Inhaled pirfenidone solution (AP01) for IPF: a randomised, open-label, dose-response trial

by Selleckchem | Apr 11 2023

Introduction: Oral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects, including nausea, rash, photosensitivity, weight loss and fatigue. Reduced doses may be suboptimal in slowing disease progression.

Methods: This phase 1b, randomised, open-label, dose-response trial at 25 sites in six countries (Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12618001838202) assessed safety, tolerability and efficacy of inhaled pirfenidone (AP01) in IPF. Patients diagnosed within 5 years, with forced vital capacity (FVC) 40%-90% predicted, and intolerant, unwilling or ineligible for oral pirfenidone or nintedanib were randomly assigned 1:1 to nebulised AP01 50 mg once per day or 100 mg two times per day for up to 72 weeks.

Results: We present results for week 24, the primary endpoint and week 48 for comparability with published trials of antifibrotics. Week 72 data will be reported as a separate analysis pooled with the ongoing open-label extension study. Ninety-one patients (50 mg once per day: n=46, 100 mg two times per day: n=45) were enrolled from May 2019 to April 2020. The most common treatment-related adverse events (frequency, % of patients) were all mild or moderate and included cough (14, 15.4%), rash (11, 12.1%), nausea (8, 8.8%), throat irritation (5, 5.5%), fatigue (4, 4.4%) and taste disorder, dizziness and dyspnoea (three each, 3.3%). Changes in FVC % predicted over 24 and 48 weeks, respectively, were -2.5 (95% CI -5.3 to 0.4, -88 mL) and -4.9 (-7.5 to -2.3,-188 mL) in the 50 mg once per day and 0.6 (-2.2 to 3.4, 10 mL) and -0.4 (-3.2 to 2.3, -34 mL) in the 100 mg two times per day group.

Discussion: Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01. Mean FVC % predicted remained stable in the 100 mg two times per day group. Further study of AP01 is warranted.

Comments：

A phase 1b, randomized, open-label, dose-response trial was conducted to evaluate the safety, tolerability, and efficacy of inhaled pirfenidone (AP01) in patients with idiopathic pulmonary fibrosis (IPF). Patients diagnosed within 5 years, with forced vital capacity (FVC) 40%-90% predicted, and intolerant, unwilling, or ineligible for oral pirfenidone or nintedanib were enrolled in the study. The trial was conducted at 25 sites in six countries, and a total of 91 patients were enrolled and randomly assigned to receive nebulized AP01 50 mg once per day or 100 mg two times per day for up to 72 weeks.

The primary endpoint was assessed at week 24, and the results of week 48 were presented for comparability with published trials of antifibrotics. The most common treatment-related adverse events were all mild or moderate and included cough, rash, nausea, throat irritation, fatigue, taste disorder, dizziness, and dyspnea. Changes in FVC % predicted over 24 and 48 weeks were -2.5 and -4.9 in the 50 mg once per day group and 0.6 and -0.4 in the 100 mg two times per day group, respectively. Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01, and mean FVC % predicted remained stable in the 100 mg two times per day group.

Overall, the results suggest that inhaled pirfenidone may be a safe and effective treatment option for patients with IPF who are intolerant, unwilling, or ineligible for oral pirfenidone or nintedanib. However, further study of AP01 is warranted, and data from week 72 will be reported as a separate analysis pooled with the ongoing open-label extension study.