Animal studies have shown that pirfenidone suppresses accumulation of inflammatory cells within alveoli; production of inflammatory cytokines such as IL-1β, IL-6, and TNFα; and activation of growth factors, including transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF). Pirfenidone also suppresses the decrease of interferon (IFN)-γ production in bleomycin-administered animals, shifting the immune balance to a Th1-dominant milieu [10] (Fig. 9.1). Furthermore, pirfenidone has antioxidant properties [11] and suppresses fibrocyte migration [12], which leads to its antifibrotic activity.

According to the open-label studies conducted by Raghu et al. [13], a double-blind, phase II, placebo-controlled trial was conducted in Japan, which recruited 107 patients with IPF to evaluate the efficacy of pirfenidone (maximum 1800 mg/day) [14]. The patients recruited for this study were well-defined patients with IPF belonging to the age group of 20–75 years, with PaO₂ level ≧70 torr and the lowest SpO₂ level <90 % during the 6-min steady-state exercise walk test on the treadmill (6MET). The primary endpoint was a change in the lowest SpO₂ level during the 6MET. Based on trends in the decreased frequency of acute exacerbation in the pirfenidone group observed during the former 6 months of the trial, this study was terminated at the 9th month. There was no significant difference in the primary endpoint at the 9th month; however, significant improvement in the lowest SpO₂ level was observed in a subpopulation of 80 patients, who had the lowest SpO₂ level >80 % during 6MET (p = 0.0069 at the 6th month, p = 0.0305 at the 9th month). There was a significant difference in the decline of VC between the pirfenidone group (−0.03 L) and placebo group (−0.13 L) (p = 0.0366). In addition, there was a difference in the frequency of acute exacerbation during this 9-month study period between the pirfenidone group (no patients) and the placebo group [5/35 (14 %) patients] (p = 0.0031). In the pirfenidone group, photosensitivity was found in 43.8 % of the patients, and gastrointestinal symptoms were found in approximately 30 % of the patients, but these side effects were not associated with a significant difference in the frequency of patients who discontinued the medication.

In a subsequent phase III study in Japan, 267 patients with IPF were treated with pirfenidone for 52 weeks [15]. Eligible patients belonged to the age group of 20–75 years of age, with oxygen saturation of 5 % or more difference between the resting SpO₂ level and the lowest SpO₂ level during 6MET and the lowest SpO₂ level ≥85 % during the 6MET. Patients were allocated to high-dose (1800 mg/day), low-dose (1200 mg/day), and placebo groups in a 2:1:2 ratio. The primary endpoint was the change in VC at the 52nd week, and both the high-dose (−0.09 L) and the low-dose groups (−0.08 L) showed a significant difference when compared with the placebo group (−0.16 L) (p < 0.05). The secondary endpoints included progression-free survival (PFS) and minimal SpO₂ level during the 6MET. The high-dose group showed significant improvement in PFS (p = 0.0280), whereas the low-dose group showed marginal improvement (p = 0.0655). There was no significant difference in the minimal SpO₂ during 6MET or the frequency of acute exacerbation between the pirfenidone and placebo groups. Photosensitivity was observed in 51 % of the patients in the high-dose group and 53 % of the patients in the low-dose group; however, in most of the cases, it was mild in severity, and only 3 % of the patients discontinued the study due to photosensitivity.

The CAPACITY trial was a multicenter, randomized controlled trial consisting of two concurrent studies (study 004 and 006), which recruited patients with IPF from Australia, Europe, and North America and evaluated the efficacy of pirfenidone (2403 mg/day or 1197 mg/day) on FVC decline observed at the 72nd week [16]. In study 004, the group that received 2403 mg/day of pirfenidone showed a significantly lower decline in FVC each time from the 24th week to the 72nd week, and the groups that received 1197 mg/day of pirfenidone showed an intermediate outcome between the pirfenidone 2403 mg/day group and the placebo group. However, in study 006, there was no significant difference in FVC decline between the pirfenidone and placebo groups at 72 weeks, prompting US regulatory authorities to request an additional trial for its approval by the FDA.

The ASCEND trial was conducted at 127 sites in 9 countries, and 555 patients were allocated to either an oral pirfenidone (2403 mg/day) or placebo group. Patients recruited to the study had to meet all of the following criteria: %FVC, 50–90 %; %DLCO, 30–90 %; FEV1/FVC, >0.8; and 6MWD, >150 m [3]. These criteria were aimed at enrolling patients with more advanced progressive disease than the CAPACITY 006 trial, in which the negative result could be ascribed to the attenuated disease progression in the placebo group. These criteria also intended to exclude patients with an airflow limitation, as is seen in patients with comorbid emphysema. There was a significant difference between the groups pertaining to the primary endpoint, the change in the %FVC from baseline to the 52nd week (p < 0.001). The change in FVC was −428 mL in the placebo group and −235 mL in the pirfenidone group. In addition, regarding the secondary endpoint, pirfenidone treatment improved the 6MWD and PFS. Furthermore, in a pooled analysis of the three phase III studies (692 patients in the CAPACITY studies and 555 patients in the ASCEND trial), 1-year mortality was decreased by 48 % (p = 0.01), and IPF-associated mortality was decreased by 68 % (p = 0.006) in the pirfenidone group as compared with the placebo group. Skin-related events (pirfenidone group 28.1 %, placebo 8.7 %) and gastrointestinal events were more common in the pirfenidone group, but no patient in either group exhibited more than a grade 4 event.

RECAP is an open-label extension study that recruited patients who were previously randomized to the placebo groups in one of the two CAPACITY studies. Eligible patients received oral pirfenidone as 2403 mg/day, and their lung function and survival rates were evaluated. This study included 178 patients, who showed similar lung functioning and survival rates as compared with the patients treated using pirfenidone in the CAPACITY trials [17]. This study further confirmed the clinical efficacy of pirfenidone in the treatment of IPF.

In three out of four phase III studies, pirfenidone reduced the decrease in VC or FVC, and the pooled analysis of these studies showed that its administration improves survival of patients with IPF. However, it remains unclear what are the distinct characteristics of patients who benefit from pirfenidone. On an average, the study population in the phase II study in Japan [14] showed %VC as 80 % and %DLCO as 50–60 %. In the phase III study in Japan [15], the study population showed %VC as 75–80 % and %DLCO as 50–55 %, indicating that these studies were conducted in patients with mild to moderate levels of IPF. The participants in the ASCEND trial had relatively severe disease, showing %FVC as 65 to 70 % and %DLCO as 40–45 %, with 22 % of these patients having %DLCO <35 %. In the subanalyses of the phase III study in Japan [18], patients were stratified by baseline %VC, arterial oxygen partial pressure (PaO₂), and minimal SpO₂ during 6MET. The study showed that the effect of pirfenidone on VC was most prominent in a subgroup of patients having %VC ≥70 and SpO₂ level during 6MET <90 % at baseline. However, in this study the number of patients stratified into the severe disease category was small and definite conclusions could not be made.

An open-label study by Nagai et al. [19], which comprised 8 patients with IPF and 2 patients with systemic sclerosis-associated UIP who had relatively severe disease with average %VC as 54.6 %, but some of these patients showed stabilization of the disease by pirfenidone. In another study, Okuda et al. evaluated the efficacy of pirfenidone in 76 patients with IPF including severe cases and found marginal significant effect of pirfenidone in 11 patients with %VC as <60 %, whose FVC changed from −280 mL before treatment to −80 mL after 6 months of treatment (p = 0.074) [20], and they also showed that a progressive FVC decline before treatment is associated with a good response to pirfenidone. These reports suggest that there may be some patients with severe disease who respond to pirfenidone. In contrast, Arai et al. showed that mild disease (Japanese severity grade I or II) and SLB diagnosis for IPF were associated with a favorable short-term response to pirfenidone [21]. As will be described later, some European guidelines recommend pirfenidone in mild to moderate disease based on CAPACITY data. Further investigation is necessary to elucidate the efficacy of this drug in severe IPF. As the ASCEND trial eliminated patient airflow limitations, the efficacy of pirfenidone in patients with comorbid emphysema should also be examined.

As aforementioned, photosensitivity and gastrointestinal symptoms are two major side effects of pirfenidone. In post-marketing surveillance of 1370 Japanese patients who underwent pirfenidone treatment, the most common side effect was loss of appetite (27.9 %), followed by photosensitivity (14.4 %) and nausea (7.9 %) (Inoue Y, Azuma A, Ogura T, et al. All-case post-marketing surveillance (PMS) of pirfenidone in Japan: clinical characteristics, efficacy and safety profile in >1300 patients with idiopathic pulmonary fibrosis (IPF). 2013 ERS Annual Meeting, P3369, Barcelona.). These data suggest that the frequency of photosensitivity can be reduced by educating patients to avoid ultraviolet exposure and encourage the use of sunscreen. In Japan, proton pump inhibitors (PPI), cisapride or rikkunshi-to (a herbal medicine) is used to prevent gastrointestinal symptoms, although their efficacy is often unsatisfactory. Arai et al. showed that PPI are efficacious in the management of gastrointestinal side effects caused by pirfenidone treatment [21], while others have shown a similar effect of rikkunshi-to [22]. Further investigation is necessary regarding the management of the side effects of pirfenidone to ensure its full effect.

There are only limited data available regarding the efficacy of pirfenidone in interstitial lung diseases besides IPF. Miura et al. used pirfenidone in patients with untreated systemic sclerosis-associated interstitial pneumonia, and VC improved in all patients [23]. Vos et al. reported a case of restrictive allograft syndrome (RAS) following lung transplantation, in which pulmonary function and HRCT results were found to be improved during the treatment with pirfenidone [24]. In this patient, lung histology demonstrated a combination of diffuse PPFE, alveolar fibrosis, and bronchiolitis obliterans. Some physicians hesitate to use pirfenidone in patients with PPFE due to potential adverse effects on pneumothorax. However, due to the limited medical therapy available for this disease, further investigation is necessary regarding the effect of pirfenidone on PPFE.

Retrospective data in Japan showed that pirfenidone may be effective for the prevention of lung cancer in patients with idiopathic interstitial pneumonias, including IPF (Miura Y, Saito T, Tsunoda Y et al. Clinical effect on incidence of lung cancer of pirfenidone in idiopathic interstitial pneumonias. 2014 ERS Annual meeting, Munich), which requires further confirmation in prospective studies.

Pirfenidone is also used to prevent acute exacerbation after surgery. Iwata et al. retrospectively analyzed postoperative events in twelve patients with IPF and concomitant lung cancer that received perioperative pirfenidone and compared them with those of 16 patients with IPF who underwent lung cancer surgery without pirfenidone treatment. They showed that there were no IPF-related events in patients with perioperative pirfenidone treatment, whereas six control patients developed acute exacerbation of IPF (P = 0.0167) [25]. A prospective clinical study is currently ongoing in Japan examining whether pirfenidone has a prophylactic effect on acute exacerbation following lung cancer surgery in patients with IPF.

Receptor tyrosine kinases play a crucial role in regulating cell proliferation, migration, metabolic changes, differentiation, and survival. Nintedanib (formerly known as BIBF 1120) is an intracellular tyrosine kinase inhibitor that suppresses multiple tyrosine kinase receptors, including those of VEGF, fibroblast growth factor (FGF), and platelet-derived growth factors (PDGF). Nintedanib is used in several malignant diseases, including lung cancer [26]. Chaudhary et al. showed that BIBF suppresses TGF-β2-induced αSMA expression in fibroblasts derived from patients with interstitial pneumonia, suggesting that VEGF, FGF, and PDGF are involved in the pathogenesis of pulmonary fibrosis [27]. Thus, this agent was expected to be a potential therapeutic drug for IPF. Nintedanib is believed to exert its antifibrotic effect by suppressing elevation of inflammatory cells within alveoli, fibroblast proliferation, and fibroblast to myofibroblast transformation [28]. In addition, PDGF and FGF are also involved in the pathogenesis of pulmonary arterial hypertension (PAH) [29]. Therefore, nintedanib may also have a beneficial effect on pulmonary hypertension in patients with IPF.

A phase II study was conducted in 432 patients with IPF to investigate the efficacy and optimal dosage of nintedanib in this disease [30]. The primary endpoint was the annual rate of decline in FVC. Patients were randomly assigned to one of the five groups, which included four groups that received different doses of nintedanib (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) and a placebo group. After 12 months, FVC decreased by 0.19 L in the placebo group, whereas FVC decreased by only 0.06 L in the nintedanib 150 mg twice a day group (p = 0.01 with the hierarchical testing procedure, p = 0.06 for multiplicity correction). With this dose, nintedanib decreased the frequency of acute exacerbation (p = 0.02) and improved SGRQ (p = 0.007). However, the frequency of liver enzyme elevation and discontinuation of the treatment due to gastrointestinal symptoms were higher in the nintedanib 150 mg twice a day group as compared with placebo. Next two replicate phase III trials (INPULSIS-1 and INPULSIS-2) were conducted to evaluate the efficacy and safety of 150 mg of nintedanib twice a day [4]. In these trials, 1066 patients with IPF were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The primary endpoint, which was in the 52-week rate of FVC decline, was improved with nintedanib treatment in both INPULSIS-1 (−114.7 mL vs. −239.9 mL, p < 0.001) and INPULSIS-2 (−113.6 vs. −207.3 ml, p < 0.001). Nintedanib was also shown to prolong time to the first acute exacerbation (p = 0.005) in INPULSIS − 2, but not in INPULSIS-1. Pooled analysis of these three clinical trials showed no significant effect of nintedanib on mortality, but nintedanib had a significant benefit to prolong the time to the first acute exacerbation in IPF. Diarrhea was the most frequent adverse event and was observed at a rate of 61.5 % and 63.2 % in the nintedanib groups from these studies. However, less than 5 % of the events led to the discontinuation of the study.