Paul W. Noble

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a non-neoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known provocation. IPF is a rare disease which affects approximately 5 million persons worldwide. The prevalence is estimated to be slightly greater in men (20.2/100,000) than in women (13.2/100,000). The mean age at presentation is 66 years. IPF initially manifests with symptoms of exercise-induced breathless and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones upon physical exam. Clubbing is found in approximately 50% of IPF patients. Cor pulmonale develops in association with end-stage disease. In that case, classic signs of right heart failure may be present. Etiology remains incompletely understood. Some environmental factors may be associated with IPF (cigarette smoking, exposure to silica and livestock). IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP). The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images and a lung biopsy. In the absence of lung biopsy, the diagnosis of IPF can be made by defined clinical criteria that were published in guidelines endorsed by several professional societies. Differential diagnosis includes other idiopathic interstitial pneumonia, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis and other environmental (sometimes occupational) exposures. IPF is typically progressive and leads to significant disability. The median survival is 2 to 5 years from the time of diagnosis. Medical therapy is ineffective in the treatment of IPF. New molecular therapeutic targets have been identified and several clinical trials are investigating the efficacy of novel medication. Meanwhile, pulmonary transplantation remains a viable option for patients with IPF. It is expected that, during the next decade, considerable progress will be made toward the understanding and treatment of this devastating illness.

Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.

BACKGROUND Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. METHODS We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. Georges Respiratory Questionnaire, both assessed over a 52-week period. RESULTS A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. CONCLUSIONS In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.).

A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.

BACKGROUND In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. METHODS In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. RESULTS In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation. CONCLUSIONS Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).

Regulation of lung injury and repair by Toll-like receptors and hyaluronan

Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88−/− and Tlr4−/−Tlr2−/− mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell–specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell–surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-κB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.

Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials.

BACKGROUND Idiopathic pulmonary fibrosis is a progressive and fatal lung disease with inevitable loss of lung function. The CAPACITY programme (studies 004 and 006) was designed to confirm the results of a phase 2 study that suggested that pirfenidone, a novel antifibrotic and anti-inflammatory drug, reduces deterioration in lung function in patients with idiopathic pulmonary fibrosis. METHODS In two concurrent trials (004 and 006), patients (aged 40-80 years) with idiopathic pulmonary fibrosis were randomly assigned to oral pirfenidone or placebo for a minimum of 72 weeks in 110 centres in Australia, Europe, and North America. In study 004, patients were assigned in a 2:1:2 ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, or placebo; in study 006, patients were assigned in a 1:1 ratio to pirfenidone 2403 mg/day or placebo. The randomisation code (permuted block design) was computer generated and stratified by region. All study personnel were masked to treatment group assignment until after final database lock. Treatments were administered orally, 801 mg or 399 mg three times a day. The primary endpoint was change in percentage predicted forced vital capacity (FVC) at week 72. Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, numbers NCT00287729 and NCT00287716. FINDINGS In study 004, 174 of 435 patients were assigned to pirfenidone 2403 mg/day, 87 to pirfenidone 1197 mg/day, and 174 to placebo. In study 006, 171 of 344 patients were assigned to pirfenidone 2403 mg/day, and 173 to placebo. All patients in both studies were analysed. In study 004, pirfenidone reduced decline in FVC (p=0·001). Mean FVC change at week 72 was -8·0% (SD 16·5) in the pirfenidone 2403 mg/day group and -12·4% (18·5) in the placebo group (difference 4·4%, 95% CI 0·7 to 9·1); 35 (20%) of 174 versus 60 (35%) of 174 patients, respectively, had a decline of at least 10%. A significant treatment effect was noted at all timepoints from week 24 and in an analysis over all study timepoints (p=0·0007). Mean change in percentage FVC in the pirfenidone 1197 mg/day group was intermediate to that in the pirfenidone 2403 mg/day and placebo groups. In study 006, the difference between groups in FVC change at week 72 was not significant (p=0·501). Mean change in FVC at week 72 was -9·0% (SD 19·6) in the pirfenidone group and -9·6% (19·1) in the placebo group, and the difference between groups in predicted FVC change at week 72 was not significant (0·6%, -3·5 to 4·7); however, a consistent pirfenidone effect was apparent until week 48 (p=0·005) and in an analysis of all study timepoints (p=0·007). Patients in the pirfenidone 2403 mg/day group had higher incidences of nausea (125 [36%] of 345 vs 60 [17%] of 347), dyspepsia (66 [19%] vs 26 [7%]), vomiting (47 [14%] vs 15 [4%]), anorexia (37 [11%] vs 13 [4%]), photosensitivity (42 [12%] vs 6 [2%]), rash (111 [32%] vs 40 [12%]), and dizziness (63 [18%] vs 35 [10%]) than did those in the placebo group. Fewer overall deaths (19 [6%] vs 29 [8%]) and fewer deaths related to idiopathic pulmonary fibrosis (12 [3%] vs 25 [7%]) occurred in the pirfenidone 2403 mg/day groups than in the placebo groups. INTERPRETATION The data show pirfenidone has a favourable benefit risk profile and represents an appropriate treatment option for patients with idiopathic pulmonary fibrosis. FUNDING InterMune.

Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.

BACKGROUND Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis. METHODS In a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Secondary end points included acute exacerbations, quality of life (measured with the St. Georges Respiratory Questionnaire [SGRQ]), and total lung capacity. RESULTS A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group. CONCLUSIONS In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683 .).

Hyaluronan and its catabolic products in tissue injury and repair.

Hyaluronan is an unbiquitous glycosaminoglycan present in most tissues. Under homeostatic conditions hyaluronan exists as a high molecular mass polymer that has important roles in tissue structural integrity. Under conditions of stress such as following tissue injury, hyaluronan becomes depolymerized and lower molecular mass polymers are generated. The biological properties of these hyaluronan fragments appear to be distinct from the larger precursor molecules. This review examines the biological role of hyaluronan fragments in tissue injury and repair.

The Clinical Course of Patients with Idiopathic Pulmonary Fibrosis

Context The natural history of idiopathic pulmonary fibrosis (IPF) is unclear. Contribution A total of 168 participants with mild to moderate IPF assigned to placebo in a randomized trial were followed at 12-week intervals for about 76 weeks. For 32 of 36 patients who died, IPF was a related or main cause of death. Although physiologic variables such as FVC changed little, acute clinical deterioration preceded death in half of the patients who died of IPF. Implications Clinicians may need to rethink referral timing for lung transplantation because many patients with IPF may experience precipitous clinical declines rather than gradual progression of disease. The Editors Idiopathic pulmonary fibrosis (IPF), the most frequent of the idiopathic interstitial pneumonias, is associated with the worst prognosis (1, 2). However, data on the natural history of IPF are sparse. To clearly describe the pace of progression and the cause of death in a well-characterized cohort with mild to moderate IPF, we analyzed data from the placebo group of a randomized, double-blind, controlled clinical trial evaluating therapy with interferon-1b in patients with IPF (3). These data provide important insight into the natural history of IPF and events preceding death in patients with IPF. The data suggest that a gradual, progressive decline does not occur in many patients, thereby supporting the need for early referral for lung transplantation. Methods Overview Using data from a recently completed clinical trial (3), we performed a series of exploratory analyses of physiologic variables, dyspnea measures, hospitalizations, and characteristics of mortality in patients randomly assigned to receive placebo. The prespecified primary end point analysis for the phase III study was to occur after the 306th randomly assigned patient was scheduled to complete 48 weeks of therapy. Patients were enrolled over an approximately 1-year period. Thus, follow-up times for the patients varied, and the numbers of patients available for visits beyond 48 weeks diminished over time. In the published report of the primary analysis of the trial, the median length of observation was 58 weeks (3). In the current report, we summarize data from randomization through the completion of blinded study therapy (the observation period); the median for this period was 76 weeks. Study Participants Study participants were all patients randomly assigned to the placebo group (n= 168) in the trial (3). Criteria for enrollment included a diagnosis of IPF according to American Thoracic Society criteria (4), an FVC of 50% to 90%, diffusing capacity of carbon monoxide (DLco) of 25% or greater, definite or probable IPF on high-resolution computed tomography according to prespecified criteria, and worsening of disease during the preceding year despite a total corticosteroid dose of 1800 mg or greater within the preceding 2 years (3). Patients were permitted to continue taking prednisone (15 mg/d) if the dosage remained stable. Data Collection Data were collected at 12-week intervals and recorded on standardized case report forms by trained research associates at each institution. Information derived from interview and examination of the patient included demographic and clinical data, physiologic assessments, measures of dyspnea, vital status, number of all-cause hospitalizations, and number of hospitalizations for which the primary reason was specified as respiratory. Physiologic measures included FVC, plethysmography, Dlco, and arterial blood gas at room-air ambient temperatures. The transition dyspnea score is derived from an instrument in which the patient assesses the extent of dyspnea in reference to his or her baseline at study entry (5). The transitions or changes in the patients dyspnea in 3 categories (function impairment, magnitude of task needed to evoke dyspnea, and magnitude of effort needed to evoke dyspnea) are rated in 7 grades from 3 (major deterioration) to 0 (unchanged) to 3 (major improvement); the final score ranged from 9 to 9. The lower the total score, the more severe the dyspnea. The validated University of California, San Diego, Shortness of Breath Questionnaire (6) has 24 items: Patients are asked to rate severity of shortness of breath using a 6-point scale (0 = not at all; 5 = maximal severity) during 21 different activities of daily living associated with varying levels of exertion; they are also asked to rate how their daily lives are limited by shortness of breath, fear of harm from overexertion, and fear of shortness of breath. Scores range from 0 to 120, with increasing score indicating worsening quality of life. The physician responsible for any patient who died during the study period completed a retrospective supplemental questionnaire. The investigator-physician, who had full access to all measurements obtained as a part of the study, specified the primary cause of death, whether the cause was respiratory, and whether death was related to IPF. Investigator-physicians were to cite IPF as the primary cause of death only in the absence of a known alternative cause and only if the event was witnessed. For deaths considered to be IPF-related, 1 of 4 categories was assigned on the basis of the interval from the onset of new or worsening symptoms or signs until death: abrupt (occurring within minutes to hours), acute (4 weeks), subacute (progressing over weeks or months), or unknown. In the current report, we combine the abrupt- and acute-onset events within a single category. Statistical Analysis Physiologic variables and measures of dyspnea were compared between baseline and week 72. The frequency of hospitalizations (all-cause and respiratory-related), number of hospital days in patients hospitalized, and mortality were assessed over the entire observation period. Mean values are followed by SDs. The relationships between baseline percentage predicted FVC and the incidence and length of hospitalization were examined by using the Fisher exact test or independent-sample t-test, as appropriate. Missing values were not imputed. The reasons for missing values are as follows: 1) To optimize data integrity, data obtained at visits outside a window of 7 days were not included in the analysis, 2) because trial enrollment was staggered, fewer patients were available for analysis at the latter time points, and 3) the value for a particular variable for a particular patient may be missing, even though all other values for that time point and patient are available. On the basis of the nature of the variations leading to the differences in available data over time, no apparent evidence indicated that the variations are not random. Data analyses were conducted by using SAS software, version 8.02 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source InterMune, Inc., funded this study. Authors from InterMune (Drs. Safrin, Starko, and Bradford) participated in the design and analysis of the study, as did the other authors. All authors had full access to the data. The funding source had no role in the decision to publish the results. Results Patients We analyzed 168 patients (mean age, 64 years, SD 9). Most patients were male (66%), white (86%), and nonsmokers (that is, never-smokers or ex-smokers) (91%). Mean time since the diagnosis of IPF was 378 days, SD, 295. The diagnosis of IPF was confirmed by surgical lung biopsy in 58% of patients; in 83%, findings on high-resolution computed tomography met prespecified criteria for definite IPF. At study entry, 31% of patients used supplemental oxygen and 82% were receiving systemic corticosteroids. During the observation period, 2 patients (1.2%) used azathioprine and 1 patient (0.6%) used cyclophosphamide. Physiologic Variables and Measures of Dyspnea For patients who survived to week 72, the mean percentage predicted FVC decreased from 64.5%, SD 11.1%, to 61.0%, SD 14.1%; the mean percentage predicted DLco decreased from 37.8%, SD 11.1%, to 37.0%, SD 19.9%; and the mean alveolararterial gradient increased from 23.2 mm Hg, SD 10.9, to 26.9 mm Hg, SD 13.0. The mean transition dyspnea index score was 1.29, SD 3.6, at week 72, indicating worsening dyspnea, whereas the mean University of California, San Diego, Shortness of Breath Questionnaire score changed minimally (from 45.1, SD 23.4, to 46.8, SD 25.1) (Figure 1). For patients who died during the trial, we observed a general trend toward increases in alveolararterial gradient and dyspnea and toward decreases in FVC and DLco (Figure 2). The spaghetti plots (Figure 2) highlight the finding that although dyspnea or alveolararterial gradient often increased sharply before a patients death, significant intrapatient variability occurs over time. Figure 1. Measures of physiology and dyspnea from study entry through week 72 for patients who survived throughout trial. Figure 2. Measures of physiology and dyspnea for each of the 36 patients who died during the trial; each line represents a single patient. Hospitalizations Fifty-seven (34%) patients had a total of 95 all-cause hospitalizations during the observation period. Among those hospitalized, the mean total number of hospital days was 14.3, SD 13.5. Thirty-eight (23%) patients had 57 hospitalizations for a respiratory disorder, with a mean total number of hospital days of 15.0, SD 14.6. The most commonly reported reason for respiratory hospitalization (33%) was presumed infection. When stratified by the baseline median percentage predicted FVC, patients with more severely impaired lung function (62%) were more likely to be hospitalized for any reason than patients with baseline percentage predicted FVC greater than 62%35 (42%) versus 22 (26%) patients (P= 0.05) and 58 versus 37 hospitalizations overall. Respiratory hospitalizations were similarly more frequent in the subset of patients with baseline FVC of 62% or less: 25 (30%) versus 13 (15%) patients (P= 0.04). In hospitalized patients, the total number

Hyaluronan as an Immune Regulator in Human Diseases

Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on various cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage from the environment by interacting with TLR2 and TLR4. Hyaluronan and hyaluronan-binding proteins regulate inflammation, tissue injury, and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration. This review focuses on the role of hyaluronan as an immune regulator in human diseases.

Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition

There are currently few treatment options for pulmonary fibrosis. Innovations may come from a better understanding of the cellular origin of the characteristic fibrotic lesions. We have analyzed normal and fibrotic mouse and human lungs by confocal microscopy to define stromal cell populations with respect to several commonly used markers. In both species, we observed unexpected heterogeneity of stromal cells. These include numerous cells with molecular and morphological characteristics of pericytes, implicated as a source of myofibroblasts in other fibrotic tissues. We used mouse genetic tools to follow the fates of specific cell types in the bleomcyin-induced model of pulmonary fibrosis. Using inducible transgenic alleles to lineage trace pericyte-like cells in the alveolar interstitium, we show that this population proliferates in fibrotic regions. However, neither these cells nor their descendants express high levels of the myofibroblast marker alpha smooth muscle actin (Acta2, aSMA). We then used a Surfactant protein C-CreERT2 knock-in allele to follow the fate of Type II alveolar cells (AEC2) in vivo. We find no evidence at the cellular or molecular level for epithelial to mesenchymal transition of labeled cells into myofibroblasts. Rather, bleomycin accelerates the previously reported conversion of AEC2 into AEC1 cells. Similarly, epithelial cells labeled with our Scgb1a1-CreER allele do not give rise to fibroblasts but generate both AEC2 and AEC1 cells in response to bleomycin-induced lung injury. Taken together, our results show a previously unappreciated heterogeneity of cell types proliferating in fibrotic lesions and exclude pericytes and two epithelial cell populations as the origin of myofibroblasts.