FVC can also be used as part of a composite, event-driven endpoint that, by capturing distinct pathophysiological domains of disease progression, may provide a wider representation of the effects of a drug. In addition, through increasing the overall event rate, composite endpoints require fewer patients and shorter study durations compared with single event endpoints to complete the study. By contrast, FVC is not
Page 5 of 26
useful as a measure of effectiveness in individual patients, only in placebo-controlled studies. Furthermore, even though the realistic goal of treatment is disease stabilization, we do not have a tool that distinguishes between stability resulting from a drug and stability as part of the natural course of the disease in an individual patient. Lesson 5: there is tremendous interest in IPF among industry partners
ip t
Historically, the pharmaceutical industry has been reluctant to invest in research and development of drugs for rare diseases such as IPF [31]. Yet, successful drug development usually requires industry involvement,
cr
because drug development requires large financial investment. The past decade has witnessed a growing
interest in IPF and a willingness among stakeholders to work together to develop and fund clinical trials of novel
us
compounds. Several novel drugs are currently being investigated in IPF by industry partners (Tables 3 and 4). Recent positive phase III randomized controlled trials
an
ASCEND (pirfenidone)
Pirfenidone [5-methyl-1-phenyl-2-(1H)-pyridone] is a compound with antifibrotic, anti-inflammatory, and
M
antioxidant properties [32], although its precise mechanism of action remains incompletely understood. Four phase III randomized controlled trials (RCT) of pirfenidone in IPF have been performed. In the first one, 275
ed
Japanese patients were randomly assigned in a 2:1:2 ratio to high-dose (1800 mg/day) or low-dose (1200 mg/day) pirfenidone, or placebo [33]. The study showed a positive treatment benefit of pirfenidone as measured by a reduction in the rate of decline in vital capacity (VC) from baseline to week 52. This study was followed by
pt
the CAPACITY program comprising two almost identical randomized, double-blind, placebo-controlled,
Ac ce
multinational trials (PIPF-004 and PIPF-006) [10]. In the first CAPACITY study (study 004), 435 patients were assigned in a 2:1:2 dosing ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, or placebo; in the second CAPACITY study (study 006), 344 patients were assigned 1:1 to pirfenidone 2403 mg/day or placebo. The primary endpoint of both trials was change in percentage predicted FVC from baseline to week 72. In study 004, mean FVC change at week 72 was –8.0% in the pirfenidone 2403 mg/day arm compared with –12.4% in the placebo arm (P = 0.001). By contrast, in study 006, changes in percent predicted FVC were –9.0 and –9.6% in the pirfenidone and placebo arms, respectively (P = 0.501). A Cochrane systematic review and meta-analysis of the three above trials demonstrated that pirfenidone significantly reduced both the rate of decline in lung function and the risk of disease progression in patients with IPF [34]. In the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study [11], 555 IPF patients were randomized 1:1 to either pirfenidone 2403 mg/day (n = 278) or placebo (n =
Page 6 of 26
277). Of note, to enroll patients at higher risk for disease progression, certain aspects of the CAPACITY study design were modified, including exclusion of patients with major airflow limitation [ratio of the forced expiratory volume in 1 s (FEV1) to FVC
S1359-6446(15)00019-7 http://dx.doi.org/doi:10.1016/j.drudis.2015.01.001 DRUDIS 1564
To appear in: Received date: Revised date: Accepted date:
1-10-2014 3-12-2014 7-1-2015
Please cite this article as: Spagnolo, P., Wells, A.U., Collard, H.R.,Pharmacological treatment of idiopathic pulmonary fibrosis: an update, Drug Discovery Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.01.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Paolo Spagnolo1,2, Athol U. Wells3, and Harold R. Collard4 1
ip t
Pharmacological treatment of idiopathic pulmonary fibrosis: an update Medical University Clinic, Canton Hospital Baselland, Liestal, Switzerland University of Basel, Liestal, Switzerland 3 Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK 4 Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine, University of California, San Francisco, CA, USA Corresponding author: Spagnolo, P. ([email protected]) Keywords: idiopathic pulmonary fibrosis; treatment; nintedanib; pirfenidone; clinical trials; interstitial lung disease. Teaser: Idiopathic pulmonary fibrosis is a chronic disease for which there is no cure. New evidence shows that two compounds (pirfenidone and nintedanib) reduce functional decline and disease progression in this devastating disorder.
us
cr
2
an
Author biographies Paolo Spagnolo
Paolo Spagnolo is an associate professor of respiratory medicine and a senior clinical research fellow at the
M
Medical University Clinic of the Canton Hospital Baselland in Liestal. Between 2010 and 2013, he was lecturer in respiratory medicine in the Department of Oncology, Hematology and Respiratory Medicine at the University of
ed
Modena and Reggio Emilia. From 2002 to 2008, Dr Spagnolo worked as a clinical research fellow at the Interstitial Lung disease Unit, Royal Brompton Hospital. In 2008, he completed his PhD at Imperial College
pt
London, with a thesis on genetic susceptibility to sarcoidosis. His main research interests are sarcoidosis and IPF, with special focus on genetic predisposition, prediction of disease behavior, and clinical trials of novel
Ac ce
therapies. Dr Spagnolo is the author or co-author of more than 50 journal articles, review articles, editorials, and book chapters.
Harold R. Collard
Harold R. Collard is an associate professor of medicine in the Division of Pulmonary and Critical Care Medicine at the University of California San Francisco (UCSF) and the director of the Interstitial Lung Disease Program at UCSF. He is a clinical and translational researcher focused on interstitial lung disease. Dr Collard is currently conducting projects investigating: (i) acute exacerbations of IPF; (ii) predicting disease progression; (ii) factors contributing to patients’ symptoms of shortness of breath and ways to improve patients’ quality of life; and (iv) clinical trials of novel therapies for patients with interstitial lung disease. He sits on the American Thoracic Society – European Respiratory Society group revising guidelines in IPF, as well as other joint groups involved in
Page 1 of 26
the definition of nonspecific interstitial pneumonia, and acute exacerbations of IPF. He is the author or co-author of approximately 150 journal articles, review articles, editorials, and book chapters. Athol U. Wells Athol U. Wells is professor of respiratory medicine in the Faculty of Medicine at Imperial College London and
ip t
head of the Interstitial Lung Disease Unit at The Royal Brompton Hospital. Dr Wells chairs the British Thoracic Society group revising guidelines in diffuse lung disease and sits on the American Thoracic Society – European
cr
Respiratory Society group revising guidelines in IPF, as well as other joint groups involved in the definition of nonspecific interstitial pneumonia, smoking-related diffuse lung disease, and acute exacerbations of IPF. His
us
research interests include prognostic evaluation in diffuse lung disease using HRCT and pulmonary function tests, definition of relations between structure and function in diffuse lung disease, definition of disease type and
an
severity in genetic and laboratory studies, and studies of new therapies in diffuse lung disease. He has authored or co-authored more than 300 journal articles, review articles, editorials, and book chapters.
M
Idiopathic pulmonary fibrosis (IPF) is a progressive and almost invariably lethal disease that affects primarily older adults. After a decade of negative (or inconsistent) results, two recent clinical trials have
ed
demonstrated that slowing disease progression with medication is possible. An improved understanding of disease pathogenesis, epidemiology, and diagnostic criteria has been key to this success. Yet, this is only the beginning. It is hoped that continuous efforts by dedicated scientists and
pt
clinicians, patient organizations, health authorities, and pharmaceutical companies will soon lead to the
Introduction
Ac ce
development of more effective and better-tolerated treatment strategies for this devastating disease.
IPF is the most common and lethal of the idiopathic interstitial pneumonias (IIPs), a heterogeneous group of disorders characterized by varying patterns of inflammation and fibrosis [1,2]. The disease, which is relentlessly progressive, is limited to the lungs and occurs primarily in older adults. Retrospective longitudinal studies suggest a median survival time of 2–3 years after diagnosis, but recent clinical trials that recruited patients with mild to moderate functional impairment reported a lower mortality rate [1,3–6]. In the USA alone, approximately 40 000 patients die of this disease annually and recent data indicate a substantially higher incidence and prevalence of IPF in patients aged 65 years and older than previously reported [7]. According to current evidence-based guidelines, the diagnosis of IPF requires the exclusion of all known causes of pulmonary fibrosis (e.g., inhalation of fibrogenic dusts or aerosolized organic antigens, collagen vascular disease, or drug
Page 2 of 26
exposure) and the presence of a usual interstitial pneumonia (UIP) pattern, which is defined radiologically by subpleural, basal-predominant reticular changes, traction bronchiectasis, and honeycombing (Figure 1) and histologically by patchy involvement of lung parenchyma (e.g., alternating areas of dense fibrosis and lessaffected or normal lung); architectural distortion with/without honeycombing; and presence of active fibroblastic
ip t
foci adjacent to areas of densely collagenized fibrosis, all in a subpleural distribution (Figure 2) [1].
Our understanding of the pathobiology of IPF has significantly evolved over the past decade. The disease
cr
appears to be driven by abnormal and/or dysfunctional alveolar epithelial cells (AECs) that promote fibroblast recruitment, proliferation, and differentiation, resulting in scarring of the lung, architectural distortion, and
us
irreversible loss of function [8]. Accordingly, more recent clinical trials have shifted their focus from antiinflammatory and immunosuppressant compounds to molecules targeting the wound-healing cascade and
an
fibrogenesis. Until recently, the results of these studies have been disappointing, probably because of the multitude of mediators, growth factors, and signaling pathways involved in the fibrotic process [9]. As such, the
M
only care options endorsed by guidelines published in 2011 were pulmonary rehabilitation, long-term oxygen therapy, lung transplantation, and enrolment in a clinical trial [1].
ed
Since the publication of the guideline document, two new drugs have consistently shown a positive effect on disease progression in IPF: pirfenidone and nintedanib [10–12]. However, at the time of publication of the guidelines, pirfenidone was already approved in Japan and the results of the Clinical Studies Assessing
Ac ce
not yet been published in full.
pt
Pirfenidone in idiopathic pulmonary fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY) trials had
Here, we provide an overview of the most recent clinical trials in IPF and discuss how their results are likely to change the clinical and clinical research landscape of this devastating disease. Pathogenesis of IPF
Over the past decade, the traditional concept of inflammation as the primary pathologic process in IPF has been discarded [13,14]. Today, most clinicians believe IPF to be a disease of aging that results most directly from dysfunctional, senescent lung epithelial cells and fibroblasts [15]. In this pathobiological model, repetitive alveolar stress (e.g., silent microaspiration, chronic low grade infection, or cigarette smoking) occurs in a susceptible lung epithelium (e.g., with genetic or epigenetic abnormalities, telomere shortening, or poor regenerative capacity), leading to the release of cytokines and growth factors [e.g., transforming growth factor
Page 3 of 26
(TGF-β), platelet-derived growth factor (PDGF), Wnts, C-X-C motif chemokine 12 (CXCL12), and chemokine (CC motif) ligand 2 (CCL2)] that activate and recruit fibroblasts and promote fibroproliferation (Figure 3). The observation that drugs with treatment effects (e.g., pirfenidone and nintedanib) are pleiotropic in their mechanism of action suggests that multiple mediators and signaling pathways are involved in disease
ip t
pathogenesis and that truly effective therapies (either single agent or combination) will need to target profibrotic signaling pathways at multiple levels.
cr
Traditional approaches to the pharmacological treatment of IPF
The management of IPF has largely been based on the recommendations of evidence-based guidelines
us
published in 2011 [1], which adopted the American Thoracic Society GRADE methodology to assess the quality of available data [16]. These guidelines did not strongly recommend any pharmacological treatments for patients
an
with IPF (Table 1). Importantly, the historical approach to therapy with prednisone or prednisone plus an immunomodulator, such as azathioprine or cyclophosphamide, was not recommended. Some treatment
M
regimens [combination of N-acetylcysteine (NAC)/prednisone/azathioprine; NAC monotherapy; warfarin; and pirfenidone] were considered unproven but reasonable therapeutic choices for a few IPF patients, based on their
ed
individual values and preferences.
Lessons learned over the past decade of IPF clinical trials The past decade has seen tremendous progress in the management of IPF, largely because of the investment
pt
of key stakeholders (patients, scientists, industry sponsors, and government agencies) in the development and
Ac ce
conduct of high-quality clinical trials (Table 2). Although these advances took longer than hoped, we learned many lessons along the way that will benefit future clinical trial design. Lesson 1: there is no good animal model for IPF Over the years, numerous agents have been shown to inhibit experimentally induced lung fibrosis in mice. Yet, almost all of these compounds have failed to demonstrate comparable antifibrotic effects in humans. One important potential explanation for this is that the bleomycin model, the most widely used animal model of pulmonary fibrosis, does not recapitulate the underlying pathobiology of IPF [17] (although a compound that is ineffective in the bleomycin model is unlikely to be developed further). Indeed, there is no known animal model for IPF. This is not to say that animal models are irrelevant to the drug development pathway (e.g., they allow for specific analyses of signaling pathways and interactions among various cell types), but relying on an animal
Page 4 of 26
model alone to argue for likely efficacy in IPF has proven unwise. Additional preclinical data from IPF patient tissues (e.g. blood or lung) is valuable. Lesson 2: IPF is a disease of abnormal fibroproliferation As previously discussed, the pathogenetic paradigm of IPF has shifted from a primarily inflammatory process to
ip t
a primarily fibroproliferative one [15], although a relative role for inflammation in the initiation and progression of the fibrotic process cannot be excluded, at least in selected disease subsets [18–20]. Several observations from
cr
epidemiologic and genetic studies suggest that IPF develops in genetically susceptible individuals as a
consequence of an aberrant wound-healing response to repetitive epithelial stress [21]. However, novel
us
pathogenetic concepts also suggest a key role for the aberrant extracellular matrix in the fibroproliferative process [22]. Accordingly, drug development in IPF has adjusted to this paradigm and focused on modulation of
an
wound-healing cascades with the intent of inhibiting the fundamental fibrogenetic mechanisms. Lesson 3: IPF is probably a disease with multiple, redundant pathways
M
IPF appears to be characterized by abnormalities in multiple pathways involved in the wound-healing process, many of which display considerable redundancy. Clinical trials of targeted therapies (e.g., bosentan and
and nintedanib) appear efficacious.
ed
etanercept) have shown no benefit, whereas drugs that are highly pleiotropic in their activity (e.g., pirfenidone
Lesson 4: there are no readily measurable tools with which to judge drug effectiveness in individual patients
pt
There has been much discussion regarding what constitutes appropriate primary endpoints in clinical trials in IPF
Ac ce
[23–25]. Using current trial designs, mortality appears prohibitive as a primary endpoint because of the number of patients and study duration required for an adequately powered study [26]. In addition, owing to the availability of two drugs with definite treatment effects (e.g., pirfenidone and nintedanib), it would be unethical to perform a mortality study in patients with mild to moderate disease. Mortality studies might be best suited for patients with end-stage disease, patients who are having an acute exacerbation [27,28], or other subsets of patients who are deemed to be at high risk of disease progression [29]. Change in forced vital capacity (FVC) is considered a marker of disease progression in IPF and is a widely used primary endpoint, given its efficiency, reliability, and regulatory precedent [30]. FVC can also be used as part of a composite, event-driven endpoint that, by capturing distinct pathophysiological domains of disease progression, may provide a wider representation of the effects of a drug. In addition, through increasing the overall event rate, composite endpoints require fewer patients and shorter study durations compared with single event endpoints to complete the study. By contrast, FVC is not
Page 5 of 26
useful as a measure of effectiveness in individual patients, only in placebo-controlled studies. Furthermore, even though the realistic goal of treatment is disease stabilization, we do not have a tool that distinguishes between stability resulting from a drug and stability as part of the natural course of the disease in an individual patient. Lesson 5: there is tremendous interest in IPF among industry partners
ip t
Historically, the pharmaceutical industry has been reluctant to invest in research and development of drugs for rare diseases such as IPF [31]. Yet, successful drug development usually requires industry involvement,
cr
because drug development requires large financial investment. The past decade has witnessed a growing
interest in IPF and a willingness among stakeholders to work together to develop and fund clinical trials of novel
us
compounds. Several novel drugs are currently being investigated in IPF by industry partners (Tables 3 and 4). Recent positive phase III randomized controlled trials
an
ASCEND (pirfenidone)
Pirfenidone [5-methyl-1-phenyl-2-(1H)-pyridone] is a compound with antifibrotic, anti-inflammatory, and
M
antioxidant properties [32], although its precise mechanism of action remains incompletely understood. Four phase III randomized controlled trials (RCT) of pirfenidone in IPF have been performed. In the first one, 275
ed
Japanese patients were randomly assigned in a 2:1:2 ratio to high-dose (1800 mg/day) or low-dose (1200 mg/day) pirfenidone, or placebo [33]. The study showed a positive treatment benefit of pirfenidone as measured by a reduction in the rate of decline in vital capacity (VC) from baseline to week 52. This study was followed by
pt
the CAPACITY program comprising two almost identical randomized, double-blind, placebo-controlled,
Ac ce
multinational trials (PIPF-004 and PIPF-006) [10]. In the first CAPACITY study (study 004), 435 patients were assigned in a 2:1:2 dosing ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, or placebo; in the second CAPACITY study (study 006), 344 patients were assigned 1:1 to pirfenidone 2403 mg/day or placebo. The primary endpoint of both trials was change in percentage predicted FVC from baseline to week 72. In study 004, mean FVC change at week 72 was –8.0% in the pirfenidone 2403 mg/day arm compared with –12.4% in the placebo arm (P = 0.001). By contrast, in study 006, changes in percent predicted FVC were –9.0 and –9.6% in the pirfenidone and placebo arms, respectively (P = 0.501). A Cochrane systematic review and meta-analysis of the three above trials demonstrated that pirfenidone significantly reduced both the rate of decline in lung function and the risk of disease progression in patients with IPF [34]. In the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study [11], 555 IPF patients were randomized 1:1 to either pirfenidone 2403 mg/day (n = 278) or placebo (n =
Page 6 of 26
277). Of note, to enroll patients at higher risk for disease progression, certain aspects of the CAPACITY study design were modified, including exclusion of patients with major airflow limitation [ratio of the forced expiratory volume in 1 s (FEV1) to FVC
