Antifibrotic activities of pirfenidone in animal models

Abstract

Pirfenidone is an orally active small molecule that has recently been evaluated in large clinical trials for the treatment of idiopathic pulmonary fibrosis, a fatal disease in which the uncontrolled deposition of extracellular matrix leads to progressive loss of lung function. This review describes the activity of pirfenidone in several well-characterised animal models of fibrosis in the lung, liver, heart and kidney. In these studies, treatment-related reductions in fibrosis are associated with modulation of cytokines and growth factors, with the most commonly reported effect being reduction of transforming growth factor-β. The consistent antifibrotic activity of pirfenidone in a broad array of animal models provides a strong preclinical rationale for the clinical characterisation of pirfenidone in pulmonary fibrosis and, potentially, other conditions with a significant fibrotic component.

Conflict of interest statement

Statement of Interest

All authors are employee shareholders of InterMune, Inc., which recently received European marketing authorisation for Esbriet® (pirfenidone) in the treatment of adult patients with mild to moderate idiopathic pulmonary fibrosis. The article describes unpublished data from the laboratory of H. Oku, an employee of Shionogi and Co. Ltd, which markets pirfenidone for the treatment of idiopathic pulmonary fibrosis in Japan.

Figures

Figure 1.

Chemical structure of pirfenidone.

Figure 2.

The antifibrotic activity of pirfenidone in preclinical models of pulmonary fibrosis. a) Experimental design and effects of prophylactic pirfenidone treatment on bleomycin-induced pulmonary fibrosis [38]. b) Effects of delayed pirfenidone treatment on bleomycin-induced pulmonary fibrosis (H. Oku, Shionogi and Co. Ltd, Osaka, Japan; personal communication). c) Effects of prophylactic pirfenidone treatment on bleomycin-induced pulmonary fibrosis [44]. d) Experimental design and effects of pirfenidone in an orthotopic lung transplant model [45]. e) The effects of pirfenidone in a mouse model of airway remodelling and hyperresponsiveness induced by sensitisation and challenge with ovalbumin [47]. BAL: bronchoalveolar lavage; bFGF: basic fibroblast growth factor; IL: interleukin; IFN: interferon; OVA: ovalbumin; PDGF: platelet-derived growth factor; SD: Sprague-Dawley; SDF: stromal cell-derived factor; TGF: transforming growth factor.

Figure 3.

Summary of activities observed in animal models and cell-based assays. ECM: extracellular matrix.