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Pirfenidone: Clinical trials and clinical practice in patients with idiopathic pulmonary fibrosis
respiratory investigation 54 (2016) 298 –304
Contents lists available at ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Review
Pirfenidone: Clinical trials and clinical practice in patients with idiopathic pulmonary fibrosis Masashi Bandon Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi, Japan
ar t ic l e in f o
abs tra ct
Article history:
Pirfenidone is an oral drug that exerts not only anti-fibrotic activity but also pleiotropic
Received 17 November 2015
effects, such as anti-inflammatory and anti-oxidative effects. Because it suppresses
Received in revised form
reduction in vital capacity and improves progression-free survival, it was approved in
18 March 2016
October 2008 in Japan for the first time in the world as an anti-fibrotic agent for treatment
Accepted 22 March 2016
of idiopathic pulmonary fibrosis (IPF). In October 2014, the agent was approved in the U.S.,
Available online 26 April 2016
based on the results of the ASCEND study. Today, it is commercially available in 38
Keywords:
countries worldwide.
Idiopathic pulmonary fibrosis
In clinical practice, it is important to pay attention to the balance between the
Pirfenidone
effectiveness and adverse events (such as gastrointestinal symptoms and photosensitivity
Clinical trial
reactions, among others) of treatment with pirfenidone. It is important to investigate
Clinical practice
pirfenidone's most cost-effective usage, and the ideal time of treatment initiation, the condition in which treatment should be initiated, and duration of treatment. & 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
4. 5.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 Mechanism of pirfenidone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 Pirfenidone in clinical trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 3.1. Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 3.2. Foreign countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 3.3. Systematic review and meta-analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 Positioning of pirfenidone in the international guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 Current status of treatment with pirfenidone in clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 5.1. Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 5.1.1. A prospective epidemiological study by web registration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 5.1.2. A survey on the experience of long-term pirfenidone administration with a clinical survey sheet . . . . 302 5.1.3. Post-marketing surveillance of patients treated with pirfenidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
n
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http://dx.doi.org/10.1016/j.resinv.2016.03.007 2212-5345/& 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
respiratory investigation 54 (2016) 298 –304
299
5.1.4. Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 5.2. Foreign countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 6. Future challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
1.
Introduction
Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause in adults [1]. The natural history of IPF is variable and unpredictable at the time of diagnosis [2]. In consideration of treatment strategies for IPF, it is most important to evaluate aspects of the clinical course and multiple factors for poor prognosis, and elucidate the necessity of treatment intervention and treatment goals. The preferred therapeutic approach for IPF began to change after the emergence of the physiopathological hypothesis of the disease, in which the development of the condition was proposed as an epithelial-mesenchymal reparative abnormality that could commence without previous inflammation [3]. Based on this new concept, different research avenues were opened with the aim of inhibiting the fibrogenic process triggered in the disease; this was the beginning of the “anti-fibrotic” era. Pirfenidone is an oral anti-fibrotic drug; it was approved for IPF in Japan in October 2008 for the first time in the world. Seven years have passed since it became commercially available, and it has become a key drug for treatment of IPF in Japan. Experiences of using the agent in clinical practice have been collected. Meanwhile, the results of the ASCEND study were reported in 2014, and the Food and Drug Administration (FDA) in the U.S. approved the agent as a treatment for IPF that year. Currently, it is on the market in 38 countries worldwide.
2.
Mechanism of pirfenidone
Pirfenidone is a low-molecular-weight compound with a pyridone ring and was first synthesized by Margolin in the U.S. in 1974 [4]. It shows pleiotropic effects, such as suppression of the production of reactive oxygen species; inflammatory cytokines such as TNF-α, IL-1β, and IL-6 derived from monocytes (anti-inflammatory and anti-oxidative activities); expression of growth factors such as TGF-β, b-FGF, and PDGF; and proliferation and collagen synthesis of fibroblasts (antifibrotic activity). It also improves the balance of Th1/Th2 by inhibiting the decrease in IFN-γ [5–7], although its exact mechanism is unknown. Recently, new mechanisms of action have been reported, such as the inhibition of the conversion of the phenotype of fibroblasts into myofibroblasts by inhibiting the intracellular signal pathway of TGF-β and the inhibition of fibrotic activity via suppression of the formation of nod-like receptor (NLR) P3 inflammasomes in cardiac muscle [8,9]. It is anticipated that a new mechanism of action will be elucidated by basic and clinical research.
3.
Pirfenidone in clinical trials
The first clinical trial to investigate the use of pirfenidone in IPF was a phase II open-label trial for severe IPF that started in the U.S. in 1995 [10], in which stabilization of respiratory function was observed for two years. Later, a phase II clinical trial [11] and a phase III trial [12] were carried out for the first time in Japan. Two phase III trials (CAPACITY and ASCEND studies) [13,14] were carried out in North America, Europe, and Australia.
3.1.
Japan
The study period was determined as 1 year in the phase II trial [11], but interim analysis 6 months after the start of the study showed significant acute exacerbation in the placebo group, and the key was opened at 9 months. When all subjects were analyzed, there was no significant difference in the primary endpoint. However, there was a significant difference when the subjects were limited to the cases that completed a walking test with SpO2 maintained at Z80%. In addition, vital capacity (VC) reduction, a secondary endpoint, was significantly suppressed. In the phase III trial [12], the annual rate of decline in VC, a primary endpoint, was significantly suppressed in the highdose (1800 mg/day) and low-dose pirfenidone groups (1200 mg/day) compared with those of the placebo group. Progression-free survival (PFS), a major secondary endpoint, was significantly prolonged in these groups compared with that of the placebo group. Azuma et al. [15] examined the association between pirfenidone efficacy and the baseline lung functions including %VC, arterial oxygen partial pressure, and the lowest SpO2 in the 6-min steady-state exercise test (6MET). The results of these explanatory analyses identified IPF patients having baseline %VC Z70% and SpO2o90% during 6MET as the subpopulation that benefited most from pirfenidone treatment.
3.2.
Foreign countries
The CAPACITY trial [13] was carried out in a twin-trial manner (CAPACITY 1 and 2), and a reduction in FVC from the baseline, a primary endpoint, and PFS, secondary endpoint, showed a significant difference in the CAPACITY 2 trial but not in the CAPACITY 1 trial. When the results of the two trials were integrated, there was a significant difference found in not only the primary endpoint but also in PFS, sixminute walking distance, change in % FVC in each category, and IPF-associated death, compared with those of the placebo group. On the basis of these results, the U.S. FDA decided against approving pirfenidone for IPF in May 2010. An additional trial (ASCEND trial) was then planned in North America and Australia. In Europe, meanwhile, the European Medicines
respiratory investigation 54 (2016) 298 –304
(0.32 (0.75 (0.19 (0.50 (0.64 (1.33 0.53 0.83 0.59 0.64 0.74 2.26 RR RR RR RR RR RR Risk with Pirfenidone
36 per 1000 (22 to 59) 372 per 1000 (332 to 416) 15 per 1000 (5 to 47) 107 per 1000 (84 to 139) 308 per 1000 (267 to 358) 68 per 1000 (40 to 115) 67 per 1000 442 per 1000 26 per 1000 168 per 1000 417 per 1000 30 per 1000 All cause-mortality Progression free-survival Acute exacerbation Worsening of IPF Change on 6MWT Change on aminotransferases
The results of the three clinical trials reported up to 2011 [11– 13] were reflected in the contents of the evidence-based diagnosis and management guidelines for IPF by the ATS/ ERS/JRS/ALAT [1]. Pirfenidone was not recommended for IPF, but the level of “not recommended” was described as weak when it was categorized into “strong” and “weak.” However, guidelines and statements in EU countries often recommend pirfenidone administration for mild and moderate IPF at % FVC 450% and % DLco 435% [17]. On the basis of the results of the ASCEND trial and the integrated analysis of CAPACITY, positioning of pirfenidone was changed to a drug with conditional recommendation for use in the clinical practice
Risk with placebo
4. Positioning of pirfenidone in the international guidelines
Table 1 – Summary of meta-analysis result.
Aravena et al. [16] conducted a systematic review to evaluate the effectiveness of pirfenidone compared to placebo in IPF using the GRADE approach. They included five randomized controlled trials [11–14]. The meta-analysis showed a decrease in all cause-mortality and IPF-related mortality (Table 1); other outcomes evaluated were the worsening of IPF and acute exacerbation. In addition, there was a decrease in progression-free survival. Therefore, they concluded that pirfenidone treatment should be considered not only for its benefits in pulmonary function tests but also for its clinically relevant outcomes.
1: Non primary outcome from RCTs, 2: High heterogeneity; 6MWT: Six minutes walk test; RCT: Randomized controlled trial; RR: Risk ratio; CI: Confidence interval.
○ MODERATE1 ○ MODERATE1 ○○ LOW1,2 ○ MODERATE1 HIGH ○ MODERATE1 to to to to to to
0.88) 0.94) 1.84) 0.83) 0.86) 3.83)
1247 (3 RCTs) 728 (3 RCTs) 235 (2 RCTs) 1615 (5 RCTs) 1236 (3 RCTs) 764 (5 RCTs)
NO of participants Relative effect
Systematic review and meta-analysis Anticipate absolute effects (Study population) (95% CI)
3.3.
Quality of the evidence (GRADE)
Agency (EMA) approved the agent in March 2011, and it became available on the market in countries such as Germany and Denmark. In Asia, it was commercially available in Korea starting in October 2012. The ASCEND trial [14] was conducted in nine countries including the U.S., Australia, and South America (the pirfenidone group [2403 mg/day], 278; and the placebo group, 277) and the results were made public in May 2014. The linear slope of decline in FVC at week 52 was 164 ml in the pirfenidone group and 280 ml in the placebo group, representing an absolute difference of 116 ml. In addition, pirfenidone significantly reduced the proportion of patients who had a decline of 10% or more in the percentage of the %FVC, or who died, and increased the proportion of patients who had no decline in the percentage of the %FVC as compared with placebo. It should be noted that there was a significant difference between the placebo group in the primary endpoint from as early as week 13. Furthermore, integrated analysis of CAPACITY 1 and 2 revealed a reduction in overall yearly fatal risk by 48% and death-related risk by 68%. Adverse events such as gastrointestinal disorders and skin problems frequently occurred in the pirfenidone group, but critical adverse events requiring termination of pirfenidone administration rarely occurred. Thus, the FDA approved pirfenidone for the treatment of IPF in October 2014. It is currently commercially available in 38 countries worldwide, including Japan, 27 EU countries, Canada, Korea, China, India, and Argentina.
Outcomes
300
301
respiratory investigation 54 (2016) 298 –304
Table 2 – Recommendations.
For patients with IPF, the guideline committee recommends: Clinicians NOT use imatinib. Clinicians NOT use warfarin anticoagulation in patients who do not have a known alternative indication for its use. Clinicians NOT use the combination therapy of N-acetylcysteine, azathioprine, and prednisone. Clinicians NOT use ambrisentan, a selective ER-A endothelin receptor antagonist, regardless of the presence or absence of PH. For patients with IPF, the guideline committee suggests: Clinicians use nintedanib. Clinicians use pirfenidone. Clinicians NOT use sildenafil, a phosphodiesterase-5 inhibitor. Clinicians NOT use bosentan or macitentan, both dual ER-A and ER-B endothelin receptor antagonists. Clinicians NOT use N-acetylcysteine monotherapy. Clinicians use regular anti-acid treatment.
guideline for IPF treatment updated in 2015 by the ATS/ERS/ JRS/ALAT (Table 2) [18].
Quality of evidence
Strength of recommendation
Confidence in estimates
⊖ ⊖⊖
Strong Strong
Moderate Low
⊖⊖
Strong
Low
⊖⊖
Strong
Low
⊖ ⊖ ⊖ ⊖⊖
Conditional Conditional Conditional Conditional
Moderate Moderate Moderate Low
⊖⊖ ⊖⊖⊖
Conditional Conditional
Low Very Low
practice with regards to IPF [19]. This was a multicenter collaborative study, and clinical findings and information on the clinical course and details of treatment in idiopathic
5. Current status of treatment with pirfenidone in clinical practice
interstitial pneumonia cases, including IPF cases, were inputted via the internet prior to the start of the study. In total, 321 cases from 19 institutes were registered. With
5.1.
Japan
regard to the details of treatment for IPF and their change
5.1.1.
A prospective epidemiological study by web registration
of cases up to the end of the fiscal year 2008 when pirfeni-
A prospective surveillance study on diffuse lung disease was carried out in Japan to elucidate the current status of clinical
done was approved, whereas “no treatment” decreased to
(Fig. 1), “no treatment” was most frequently observed in 78.7%
44.6% and pirfenidone was administered in 32.9% of cases,
Fig. 1 – The treatments and their changes in IPF. Until the end of the 2008 fiscal year, “no treatment” was most frequently chosen (78.7% of patients). It was reduced to 44.6% of cases in the fiscal years of 2009 to 2013. On the other hand, there were only negligible changes in steroid monotherapy, which changed from 6.2% to 7.5% of cases after 2009, and in combination therapy of steroids and immunosuppressive agents, which increased slightly from 11.2% to 13.1% in the same period. NAC; N-acetylcysteine.
302
respiratory investigation 54 (2016) 298 –304
including pirfenidone monotherapy in 17.4%, between the fiscal year 2009 and the end of the fiscal year 2013. After the end of the fiscal year 2013, it became a key drug for IPF treatment in Japan.
5.1.2. A survey on the experience of long-term pirfenidone administration with a clinical survey sheet Experiences of long-term pirfenidone administration in clinical practice were surveyed in a multicenter collaborative study. The study aimed to elucidate not only the reason of treatment discontinuation within one year but also the benefits regarding respiratory function (FVC) in the cases with long-term treatment for two years or longer. The subjects of the clinical survey were IPF patients treated with pirfenidone in the institutes of collaborators of the research on diffuse lung disease supported by the Ministry of Health, Labour and Welfare [20]. From 22 institutes, 502 answers were collected and treatment was terminated within one year in 186 cases (37.1%). Adverse effects were the most frequent reason in 77 of the cases (41.4%), followed by death in 60 cases (32.3%). Pirfenidone treatment was continued for two years or longer in 111 cases (22.1%). Yearly changes in FVC varied and were dependent on the individual case. Only a small proportion showed an improvement in FVC. However, FVC showed no deterioration after two years or thereafter in more than half of the cases in which FVC was stable after introduction of treatment, which suggested the possibility that pirfenidone stabilized FVC for a long period of time (Fig. 2).
5.1.3. Post-marketing surveillance of patients treated with pirfenidone Post-marketing surveillance was conducted in all cases where administration of pirfenidone commenced between November 2008 and October 2009 [21], and safety in 1371
Fig. 2 – Changes in the percent ΔFVC 12, 24, and 36 months after pirfenidone treatment was started. The course of the decline in the FVC in patients in the stable group (n ¼47, circle) compared to that of patients in the improved group (n¼ 10, open squares) and progressive group (n¼ 11, open circle) with a follow-up time of 412 months after pirfenidone treatment was started. Data are presented as the meanþstandard deviation.
cases was analyzed. The incidence of total adverse drug reactions (ADRs) was 64.6%. ADRs with an incidence of Z 3% were decreased appetite, photosensitivity reactions, nausea, abdominal discomfort, malaise, somnolence, and abnormal hepatic function. Treatment with pirfenidone stabilized both VC and subjective symptoms in most patients (70–80%) treated for at least 6 months. This surveillance demonstrated that pirfenidone was generally well tolerated in patients with IPF, including those with severe lung function impairment.
5.1.4.
Others
Having had the experience of administering pirfenidone treatment for IPF in 76 cases at all JRS severity grades [12] of I–IV, Okuda et al. reported suppression of FVC reduction by pirfenidone and significant suppression of FVC reduction, particularly in cases with FVC reduction of 150 mL or more before introduction of treatment [22]. Having administered pirfenidone treatment in 41 cases, Arai et al. reported that treatment response was excellent in the short term in mild to moderate IPF (JRS severity grading, I/II) cases and those that had undergone surgical lung biopsy [23]. Sakamoto et al. also reported efficacy of pirfenidone in eight of 18 advanced cases (44%) with JRS severity grades of III–IV [24]. Taken together, it is reasonable to conclude that pirfenidone has the potential to be effective for advanced IPF under certain conditions.
5.2.
Foreign countries
Having experienced the administration of pirfenidone treatment in 63 cases in clinical practice in Germany, Oltmanns et al. reported that respiratory function (VC and DLco) deteriorated in 15 cases (38%) during the average treatment period of 11 months, and the period until deterioration was 8 months on average. Respiratory data were stable for as long as 18 months in 24 of 39 cases (61.5%) that were treated continuously for 3 months or longer, and adverse effects were observed in 85% of cases, most of which were treated successfully [25]. Valeyre et al. investigated the safety of long-term administration of pirfenidone and reported that most adverse effects, such as photosensitivity and gastrointestinal symptoms (such as nausea and vomiting) appeared within six months after introduction of treatment and the occurrence rate markedly decreased thereafter [26]. Loch et al. retrospectively analyzed FVC change before and after pirfenidone treatment in IPF patients in Germany and Italy, and reported that yearly changes in FVC before treatment ( 7.0%71.8%, 248.17199.3 mL) significantly improved (þ2.773.6%, þ51.47351.4 mL) after treatment, and that the response to pirfenidone was remarkable in cases with a yearly reduction in FVC by 10% or more before treatment [27]. Taken together, management of ADRs to achieve the maximum benefits after long-term treatment with pirfenidone is an issue that needs to be resolved [28].
6.
Future challenges
It is important to investigate the most effective usage of pirfenidone (including cost effectiveness in administration)
respiratory investigation 54 (2016) 298 –304
regarding when treatment with pirfenidone should commence (possibility of early treatment) for IPF patients, under what conditions it should be used (exploration of clinical background and markers to predict efficacy in the patient group with expected effectiveness), and for how long the treatment should be continued. In addition, efficacy of combination therapy with N-acetyl cysteine (NAC) [29], how to select between administration of pirfenidone and nintedanib, and whether combination therapy is effective and safe are issues that must be resolved in the future [30,31]. Furthermore, it has been reported that pirfenidone treatment is effective for preventing acute exacerbation of IPF, for prevention of acute exacerbation in the perioperative period, and for postoperative treatment in IPF cases with lung cancer [32,33]. Therefore, exploring the new clinical uses of pirfenidone is an important goal of future research.
Conflict of interest
[12] [13]
[14]
[15]
[16]
[17]
[18]
Bando received lecture fees from Shionogi & Co., Ltd., and Boehringer Ingelheim. [19]
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Contents lists available at ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Review
Pirfenidone: Clinical trials and clinical practice in patients with idiopathic pulmonary fibrosis Masashi Bandon Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi, Japan
ar t ic l e in f o
abs tra ct
Article history:
Pirfenidone is an oral drug that exerts not only anti-fibrotic activity but also pleiotropic
Received 17 November 2015
effects, such as anti-inflammatory and anti-oxidative effects. Because it suppresses
Received in revised form
reduction in vital capacity and improves progression-free survival, it was approved in
18 March 2016
October 2008 in Japan for the first time in the world as an anti-fibrotic agent for treatment
Accepted 22 March 2016
of idiopathic pulmonary fibrosis (IPF). In October 2014, the agent was approved in the U.S.,
Available online 26 April 2016
based on the results of the ASCEND study. Today, it is commercially available in 38
Keywords:
countries worldwide.
Idiopathic pulmonary fibrosis
In clinical practice, it is important to pay attention to the balance between the
Pirfenidone
effectiveness and adverse events (such as gastrointestinal symptoms and photosensitivity
Clinical trial
reactions, among others) of treatment with pirfenidone. It is important to investigate
Clinical practice
pirfenidone's most cost-effective usage, and the ideal time of treatment initiation, the condition in which treatment should be initiated, and duration of treatment. & 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
4. 5.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 Mechanism of pirfenidone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 Pirfenidone in clinical trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 3.1. Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 3.2. Foreign countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 3.3. Systematic review and meta-analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 Positioning of pirfenidone in the international guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 Current status of treatment with pirfenidone in clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 5.1. Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 5.1.1. A prospective epidemiological study by web registration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 5.1.2. A survey on the experience of long-term pirfenidone administration with a clinical survey sheet . . . . 302 5.1.3. Post-marketing surveillance of patients treated with pirfenidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
n
Tel.: þ81 285 56 7850; fax: þ81 285 44 3586. E-mail address: [email protected]
http://dx.doi.org/10.1016/j.resinv.2016.03.007 2212-5345/& 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
respiratory investigation 54 (2016) 298 –304
299
5.1.4. Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 5.2. Foreign countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 6. Future challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
1.
Introduction
Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause in adults [1]. The natural history of IPF is variable and unpredictable at the time of diagnosis [2]. In consideration of treatment strategies for IPF, it is most important to evaluate aspects of the clinical course and multiple factors for poor prognosis, and elucidate the necessity of treatment intervention and treatment goals. The preferred therapeutic approach for IPF began to change after the emergence of the physiopathological hypothesis of the disease, in which the development of the condition was proposed as an epithelial-mesenchymal reparative abnormality that could commence without previous inflammation [3]. Based on this new concept, different research avenues were opened with the aim of inhibiting the fibrogenic process triggered in the disease; this was the beginning of the “anti-fibrotic” era. Pirfenidone is an oral anti-fibrotic drug; it was approved for IPF in Japan in October 2008 for the first time in the world. Seven years have passed since it became commercially available, and it has become a key drug for treatment of IPF in Japan. Experiences of using the agent in clinical practice have been collected. Meanwhile, the results of the ASCEND study were reported in 2014, and the Food and Drug Administration (FDA) in the U.S. approved the agent as a treatment for IPF that year. Currently, it is on the market in 38 countries worldwide.
2.
Mechanism of pirfenidone
Pirfenidone is a low-molecular-weight compound with a pyridone ring and was first synthesized by Margolin in the U.S. in 1974 [4]. It shows pleiotropic effects, such as suppression of the production of reactive oxygen species; inflammatory cytokines such as TNF-α, IL-1β, and IL-6 derived from monocytes (anti-inflammatory and anti-oxidative activities); expression of growth factors such as TGF-β, b-FGF, and PDGF; and proliferation and collagen synthesis of fibroblasts (antifibrotic activity). It also improves the balance of Th1/Th2 by inhibiting the decrease in IFN-γ [5–7], although its exact mechanism is unknown. Recently, new mechanisms of action have been reported, such as the inhibition of the conversion of the phenotype of fibroblasts into myofibroblasts by inhibiting the intracellular signal pathway of TGF-β and the inhibition of fibrotic activity via suppression of the formation of nod-like receptor (NLR) P3 inflammasomes in cardiac muscle [8,9]. It is anticipated that a new mechanism of action will be elucidated by basic and clinical research.
3.
Pirfenidone in clinical trials
The first clinical trial to investigate the use of pirfenidone in IPF was a phase II open-label trial for severe IPF that started in the U.S. in 1995 [10], in which stabilization of respiratory function was observed for two years. Later, a phase II clinical trial [11] and a phase III trial [12] were carried out for the first time in Japan. Two phase III trials (CAPACITY and ASCEND studies) [13,14] were carried out in North America, Europe, and Australia.
3.1.
Japan
The study period was determined as 1 year in the phase II trial [11], but interim analysis 6 months after the start of the study showed significant acute exacerbation in the placebo group, and the key was opened at 9 months. When all subjects were analyzed, there was no significant difference in the primary endpoint. However, there was a significant difference when the subjects were limited to the cases that completed a walking test with SpO2 maintained at Z80%. In addition, vital capacity (VC) reduction, a secondary endpoint, was significantly suppressed. In the phase III trial [12], the annual rate of decline in VC, a primary endpoint, was significantly suppressed in the highdose (1800 mg/day) and low-dose pirfenidone groups (1200 mg/day) compared with those of the placebo group. Progression-free survival (PFS), a major secondary endpoint, was significantly prolonged in these groups compared with that of the placebo group. Azuma et al. [15] examined the association between pirfenidone efficacy and the baseline lung functions including %VC, arterial oxygen partial pressure, and the lowest SpO2 in the 6-min steady-state exercise test (6MET). The results of these explanatory analyses identified IPF patients having baseline %VC Z70% and SpO2o90% during 6MET as the subpopulation that benefited most from pirfenidone treatment.
3.2.
Foreign countries
The CAPACITY trial [13] was carried out in a twin-trial manner (CAPACITY 1 and 2), and a reduction in FVC from the baseline, a primary endpoint, and PFS, secondary endpoint, showed a significant difference in the CAPACITY 2 trial but not in the CAPACITY 1 trial. When the results of the two trials were integrated, there was a significant difference found in not only the primary endpoint but also in PFS, sixminute walking distance, change in % FVC in each category, and IPF-associated death, compared with those of the placebo group. On the basis of these results, the U.S. FDA decided against approving pirfenidone for IPF in May 2010. An additional trial (ASCEND trial) was then planned in North America and Australia. In Europe, meanwhile, the European Medicines
respiratory investigation 54 (2016) 298 –304
(0.32 (0.75 (0.19 (0.50 (0.64 (1.33 0.53 0.83 0.59 0.64 0.74 2.26 RR RR RR RR RR RR Risk with Pirfenidone
36 per 1000 (22 to 59) 372 per 1000 (332 to 416) 15 per 1000 (5 to 47) 107 per 1000 (84 to 139) 308 per 1000 (267 to 358) 68 per 1000 (40 to 115) 67 per 1000 442 per 1000 26 per 1000 168 per 1000 417 per 1000 30 per 1000 All cause-mortality Progression free-survival Acute exacerbation Worsening of IPF Change on 6MWT Change on aminotransferases
The results of the three clinical trials reported up to 2011 [11– 13] were reflected in the contents of the evidence-based diagnosis and management guidelines for IPF by the ATS/ ERS/JRS/ALAT [1]. Pirfenidone was not recommended for IPF, but the level of “not recommended” was described as weak when it was categorized into “strong” and “weak.” However, guidelines and statements in EU countries often recommend pirfenidone administration for mild and moderate IPF at % FVC 450% and % DLco 435% [17]. On the basis of the results of the ASCEND trial and the integrated analysis of CAPACITY, positioning of pirfenidone was changed to a drug with conditional recommendation for use in the clinical practice
Risk with placebo
4. Positioning of pirfenidone in the international guidelines
Table 1 – Summary of meta-analysis result.
Aravena et al. [16] conducted a systematic review to evaluate the effectiveness of pirfenidone compared to placebo in IPF using the GRADE approach. They included five randomized controlled trials [11–14]. The meta-analysis showed a decrease in all cause-mortality and IPF-related mortality (Table 1); other outcomes evaluated were the worsening of IPF and acute exacerbation. In addition, there was a decrease in progression-free survival. Therefore, they concluded that pirfenidone treatment should be considered not only for its benefits in pulmonary function tests but also for its clinically relevant outcomes.
1: Non primary outcome from RCTs, 2: High heterogeneity; 6MWT: Six minutes walk test; RCT: Randomized controlled trial; RR: Risk ratio; CI: Confidence interval.
○ MODERATE1 ○ MODERATE1 ○○ LOW1,2 ○ MODERATE1 HIGH ○ MODERATE1 to to to to to to
0.88) 0.94) 1.84) 0.83) 0.86) 3.83)
1247 (3 RCTs) 728 (3 RCTs) 235 (2 RCTs) 1615 (5 RCTs) 1236 (3 RCTs) 764 (5 RCTs)
NO of participants Relative effect
Systematic review and meta-analysis Anticipate absolute effects (Study population) (95% CI)
3.3.
Quality of the evidence (GRADE)
Agency (EMA) approved the agent in March 2011, and it became available on the market in countries such as Germany and Denmark. In Asia, it was commercially available in Korea starting in October 2012. The ASCEND trial [14] was conducted in nine countries including the U.S., Australia, and South America (the pirfenidone group [2403 mg/day], 278; and the placebo group, 277) and the results were made public in May 2014. The linear slope of decline in FVC at week 52 was 164 ml in the pirfenidone group and 280 ml in the placebo group, representing an absolute difference of 116 ml. In addition, pirfenidone significantly reduced the proportion of patients who had a decline of 10% or more in the percentage of the %FVC, or who died, and increased the proportion of patients who had no decline in the percentage of the %FVC as compared with placebo. It should be noted that there was a significant difference between the placebo group in the primary endpoint from as early as week 13. Furthermore, integrated analysis of CAPACITY 1 and 2 revealed a reduction in overall yearly fatal risk by 48% and death-related risk by 68%. Adverse events such as gastrointestinal disorders and skin problems frequently occurred in the pirfenidone group, but critical adverse events requiring termination of pirfenidone administration rarely occurred. Thus, the FDA approved pirfenidone for the treatment of IPF in October 2014. It is currently commercially available in 38 countries worldwide, including Japan, 27 EU countries, Canada, Korea, China, India, and Argentina.
Outcomes
300
301
respiratory investigation 54 (2016) 298 –304
Table 2 – Recommendations.
For patients with IPF, the guideline committee recommends: Clinicians NOT use imatinib. Clinicians NOT use warfarin anticoagulation in patients who do not have a known alternative indication for its use. Clinicians NOT use the combination therapy of N-acetylcysteine, azathioprine, and prednisone. Clinicians NOT use ambrisentan, a selective ER-A endothelin receptor antagonist, regardless of the presence or absence of PH. For patients with IPF, the guideline committee suggests: Clinicians use nintedanib. Clinicians use pirfenidone. Clinicians NOT use sildenafil, a phosphodiesterase-5 inhibitor. Clinicians NOT use bosentan or macitentan, both dual ER-A and ER-B endothelin receptor antagonists. Clinicians NOT use N-acetylcysteine monotherapy. Clinicians use regular anti-acid treatment.
guideline for IPF treatment updated in 2015 by the ATS/ERS/ JRS/ALAT (Table 2) [18].
Quality of evidence
Strength of recommendation
Confidence in estimates
⊖ ⊖⊖
Strong Strong
Moderate Low
⊖⊖
Strong
Low
⊖⊖
Strong
Low
⊖ ⊖ ⊖ ⊖⊖
Conditional Conditional Conditional Conditional
Moderate Moderate Moderate Low
⊖⊖ ⊖⊖⊖
Conditional Conditional
Low Very Low
practice with regards to IPF [19]. This was a multicenter collaborative study, and clinical findings and information on the clinical course and details of treatment in idiopathic
5. Current status of treatment with pirfenidone in clinical practice
interstitial pneumonia cases, including IPF cases, were inputted via the internet prior to the start of the study. In total, 321 cases from 19 institutes were registered. With
5.1.
Japan
regard to the details of treatment for IPF and their change
5.1.1.
A prospective epidemiological study by web registration
of cases up to the end of the fiscal year 2008 when pirfeni-
A prospective surveillance study on diffuse lung disease was carried out in Japan to elucidate the current status of clinical
done was approved, whereas “no treatment” decreased to
(Fig. 1), “no treatment” was most frequently observed in 78.7%
44.6% and pirfenidone was administered in 32.9% of cases,
Fig. 1 – The treatments and their changes in IPF. Until the end of the 2008 fiscal year, “no treatment” was most frequently chosen (78.7% of patients). It was reduced to 44.6% of cases in the fiscal years of 2009 to 2013. On the other hand, there were only negligible changes in steroid monotherapy, which changed from 6.2% to 7.5% of cases after 2009, and in combination therapy of steroids and immunosuppressive agents, which increased slightly from 11.2% to 13.1% in the same period. NAC; N-acetylcysteine.
302
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including pirfenidone monotherapy in 17.4%, between the fiscal year 2009 and the end of the fiscal year 2013. After the end of the fiscal year 2013, it became a key drug for IPF treatment in Japan.
5.1.2. A survey on the experience of long-term pirfenidone administration with a clinical survey sheet Experiences of long-term pirfenidone administration in clinical practice were surveyed in a multicenter collaborative study. The study aimed to elucidate not only the reason of treatment discontinuation within one year but also the benefits regarding respiratory function (FVC) in the cases with long-term treatment for two years or longer. The subjects of the clinical survey were IPF patients treated with pirfenidone in the institutes of collaborators of the research on diffuse lung disease supported by the Ministry of Health, Labour and Welfare [20]. From 22 institutes, 502 answers were collected and treatment was terminated within one year in 186 cases (37.1%). Adverse effects were the most frequent reason in 77 of the cases (41.4%), followed by death in 60 cases (32.3%). Pirfenidone treatment was continued for two years or longer in 111 cases (22.1%). Yearly changes in FVC varied and were dependent on the individual case. Only a small proportion showed an improvement in FVC. However, FVC showed no deterioration after two years or thereafter in more than half of the cases in which FVC was stable after introduction of treatment, which suggested the possibility that pirfenidone stabilized FVC for a long period of time (Fig. 2).
5.1.3. Post-marketing surveillance of patients treated with pirfenidone Post-marketing surveillance was conducted in all cases where administration of pirfenidone commenced between November 2008 and October 2009 [21], and safety in 1371
Fig. 2 – Changes in the percent ΔFVC 12, 24, and 36 months after pirfenidone treatment was started. The course of the decline in the FVC in patients in the stable group (n ¼47, circle) compared to that of patients in the improved group (n¼ 10, open squares) and progressive group (n¼ 11, open circle) with a follow-up time of 412 months after pirfenidone treatment was started. Data are presented as the meanþstandard deviation.
cases was analyzed. The incidence of total adverse drug reactions (ADRs) was 64.6%. ADRs with an incidence of Z 3% were decreased appetite, photosensitivity reactions, nausea, abdominal discomfort, malaise, somnolence, and abnormal hepatic function. Treatment with pirfenidone stabilized both VC and subjective symptoms in most patients (70–80%) treated for at least 6 months. This surveillance demonstrated that pirfenidone was generally well tolerated in patients with IPF, including those with severe lung function impairment.
5.1.4.
Others
Having had the experience of administering pirfenidone treatment for IPF in 76 cases at all JRS severity grades [12] of I–IV, Okuda et al. reported suppression of FVC reduction by pirfenidone and significant suppression of FVC reduction, particularly in cases with FVC reduction of 150 mL or more before introduction of treatment [22]. Having administered pirfenidone treatment in 41 cases, Arai et al. reported that treatment response was excellent in the short term in mild to moderate IPF (JRS severity grading, I/II) cases and those that had undergone surgical lung biopsy [23]. Sakamoto et al. also reported efficacy of pirfenidone in eight of 18 advanced cases (44%) with JRS severity grades of III–IV [24]. Taken together, it is reasonable to conclude that pirfenidone has the potential to be effective for advanced IPF under certain conditions.
5.2.
Foreign countries
Having experienced the administration of pirfenidone treatment in 63 cases in clinical practice in Germany, Oltmanns et al. reported that respiratory function (VC and DLco) deteriorated in 15 cases (38%) during the average treatment period of 11 months, and the period until deterioration was 8 months on average. Respiratory data were stable for as long as 18 months in 24 of 39 cases (61.5%) that were treated continuously for 3 months or longer, and adverse effects were observed in 85% of cases, most of which were treated successfully [25]. Valeyre et al. investigated the safety of long-term administration of pirfenidone and reported that most adverse effects, such as photosensitivity and gastrointestinal symptoms (such as nausea and vomiting) appeared within six months after introduction of treatment and the occurrence rate markedly decreased thereafter [26]. Loch et al. retrospectively analyzed FVC change before and after pirfenidone treatment in IPF patients in Germany and Italy, and reported that yearly changes in FVC before treatment ( 7.0%71.8%, 248.17199.3 mL) significantly improved (þ2.773.6%, þ51.47351.4 mL) after treatment, and that the response to pirfenidone was remarkable in cases with a yearly reduction in FVC by 10% or more before treatment [27]. Taken together, management of ADRs to achieve the maximum benefits after long-term treatment with pirfenidone is an issue that needs to be resolved [28].
6.
Future challenges
It is important to investigate the most effective usage of pirfenidone (including cost effectiveness in administration)
respiratory investigation 54 (2016) 298 –304
regarding when treatment with pirfenidone should commence (possibility of early treatment) for IPF patients, under what conditions it should be used (exploration of clinical background and markers to predict efficacy in the patient group with expected effectiveness), and for how long the treatment should be continued. In addition, efficacy of combination therapy with N-acetyl cysteine (NAC) [29], how to select between administration of pirfenidone and nintedanib, and whether combination therapy is effective and safe are issues that must be resolved in the future [30,31]. Furthermore, it has been reported that pirfenidone treatment is effective for preventing acute exacerbation of IPF, for prevention of acute exacerbation in the perioperative period, and for postoperative treatment in IPF cases with lung cancer [32,33]. Therefore, exploring the new clinical uses of pirfenidone is an important goal of future research.
Conflict of interest
[12] [13]
[14]
[15]
[16]
[17]
[18]
Bando received lecture fees from Shionogi & Co., Ltd., and Boehringer Ingelheim. [19]
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