Following evaluation in Phase II and Phase III clinical trials in patients with IPF.[24–26], pirfenidone was approved by the European Commission in February 2011 Pirfenidone is indicated for the treatment of patients with mild-to-moderate IPF. Mild-to-moderate disease was characterised in two pivotal Phase III studies using the following functional criteria: FVC ≥50% of predicted value, carbon monoxide diffusing capacity (DLCO) ≥35% of predicted value and a 6 minute walk test (6MWT) distance of ≥150 m.
Based on the positive results of a Phase II study by Azuma et al., a multicentre, double-blind, placebo-controlled, randomised Phase III clinical trial was conducted in Japan to determine the efficacy and safety of pirfenidone in 275 patients with IPF. Patients were randomised to pirfenidone 1800 mg per day, pirfenidone 1200 mg per day or placebo using a 2:1:2 ratio, with 267 patients evaluated for the efficacy of pirfenidone. The dose of pirfenidone was increased in a stepwise manner up to the treatment dose over four weeks. The primary endpoint was vital capacity (VC) from baseline to 52 weeks. This was changed before unblinding of the study (it was previously the lowest arterial oxygen saturation measured by pulse oximetry (SpO2) during the six-minute steady state exercise test). This decision was based on the evolved knowledge of assessment with objective measurements in IPF, along with the lack of validation of the steady state exercise test and problems in reproducing SpO2 measurements. Secondary endpoints included progression-free survival (this was defined as time until the first progressive event, i.e. either decrease in VC of >10% or death) and change in the lowest SpO2 during the six-minute steady state exercise test.
Statistically significant differences were observed between the pirfenidone 1,800 mg group and the placebo group for both the primary and secondary endpoints. Pirfenidone was associated with a 44% reduction in the VC decline compared with placebo (-0.09 L vs -0.16 L; p=0.0416), along with a significant increase in progression-free survival (p=0.0280). Pirfenidone was relatively well tolerated, the most common adverse event observed with pirfenidone was photosensitivity, which was rated as mild in the majority of patients, and has previously been documented as a side effect associated with pirfenidone treatment.[25, 27] The data from this Phase III trial led to the approval of pirfenidone in Japan in 2008 for the treatment of IPF.
Two concurrent, similarly designed Phase III trials (studies 004 and 006, the “CAPACITY” studies), were conducted at 110 sites across North America, Australia and 11 European countries. Both were randomised, double-blind, placebo-controlled studies with treatment periods of 72 weeks. The studies were designed to confirm the results of a Phase II study suggesting that pirfenidone reduced the deterioration in lung function in patients with IPF.
Patients aged 40–80 years with mild-to-moderate IPF, diagnosed within the previous 48 months, were randomised to treatment with either oral pirfenidone or oral placebo. In study 004, patients were assigned to pirfenidone 2403 mg/day, 1197 mg/day or placebo in a 2:1:2 ratio. In study 006, patients were assigned to pirfenidone 2403 mg/day or placebo in a 1:1 ratio. Pirfenidone was administered with food three times a day and increased to the full dose (2403 mg/day) over two weeks. The lower dose of 1197 mg/day was included in study 004 to investigate any dose-response effect in terms of efficacy.
The primary endpoint of both studies was change in percentage predicted FVC from baseline to week 72. Secondary endpoints at week 72 included categorical decline in FVC ≥10%, progression-free survival (time to confirmed ≥10% decline in percentage predicted FVC, ≥15% decline in percentage predicted DLCO or death), mean change in 6MWT distance, mean change in percentage predicted DLCO, mean change in dyspnoea score, mean percentage change in worst SpO2 during 6MWT and time to worsening of IPF. Mortality was included as an exploratory endpoint. Categorical change in high-resolution computed tomographic (HRCT)-diagnosed fibrosis was included as a secondary endpoint in study 006.
In study 004, pirfenidone 2403 mg/day significantly reduced mean decline from baseline to week 72 in percentage predicted FVC, compared with placebo (-8.0% [±16.5] vs -12.4% [±18.5], respectively; p=0.001), as well as the proportion of patients with FVC decline ≥10%. This treatment effect was evident between weeks 24 and 72. A pirfenidone effect was confirmed (p=0.0007) after repeat-measured analysis of the predicted percentage change in FVC across all assessment timepoints. In the pirfenidone 1197 mg/day group, the primary endpoint outcomes were intermediate to those of the 2403 mg/day pirfenidone and placebo groups.
While the difference between groups in mean FVC change at Week 72 was not significant in Study 006 (-9.0% [SD 19.6] and -9.6% [19.1] respectively, p=0.501), this may have been due to a lower than expected rate of FVC decline in Study 006 after 1 year in the placebo group. Moreover, a consistent pirfenidone effect was apparent until Week 48 (p=0.005) and also in an analysis of all study timepoints (p=0.007). Thus, the data from this study generally supported those from Study 004, with a positive treatment effect of pirfenidone being observed at all timepoints from weeks 12 to 48 but not at later time points.
The effect of pirfenidone treatment on percentage predicted FVC at week 72 was supported by pooled analysis of data from both studies. Mean decline in percentage predicted FVC was -8.5% and -11.0% for the pirfenidone 2403 mg/day and placebo groups, respectively (p=0.005). Additionally, the pooled analysis demonstrated a 30% reduction in the percentage of patients with a categorical decline in FVC ≥10% at week 72 (p=0.003), a 31% reduction in the mean decline in 6MWT distance (p>0.001) and a 26% reduction in the risk of death or disease progression (HR 0.74; 95% CI 0.57, 0.96; p=0.025).
Exploratory analysis of mortality data revealed that the hazard ratios for all-cause mortality (p=0.315) and mortality related to IPF at any time during the study (p=0.117), although not significant, numerically favoured pirfenidone over placebo. This was also the case with on-treatment IPF-related mortality, which occurred in 3% of patients treated with pirfenidone and 7% of those given placebo (p=0.03).