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Pirfenidone: significant treatment effects in idiopathic pulmonary fibrosis
Article first published online: 14 JUN 2012
© 2012 Blackwell Publishing Ltd
The Clinical Respiratory Journal
Volume 6, Issue 3, pages 131–143, July 2012
How to Cite
Hilberg, O., Simonsen, U., du Bois, R. and Bendstrup, E. (2012), Pirfenidone: significant treatment effects in idiopathic pulmonary fibrosis. The Clinical Respiratory Journal, 6: 131–143. doi: 10.1111/j.1752-699X.2012.00302.x
All authors wrote and revised the paper
Conflict of interest
The authors have stated explicitly that there are no conflicts of interest in connection with this article.
- Issue published online: 14 JUN 2012
- Article first published online: 14 JUN 2012
- Manuscript Accepted: 31 MAY 2012
- Manuscript Received: 30 MAY 2012
- Manuscript Revised: 30 MAY 2012
Pirfenidone has been shown in three recently published trials to slow down the progression of the devastating interstitial lung disease, idiopathic pulmonary fibrosis (IPF). The precise mechanisms that initiate and perpetuate the histopathological process leading to lung fibrosis in IPF are still uncertain, but increased concentrations of reactive oxidative species and fibrogenetic factors have been observed in the pulmonary tissue of patients. Although the exact mechanisms of its action are unknown, pirfenidone is a small molecule with antifibrotic and some hydroxyl scavenger properties that has recently been approved in Europe and elsewhere for the treatment of IPF. Along with the new ATS/ERS/JRS/ALAT 2011 statement for ‘Evidence Based Guidelines for Diagnosis and Management’, there is now a more profound basis for offering IPF patients an evidence-based evaluation and treatment. This review summarizes the background to the recommended use of pirfenidone for the treatment of IPF.
Please cite this paper as: Hilberg O, Simonsen U, du Bois R and Bendstrup E. Pirfenidone: significant treatment effects in idiopathic pulmonary fibrosis. Clin Respir J 2012; 6: 131–143.
During the last decade, there has been a significant development in the treatment modalities for cancer. Idiopathic pulmonary fibrosis (IPF) has been compared with cancer because of its mortality rate that is higher than many cancers with a median survival of 2–3 years. The incidence of IPF seems to be on the increase, but despite this, the cause and pathogenesis have not been completely elucidated . IPF is the most common of the idiopathic interstitial pneumonias, and as it has the worst prognosis, it represents a significant challenge to the pulmonary physician. In a recent review, Ley et al.  discuss the clinical course and predictors of survival of IPF presenting four clinical recognizable patterns of IPF: the ‘slow decliner’ with a subclinical period, the ‘moderate decliner’ with a faster progression of the disease, the ‘rapid decliner’ with a very rapid progressive pattern often leading to death within a year (probably equivalent to the Hamman–Rich syndrome) and the ‘exacerbator’ characterized by sudden declines because of acute exacerbations. The recognition of these patterns or phenotypes is important when choosing candidates for lung transplantation and may be even more important in the future, possibly allowing physicians to choose patients for targeted therapy when specific treatments are developed as is seen in cancer therapy .
With the approval of pirfenidone for IPF treatment, a hope has been kindled for both patients and physicians, suggesting that we, in the future, will be able to modify the disease course of IPF and thus improve the prognosis for this devastating disease.
The new official ATS/ERS/JRS/ALAT statement has defined IPF as a specific form of chronic progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, and limited to the lungs. IPF is characterized by progressive worsening of dyspnea and lung function and is associated with a poor prognosis .
The former major and minor criteria proposed in the ATS/ERS statement 2000  have been eliminated and the new guidelines now emphasize a multidisciplinary approach involving pulmonologist, radiologist and pathologist to establish a confident diagnosis. The diagnosis of IPF is based on exclusion of known causes of IPF, specific high-resolution computerized tomography (HRCT) patterns definite usual interstitial pneumonia (UIP), possible UIP and inconsistent with UIP and histopathological patterns (UIP, probable UIP, possible UIP and not UIP). HRCT is now considered as one of the key features in diagnosing IPF (see Table 1 2). The typical HRCT (see Fig. 1) shows subpleural, basal reticulation and honeycombing with or without traction bronchiectasis and presence of a definite UIP pattern abolishes the need for a surgical biopsy. If HRCT shows possible UIP pattern or a pattern inconsistent with UIP, a lung biopsy should be taken.
|UIP||Probable UIP||Possible UIP||Nonclassifiable fibrosis||Not UIP|
|Possible UIP||IPF||IPF||Probable IPF||Probable IPF||Not IPF|
|Not UIP||Possible IPF||Not IPF||Not IPF||Not IPF||Not IPF|
|Number of patients and dose||Inclusion criteria||Efficacy, variables||Observation time||Primary result||Other findings||Reference|
|54||Open label||Survival, lung function||12 and 24 months||‘Stabilization of lung function’||Few adverse effects|||
|40 mg/kg||TLC 59% FVC|
|59% DLco 34%||Adverse effects|
|10||Open label||Radiology score||12 months||No deterioration in radiology|||
|107||PaO2 > 70 mmHg||Desaturation during 6-min walk||6 or 9 months||Trend||Positive effect on VC and exacerbation|||
|Placebo: 35||Saturation < 90% during exercise||TLC/VC/DLco|
|1800 mg: 72|
|267||Desaturation during exercise test > 5%, but saturation > 85%||VC, progression free survival||12 months||Decrease in VC decline (P = 0.0416)||Photosensitivity was the major adverse event|||
|1800 mg: 108|
|1200 mg: 55|
|435||FVC 50–90%||FVC||72 months||Decrease in FVC decline (P = 0.001)||Pooled Capacity I and II showed reduced IPF mortality||Capacity I |
|Placebo: 174||DLco 35–90%|
|2403 mg: 174||6MWT > 150 m|
|1194 mg: 87|
|344||FVC 50–90%||FVC||72 months||Not significantly different||Difference in favor of pirfenidone until week 48||Capacity II |
|Placebo: 173||DLco 35–90%||Reduced decline in 6MWT|
|2403 mg: 171||6MWT>150 m|
|78||Open label||Radiology score||12 months||Lower number in active group shows decline in VC, significant smaller change in CT||Correlation between CT and decline in VC|||
|Controls 40||Decline in %pred VC > 10%|
|Dose not stated in the paper|
Recently, important clinical predictors including age, cough as a single symptom, history of respiratory hospitalization within the previous 24 weeks, percentage predicted forced vital capacity (FVC) and 24-week change in percentage predicted FVC have been added to the list of already known risk factors [6-8]. Along with an increasing knowledge about mechanisms and treatment, this provides the physician with an opportunity to improve individualization of diagnosis and treatment.
Although many of the pathways that are involved in fibrogenesis in IPF are known, two key areas remain uncertain: why the lung becomes repeatedly injured and why fibrotic repair, once started, is not regulated . What is known is that the initial event involves alveolar epithelial injury and several factors including viral infections [10, 11] and gastroesophageal reflux  have been listed as possible eliciting candidates. The mechanisms of fibrogenesis have been extensively explored by the use of animal models. In mouse models, the single dose bleomycin model has been the most commonly used, but the histopathology induced in this and other models lacks many of the typical features of UIP  Moreover, several studies test the prevention of development of fibrosis rather than the modulation of the progression to fibrosis after the lung injurious process has started, a model that better reflects human clinical disease. There is, therefore, a pressing need for the development of new animal models to test potential drug candidates against lung fibrosis, not just administered in a preventative model but also when they are used in therapeutic models of drug efficacy.
Emerging evidence suggests that genetic predisposition is an important factor in the development of IPF, especially familial disease. Several loci have been identified, including those that appear to have an effect on alveolar and bronchial epithelial cell function including mutations in lung surfactant proteins C and A1 and the MUC5B gene. Other genes in which mutations appear to increase the risk of IPF include two genes necessary for telomerase function, TERT and TERC. Mutations of these genes are found particularly in familial pulmonary fibrosis [14-16]. In Scandinavia, ELMOD2 has been identified as a candidate gene in Finnish familial IPF .
The main treatment approach to IPF was until recently based on the perception of IPF as an inflammatory disease and high-dose corticosteroids were considered the mainstay of treatment although the observed effect was minimal [25, 26]. Cyclophosphamide, which has been shown to have a role in treating the diffuse lung disease of scleroderma, has not been demonstrated to be effective in IPF and the same is true for azathioprine [27, 28]. During the last decade, several novel treatments for IPF including bosentan (endothelin receptor antagonist) , imatinib (tyrosine kinase inhibitor) , etanercept [tumor necrosis factor (TNF)-α inhibitor] , interferron-γ-1b  and anticoagulation (warfarin)  have been evaluated in randomized clinical trials without convincing evidence for a benefit triple therapy, i.e. the combination of corticosteroids, the immunosuppressant azathioprine and the antioxidant N-acetylcysteine that was shown to slow progression in one study  [must now be viewed with some caution  after interim results from the IPFnet PANTHER study, disclosed only in a press release thus far, reported increased mortality, morbidity and hospital admissions in those patients on the active triple arm compared with placebo, although the final report is awaiting publication and proper scrutiny . Inhaled N-acetylcysteine as monotherapy has been shown to have some effect in a small study in early IPF . More recently, a multiple kinase inhibitor has been shown to improve rate of decline in lung function and other indices in a phase II study, but this requires confirmation in ongoing phase III studies . In the ATS/ERS/JRS/ALAT 2011 statement, guidelines are set out for treatment options. Using the GRADE system of evaluation that assigns varying degrees of strength of either a positive or negative recommendation, only lung transplantation was given a positive recommendation as evidence-based treatment for prolonging survival in IPF . All other treatments reviewed were awarded a negative with four of these ‘scored’ as ‘weak negative’. This translates into a suggestion that treatment with pirfenidone is a reasonable choice, appropriate for a minority of patients . A recent Cochrane review, which uses rigorous methodology to identify good quality studies of a particular agent or agents and then applies meta-analytical techniques to determine whether or not any of the agents is shown to be of benefit, has in contrast concluded that pirfenidone is of benefit. In this Cochrane review, analyzing four phase II or phase III studies, pirfenidone was found to improve progression-free survival by approximately 30% and to prevent the rate of pulmonary function decline [38-42].
Pirfenidone is a pyridine [5-methyl-1-phenyl-2-(1H)-pyridone] originally synthesized by Gadekar as an agent that had analgesic, antipyretic and anti-inflammatory actions . Pirfenidone is an orally available synthetic small molecule with a molecular weight of 185 g/mol (see Fig. 2) and it is able to move through cell membranes without requiring a receptor. It is easily absorbed from the gastrointestinal tract after oral administration with a peak blood level after 1–2 h. It crosses the blood-brain barrier and is eliminated during the urine within 6 h .
Mechanisms of action
The precise cellular mechanism whereby pirfenidone modulates fibrogenesis is still not understood in detail, but its effects are probably multitargeted because both antioxidant, antitransforming growth factor (anti-TGF) and antiplatelet derived growth factor effects have been demonstrated. Although multiple different mechanisms of action of pirfenidone in IPF have been suggested, studies of pirfenidone and novel analogues suggest that substitution of one of the side groups may enhance the antifibrotic activity and further work in this area will possibly contribute to a better understanding of the mechanisms behind IPF and treatment .
Pirfenidone is ineffective as a scavenger of superoxide radicals  but is a scavenger of hydroxyl radicals . Although the human therapeutic dose of pirfenidone used in clinical trials for the treatment of IPF is very high, ranging from 1197 to 2403 mg/day, the resulting plasma concentrations of 8–9 mg/L are in the low end of the hydroxyl scavenging effect of millimolar concentrations of pirfenidone [47, 48]. Therefore, a targeted mechanism of action leading to the antifibrotic effects of pirfenidone cannot be excluded. The antifibrotic effects of pirfenidone may be in part because of a reduction of oxidative stress induced by toxic hydroxyl radicals . Increased oxidative stress or increased reactive oxygen species (ROS) production have been implicated in a wide variety of pathologies, including IPF. Pirfenidone inhibits NADPH-induced lipid peroxidation in isolated sheep liver microsomes in a dose-dependent manner. Increasing scientific evidence points to Nox4 as the key source of ROS in the pathogenesis of IPF. It has been shown that Nox4 is up-regulated in both mouse models of IPF and in lung fibroblasts of human IPF patients (see Fig. 3 for possible mechanisms of action in IPF of pirfenidone). As is the case with the etiology and the precise pathogenesis of IPF, it is even more difficult to speculate on the precise mechanisms of action of pirfenidone in IPF.
The bleomycin single dose mouse model has been used extensively in the evaluation of pirfenidone but is, as mentioned, incomplete and lacking many of the typical features of UIP . Nonetheless, the model may give some indications of the antifibrotic effects of pirfenidone at a mechanistic level. Pirfenidone regulates the activity of TGF-β and TNF-α in vitro, inhibits fibroblast proliferation and collagen synthesis and reduces cellular and histological markers of fibrosis in animal models of lung fibrosis .
In a hamster model that was the original basis for suggesting the antifibrotic properties of pirfenidone, it was found that pirfenidone could suppress the bleomycin-induced increased vascular permeability. This was done by inhibition of transmigration of neutrophils, macrophages and lymphocytes into the lung interstitium and the blockage of the synthesis and release of a variety of potent pro-inflammatory and profibrogenic cytokines such as TGF-β and ROS from these cells. It was concluded that the ability of pirfenidone to independently affect both anti-inflammatory and antifibrotic mechanisms makes it an important drug in the management of lung fibrosis by arresting both the inflammatory phase and fibroproliferative components in the development of progressive lung fibrosis [50-53].
Inherited pulmonary fibrosis
General antifibrotic effects in pulmonary fibrosis are unfortunately not evident, since in a recent study in patients with Hermansky–Pudlak syndrome, pirfenidone failed to show any benefits despite the promising outcome of a previous study .
Other fibrotic diseases
As well as its impact on lung fibrosis, the antifibrotic properties of pirfenidone have also been demonstrated in other diseases. A recent randomized, double-blind, placebo-controlled study in diabetic nephropathy of 77 patients suggests that pirfenidone is a promising agent for individuals with overt diabetic nephropathy .
A pilot study in advanced liver fibrosis has shown promising results . Another open-label study of seven patients with established radiation-induced fibrosis indicated an improvement in SF36 and physical score .
Based on the known mechanisms of bronchiolitis obliterans after lung transplantation, pirfenidone has been suggested as a possible treatment option [58-60], although the concept has yet to be verified in human studies.
Clinically relevant end points in human IPF studies of novel therapy
Given the pathology of IPF with established, often extensive, fibrosis without significant inflammation at the time of diagnosis in most patients, the anticipated treatment effect of any agent cannot realistically be one of improvement or cure, but rather a slowing down and ideally total cessation of the relentless deterioration, and the best response will in most IPF patients, therefore, be prevention of disease progression.
Several end points have been used in the different randomized trials in IPF. Decreased mortality or improved survival is the ‘strongest'/optimal end point, but in most previous placebo-controlled studies, only patients with mild-to-moderate IPF have been included, making trials powered for mortality very expensive and impractical.
The earliest IPF studies used time-to-progression or progression-free survival (defined as more than 10% decline in FVC, more than 15% decline in DLco (diffusion capacity), acute exacerbation, death or lung transplantation listing) as the primary end point, whereas recent trials mostly have focused on FVC.
FVC is now considered a relevant clinical marker of disease progression and survival in IPF. Change in FVC is a reliable, reproducible and valid marker for predicting likely outcome in IPF based on several prospective and retrospective studies [61-63]. A 10% decline in FVC within 6–12 months is related to a significantly increased mortality over the subsequent year, and a less major change of 5%–10% over 24 weeks has also been shown to be highly predictive of mortality. Furthermore, evaluation of the first Japanese phase III pirfenidone study showed that changes in VC at month 3 can be used as a prognostic biomarker in IPF . FVC impairment is related to patient symptom scores for dyspnea and other health status measures . The minimal clinically important difference for FVC has been shown to be 2%–6%, and although such a minor change might occur without obvious clinical or subjective worsening for patients, it should warn physicians that the patient may well be deteriorating and that future trends need to be examined carefully with a view to modulating management if necessary.
Secondary end points that have been studied include other pulmonary function parameters (total lung capacity, diffusion capacity for carbon monoxide, SpO2), quality-of-life measures (St. George's Respiratory Questionnaire, 36-item Short-Form questionnaire, EuroQOl, Group Five Dimension Self-Report Questionnaire and Health state score and visual analog score), dyspnea (Transition dyspnea index and Mahler dyspnea scale), number of or time to acute exacerbations, radiographic progression on HRCT and the alveolar-arterial oxygen tension gradient and survival. The 6-min walk test (6MWT) was predictive of mortality in one study but has not yet been sufficiently validated and is therefore generally still used as a secondary end point . Despite having somewhat fallen into disrepute, one recent study has shown that categorical change in distance walked in 6-min can be predictive of subsequent mortality, suggesting that perhaps categorical change in this measure may be of value in future studies . Recently, a review of different clinically meaningful primary end points in phase 3 clinical trials of IPF highlighted the difficulties in validating surrogate markers for mortality and the complexities, therefore, of choosing the most sensible end point .
Randomized and open-label clinical studies of pirfenidone in IPF
The first clinical study of pirfenidone was an open-label phase II study comprising 54 patients with a mean age of 62 years and duration of symptoms of 4.6 years (Table 2). Individuals were followed for 2 years with a 1- and 2-year survival of 78% and 63%. The authors state ‘Patients whose lung functions had deteriorated prior to enrollment appeared to stabilize after beginning treatment’. Unfortunately, there was no control group, and the results presented do not allow a quantitative evaluation of lung function because of survival bias. There were few observed adverse effects of pirfenidone (dose 40 mg/kg, maximum of 3600 mg) and the results were described as ‘encouraging’ .
In a smaller, also open-label study over a period of 1 year in patients with advanced IPF (n = 8) or with pulmonary fibrosis secondary to diffuse systemic sclerosis (n = 2), plasma concentration of pirfenidone was measured after a dosage of 40 mg/kg. No effect of concomitant treatment on plasma pirfenidone concentration was found. The radiological scores and arterial blood oxygen pressure did not deteriorate significantly in treated patients over the 1-year study period . These results were encouraging, but because of the limited number of patients, no conclusion could be drawn.
In a phase II study in Japan, 107 IPF patients participated: 72 patients were treated with pirfenidone and 35 patients with placebo . The majority of the patients were steroid naive (86%). Patients between 20 and 75 years of age with adequate oxygenation at rest (PaO2 > 70 mmHg) and demonstrating SpO2 ≤ 90% during exertion while breathing air within 1 month before enrollment were included. Pirfenidone and placebo were titrated from 200 to 600 mg t.i.d. (three times a day), the latter being considered the maximum-tolerated maintenance dose. In case of nontolerance, down-titration was based on the severity and duration of the adverse event. The primary end point was defined as the 6- and 9-month change in the lowest SpO2 during a 6-min steady-state exercise test (6MET) from the baseline level was not met (P = 0.1489). In a subpopulation of more ‘fit’ IPF patients, who were able to complete the baseline exercise testing without dropping SpO2 below 80%, the effect was statistically significant (P = 0.0069 at 6 months, P = 0.0305 at 9 months).
The study was aborted before reaching primary end point because of a significant reduction of the incidence of acute exacerbations in the pirfenidone-treated group. Among the other secondary end points, a significant reduction in decline in VC was found in the pirfenidone-treated group as compared with the placebo group, most evident at 9 months (P = 0.366). No statistical difference was found in TLC (total lung capacity), DLco, PaO2, disease progression by HRCT patterns, dyspnea or quality-of-life scores.
Another double-blind, placebo-controlled phase III study in Japanese patients included 267 patients between 20 and 75 years of age with IPF (HRCT with definite UIP pattern or HRCT with probable UIP pattern and histopathology with definite or probable UIP pattern). Inclusion criteria were based on (i) oxygen desaturation of ≥5% difference between resting SpO2 and the lowest SpO2 during a 6MET and (ii) the lowest SpO2 during the 6MET of >85% while breathing room air . The primary end point was change in VC after 52 weeks. The study comprised three arms: 108 patients receiving 1800 mg/day, 55 receiving 1200 and 104 receiving placebo. Significant differences were observed in VC decline between the placebo group (−0.16 L) and the high-dose group (−0.09 L). The absolute difference was 70 mL and the relative difference was 44% (P = 0.0416) between groups. Differences between the two groups with regard to progression-free survival time (P = 0.028) were also observed in favor of pirfenidone, while other secondary end points (TLC, DLco and SpO2) did not reach statistical significance.
The two major studies confirming the usefulness of pirfenidone in IPF have recently been published . The Capacity program comprised two studies (004 and 006). The inclusion criteria in both studies were patients aged 40–80 years with a diagnosis of IPF (HRCT based). If predefined HRCT criteria were not met, the patient needed to have had a surgical biopsy in confirmation of the diagnosis in the previous 48 months and no evidence of improvement in measures of disease severity over the preceding year. Also, FVC of at least 50% predicted, DLco at least 35% predicted, either FVC or DLco no higher than 90% predicted and 6MWT distance of at least 150 m were required.
In study 004, 435 patients were enrolled and assigned in a 2:1:2 ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day or placebo. In study 006, 344 patients were assigned in a 1:1 ratio to pirfenidone 2403 mg/day or placebo. Treatments were administered orally three times a day. The primary end point was change in percentage predicted FVC at week 72 at the end of the study. In study 004, pirfenidone reduced the decline in FVC (P = 0.001). Mean FVC change at week 72 was −8.0% in the pirfenidone 2403 mg/day group and −12.4% in the placebo group. 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 implying a dose-response relationship. 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% in the pirfenidone group and −9.6% in the placebo group; however, a consistent pirfenidone effect was apparent until week 48 (P = 0.005) (Fig. 4). There was a less decline in 6MWT distance with pirfenidone in the 006 study.
No statistical difference was found in DLco, dyspnea, worst PaO2 during 6MWT or disease progression by HRCT patterns in either study.
Pooled data from Capacity 004 and 006 showed that pirfenidone reduced the decline in the 6MWT, prolonged progression-free survival and reduced IPF-related on-treatment mortality in the 2403 mg/day group.
In a recent Cochrane meta-analysis including all three phase III studies, pirfenidone was found to improve progression-free survival [hazard ratio 0.70, 95% confidence interval (CI) 0.56–0.88; P = 0.002] and, in the phase II and phase III Japanese studies, rate of decline in VC (mean difference 0.08 L, 95% CI 0.03–0.13, P = 0.0006) .
The most recent study included 78 patients: 38 consecutive patients treated with pirfenidone and 40 age-matched controls from a historical cohort. Deterioration of respiratory status was defined as 10% or greater decline in percentage predicted VC after 12-month treatment. The dosage of pirfenidone is not given in the paper. A significantly larger proportion of pirfenidone-treated patients showed stable respiratory status (21/38, 65.6%) than the control (15/40, 37.5%). The change in fibrous lesion on CT evaluation at the start and after 1 year of treatment was significantly smaller in the pirfenidone group than the control in both visual score (P = 0.006) and computer analysis (P < 0.001). The authors conclude that CT can be used to assess pirfenidone-induced slowing of progression of pulmonary fibrosis .
Side effects of pirfenidone
In all the five clinical studies, pirfenidone was generally well tolerated. In the Capacity studies, nausea was seen in 36% of the patients in the pirfenidone group compared with 17% in the placebo-group, but also dyspepsia, vomiting and anorexia, rash, photosensitivity and dizziness were more commonly reported  (see Table 3). Rash, photosensitivity and increased liver transaminases could all be controlled by either dose reduction or termination of treatment. No serious adverse events including an increased risk of infections were noted. Because pirfenidone is predominantly metabolized by CYP1A2 and, to a lesser extent, CYP2C9, CYP2C19, CYP2D6 and CYP2E1, the pharmacokinetics of pirfenidone may potentially be altered by coadministration with inhibitors or inducers of one or more of these enzymes .
IPF is a progressive and irreversible devastating lung disease with few treatment options beside lung transplantation and palliation. After the first ATS/ERS statements in 2000 on IPF and subsequently in 2002 on the classification of idiopathic interstitial pneumonias, a revolution has taken place in the IPF community and several randomized placebo-controlled studies have been performed. Unfortunately, very few of the investigated drugs have shown convincing evidence for a disease-modifying effect. During recent years, new antifibrotic drugs have been introduced with the potential of slowing down disease progression and possibly blocking the occurrence of acute exacerbations. Most patients with IPF have established fibrosis, as evidenced by reticular changes on HRCT, at the time of diagnosis and it is unrealistic to expect any agent to remove these. Thus, the most realistic treatment goal is to prevent further disease progression.
Pirfenidone is the first antifibrotic drug available for IPF patients and has already been approved for treatment of mild-to-moderate IPF in Europe, Japan, India and China. More drugs are expected to be introduced during the coming years, but at the present time pirfenidone, palliation and lung transplantation are the only treatment options. Pirfenidone offers new hope of prolonged survival for patients with this devastating disease, although definitive evidence of an effect on mortality, and not just pulmonary function indices, has not been shown. However, given that a categorical decline in FVC is considered the best biomarker of disease progression and that a more than 5% decline in 24 weeks is associated with increased mortality, it would seem to the authors that change in FVC is a sensible, balanced end point for clinical trials and is clinically meaningful. Admittedly, pirfenidone is not a miracle drug and treatment effects are modest, but for the moment, pirfenidone seems to be the best available treatment option for patients with a disease that has a worse prognosis than many malignant diseases .
The indication for pirfenidone treatment is in definite IPF based on the diagnostic criteria from the recent ATS/ERS/JRS/ALAT statement and mild-to-moderate disease. Criteria for ‘mild-to-moderate’ disease have not, however, been defined and until then, the inclusion criteria from the capacity trials with FVC > 50% of predicted and DLco > 35% of predicted should be used. No studies have explored the efficiency of pirfenidone in patients with severe IPF although nonblinded, nonrandomized extension studies from the Capacity trials are ongoing. Right now, there is no evidence for a treatment effect in the severely diseased patient group and treatment should thus be limited to patients with mild-to-moderate disease until new evidence is presented.
Some IPF patients with mild disease can be stable for several years before progression commences. This raises the question whether all IPF patients should start pirfenidone treatment immediately after diagnosis. At the moment, there is no evidence to support otherwise, as also slowly progressive patients have been included in the clinical trials. However, it would be intriguing to postpone treatment in patients without baseline risk factors and wait until signs of progression (Table 4). Otherwise, biochemical biomarkers or a profile of markers that can identify this patient group would be of great advantage both for indication and monitoring of the treatment. On the other hand, if progression is rapid, then a window of opportunity to prevent that decline will have been lost. As with other decisions, careful discussion between patient and physician will result in the most appropriate individual decision being made.
|Level of dyspnea|
|DLco < 40% predicted desaturation ≤ 88% during 6MWT extent of honeycombing on HRCT pulmonary hypertension|
|Increase in level of dyspnea|
|Decrease in FVC ≥ 10% absolute value|
|Decrease in DLco ≥ 15% absolute value|
|Worsening of fibrosis on HRCT|
Studies of pirfenidone have shown equivocal effects on the exacerbation rate in IPF, and effect on the exacerbation rate at least in a part of the disease process could be one of its actions in humans. It is well known that pulmonary hypertension in interstitial lung disease and especially in IPF worsens the prognosis . Whether pirfenidone has the capacity to target vascular remodeling or has to be combined with other drugs targeting the vasculature has also to be clarified. Therefore, further studies of the action of pirfenidone and long-term safety are warranted as well as extended clinical trials in IPF; other fibrotic lung diseases and pulmonary vascular diseases are required.
IPF is the most common of the ‘idiopathic fibrotic lung diseases’ and some of the pathogenetic mechanisms are probably more or less the same in the other diseases. Although the connective tissue-associated lung fibrosis generally has a different pattern from NSIP (nonspecific interstitial pneumonia) and a better prognosis than IPF , mortality because of lung fibrosis and pulmonary vascular disorders is also seen especially in patients with systemic sclerosis and also in rheumatoid arthritis. Nonspecific interstitial pneumonia has a progressive fibrotic form with some of the same phenotypic patterns as IPF, and it is not known whether there is any effect of pirfenidone in these diseases. Animal studies and the effect on other fibrotic diseases in the human body suggest that pirfenidone has a universal effect on fibrosis. However, the lack of effect on lung fibrosis in Hermansky–Pudlak syndrome suggests that the effect is not general and that clinical studies will be required to determine the use of pirfenidone outside IPF as well as further investigations into the mechanisms of action of pirfenidone.
Conclusion and perspectives
IPF has for many years been one of the diseases in pulmonary medicine with the poorest prognosis. The etiology is still unknown and the pathophysiology is only partly understood. Treatment has been so far palliative except for lung transplantation. Because the lack of donor organs and often high age and comorbidities in affected patients, lung transplantation is rarely an option. During the last two decades until recently, no treatment has been proven effective. Pirfenidone slows the decline in lung function in IPF patients, increases the progression-free survival time and reduces IPF-related mortality. There are few side effects and the treatment may give new hope to IPF patients. Further studies will show whether pirfenidone is the multifaceted drug that will, in a compelling fashion, change the course of the disease. There is also a hope for further improvement by modification of this small interesting molecule.
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