Phase 2 Pirfenidone Trial Indicates Potential Effectiveness in Treating Patients With Unclassifiable ILD

Pirfenidone, sold as Esbriet, was shown to potentially benefit patients with progressive fibrosing unclassifiable interstitial lung disease (uILD) in a phase 2 trial, according to research presented at the European Respiratory Society (ERS) Congress 2019.

Study results were presented at the ERS Congress in Madrid, Spain, which runs from September 28 to October 2, and was also published today in The Lancet Respiratory Medicine.

Currently, there are no approved pharmacotherapies available for uILD, which is a debilitating, severe respiratory condition characterized by progressive fibrosis of the lung. Researchers aimed to assess the efficacy and safety of pirfenidone (Esbriet) in patients with uILD.

Pirfenidone is a prescription medicine used to treat people with a lung disease called idiopathic pulmonary fibrosis (IPF). The management of patients with ILD is split into 2 categories: patients with IPF and patients with all other forms of fibrotic ILD. Diagnosis of a specific ILD is vital for identifying appropriate management strategy and informing disease prognosis, but after extensive research, it was revealed that a final diagnosis is not always possible (unclassifiable). As some ILDs have a progressive fibrosing phenotype similar to IPF, researchers hypothesized its potential effectiveness in patients with uILD characterized by fibrosis.

Researchers conducted a double-blind, randomized, placebo-controlled phase 2 trial at 70 centers throughout Europe on 253 eligible patients with progressive fibrosing uILD between the ages of 18 to 85 years. Patients with uILD were delineated by a percent predicted forced vital capacity (FVC) of 45% or higher, percent predicted carbon monoxide diffusing capacity (DLco) of 30% or higher, and more than 10% fibrosis on high-resolution computerized tomography (CT) for those with a high-resolution CT over the previous 12 months:

• Patients randomly assigned (1:1) to 2403 mg oral pirfenidone daily (127 patients) or placebo (126 patients) using a central validated interactive voice or web-based response system
• Primary endpoint was mean predicted change in FVC from baseline over 24 weeks, measured by daily home spirometry

Secondary endpoints were change in FVC measured by site spirometry, proportion of patients who had a more than 5% or more than 10% absolute or relative decline in percent predicted FVC measured by clinic-based spirometry, as well as changes in percent predicted DLco, 6-min walk distance (6MWD), University of California San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ), Leicester Cough Questionnaire score, cough visual analogue scale, and in total/subscores of the St. George’s Respiratory Questionnaire (SGRQ). Efficacy was determined in the intention-to-treat population, which included all randomly assigned patients.

Analysis of the study’s primary endpoint was affected by intraindividual variability in home spirometry values that prevented application of the prespecified statistical model. Secondary endpoints, however, revealed the stark impact of pirfenidone compared to placebo in the reduced predicted median change in FVC measured by home spirometry (-87.7 mL [95% CI: -338.1 to 148.6] vs -157.1 mL [95% CI: -370.9 to 70.1]) and the reduced predicted mean change in FVC measured by site spirometry (treatment difference: 95.3 mL [95% CI: 35.9 to 154.6]; P=.002).

Compared with the placebo group, patients administered pirfenidone were less likely to have a decline in FVC of more than 5% (odds ratio [OR]=0.42; 95% CI: 0.25 to 0.69; P =.001) or more than 10% (OR=0.44; 95% CI: 0.23 to 0.84; P = .011). Mean change in DLco from baseline for the pirfenidone group versus the placebo group was significantly different (-0.7 [SD 7.1]) vs -2.5 [8.8]), as was the mean change in 6MWD from baseline (-2.0m [68.1] vs -26.7m [79.3]). There were no definite differences from baseline for the 2 groups when assessed for UCSD-SOBQ, Leicester Cough Questionnaire score, cough visual analogue scale, and SGRQ scores.

While the planned statistical model could not be applied to the primary endpoint data, results favoring pirfenidone as opposed to placebo were exhibited across several secondary efficacy endpoints, which supports the potential effectiveness of pirfenidone in slowing disease progression in patients with progressive fibrosing uILD. The safety and tolerability profile of pirfenidone was additionally comparable to patients with IPF.

“Results from several of the key secondary and exploratory outcomes, including lung function and exercise capacity, suggest that pirfenidone could be an effective treatment for patients with progressive fibrotic unclassifiable ILD over 24 weeks, with an acceptable safety and tolerability profile, and these results warrant further investigation,” said the authors.

Reference

Maher TM, Corte TJ, Fischer A, et al. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease. [published online September 29, 2019]. Lancet Respir Med. doi: 10.1016/S2213-2600(19)30341-8.