Pirfenidone Reduces Disease Progression in Patients with IPF

Two previous phase 3 trials have found that pirfenidone reduced disease progression in patients with idiopathic pulmonary fibrosis (IPF), as measured by the decline in forced vital capacity (FVC) or vital capacity. However, another phase 3 trial did not find the same benefits of pirfenidone for patients with IPF. These differing results prompted a recent study published online in New England Journal of Medicine to confirm the beneficial effect of pirfenidone in terms of IPF disease progression [2014; DOI:10.1056/NEJMoa1402582].

The study was conducted at 127 sites in 9 countries, including Australia, Brazil, Croatia, Israel, Mexico, New Zealand, Peru, Singapore, and the United States. Patients were eligible for inclusion in the study if they were 40 to 80 years of age and had received a centrally confirmed diagnosis of IPF. Diagnosis of IPF was classified as findings on high-resolution computed tomography scan that indicated either definite or possible usual interstitial pneumonia. Other criteria for enrollment included a range of 50% to 90% of the predicted FVC, a range of 30% to 90% of the predicted carbon monoxide diffusing capacity, ratio of the forced expiratory volume in 1 second to the FVC of ≥0.80, and a 6-minute walk distance of ≥150 meters.

A total of 555 patients with IPF were randomized to receive either oral pirfenidone 2403 mg/day or placebo for 52 weeks. A total of 278 patients were assigned to receive pirfenidone and 277 were assigned to receive placebo. The majority of patients were male (79.9% in pirfenidone group and 76.9% in placebo group), white (91.7% in pirfenidone group and 90.6% in placebo group), and ≥65 years of age (73.7% in pirfenidone group and 68.2% in placebo group).

Pirfenidone was administered to each group was given with food in 3 equally divided doses, and the dose was gradually increased to the full dose over a 2-week period. Physical examinations and clinical laboratory assessments were performed at baseline and at weeks 2, 4, 8, 13, 26, 39, and 52; pulmonary function, exercise tolerance, and dyspnea were assessed at baseline and at weeks 13, 26, 39, and 52. The study took place between July 2011 and January 2013.

The study’s primary end point was the change in FVC or death at week 52. The secondary end points were the results of the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from IPF.

At week 52, there was a relative reduction of absolute decline of ≥10 percentage points in the percentage of predicted FVC or who died for 47.9% of patients in the pirfenidone group compared to the placebo group (46 patients [16.5%] vs 88 patients [31.6%]).

There was also a relative increase of 132.5% in the proportion of patients with no decline in FVC in the pirfenidone group compared to the placebo group (63 patients [22.7%] vs 27 patients [9.7%]; P<.001).

Treatment effect was evident by week 13 and increased throughout the duration of the trial, according to the study’s findings. The mean decline from baseline in FVC was 235 mL in the pirfenidone group and 428 mL in the placebo group (P<.001).

In terms of secondary end points, pirfenidone reduced the decline in the 6-minute walk distance (P=.04) and improved progression-free survival (P<.001) compared to the placebo cohort. There was no significant change in dyspnea scores (P=.16) or rates of death from any cause (P=.10) or from IPF (P=.23) in either group. Deaths from IPF occurred in 3 patients (1.1%) in the pirfenidone group and 7 patients (2.5%) in the placebo group (hazard ratio, 0.44; 95% confidence interval, 0.11-1.72; P=.23).

Adverse events that were more common in the pirfenidone cohort were gastrointestinal and skin-related events. The most common serious adverse event was worsening in IPF, which occurred in 7 patients (2.5%) in the pirfenidone group and 27 patients (9.7%) in the placebo group.

The study’s authors noted limitations. The patients included in the study had mild-to-moderate physiological impairment, which does not allow the study’s findings to be generalized to a larger population. Also, the study required central confirmation of the diagnosis of IPF on the basis of criteria from recent guidelines.

The study’s authors concluded that pirfenidone reduced disease progression, reflected by lung function, exercise tolerance, and progression-free survival in patients with IPF.