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-b. 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. KEYWORDS: Animal model, antifibrotic, fibrosis, idiopathic pulmonary fibrosis, pirfenidone F ibrosis, the dysregulated deposition of extracellular matrix (ECM) with progressive destruction of normal tissue, is a primary or contributing factor in chronic disease states in several organs. Pulmonary fibrosis is associated with numerous diffuse parenchymal lung diseases, of which the most common are idiopathic pulmonary fibrosis (IPF) and sarcoidosis [1]. Cardiac fibrosis is associated with chronic heart failure, atrial fibrillation, and cardiac remodelling following acute myocardial infarction [2,3]. Renal fibrosis is associated with multiple forms of chronic kidney disease and correlates with impairment of kidney function [4,5]. Hepatic fibrosis is associated with chronic hepatitis B and C viral infections and nonalcoholic steatohepatitis [6]. Each of these conditions represents a significant unmet medical need, warranting significant research and clinical study into treatment for fibrotic disease.Pirfenidone (Esbriet1, Pirespa1) is an orally active small molecule comprising a modified phenyl pyridone ( fig. 1). The compound exhibits well documented antifibrotic and anti-inflammatory activities in a variety of animal and cellbased models, although its molecular target has not been elucidated. Pirfenidone was initially identified as having anti-inflammatory activity in animal models and evaluated for use as an antiinflammatory drug [7,8]. However, the unexpected identification of antifibrotic effects in animals treated with pirfenidone redefined the interest in the compound [9]. Subsequently, pirfenidone has been shown to attenuate fibrosis in numerous animal models, including fibrosis of the lung, liver, heart and kidney.The most extensive clinical studies of pirfenidone are for treatment of IPF, a chronic interstitial lung disease characterised by the unregulated deposition of ECM leading to the unremitting destruction of normal lung. Patients diagnosed with IPF typically experience progressive pulmonary insufficiency, and most die of respiratory failure. The estimated median survival upon diagnosis is approximately ...

Role of α1 and α2 chains of type IV collagen in early fibrotic lesions of idiopathic interstitial pneumonias and migration of lung fibroblasts

“…35 In general, an animal model of bleomycin-induced lung fibrosis is a fibrosis model with intraluminal buds of OP as a general process of repair from acute or subacute lung injury, 36 but not a fibrosis model with fibroblastic foci of UIP as chronic, progressive and irreversible pulmonary damage with honeycomb change. 37,38 In fact, to date, numerous agents have been shown to inhibit the fibrotic Type IV collagen in interstitial pneumonia H Urushiyama et al changes in this animal model, 39 but a few of these agents, such as pirfenidone 40,41 and nintedanib, 42,43 have shown a comparable antifibrotic effect on cases of IPF/UIP in humans. The radiographic images of COP often demonstrate migratory consolidation corresponding to fibrotic lesions of OP, and thus the progression in fibrosis of COP is more acute (median, o3 months) 1,2 than that of IPF which demonstrates a slow and gradual progression over many years.…”

Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis

“…bleomycin-induced lung fibrosis model. Despite some inherent limitations in modeling the human disease, both clinically approved antifibrotic drugs have shown efficacy in the bleomycin mouse model (14,20,21). This model typically involves either repetitive s.c. injection of bleomycin or a one-time intratracheal injection of the drug (22).…”

“…S8B). As positive controls, we used AM152, an LPA1 receptor antagonist, which acts by inhibiting fibroblast trafficking and vascular leakage (24), and pirfenidone, an FDA-approved antifibrotic drug, which has been reported to act by a number of antifibrotic mechanisms (20). CBR-096-4 (10 mg/kg) had a similar level of antifibrotic activity, as determined by histological Ashcroft scoring and automated image analysis for collagen staining (described in Methods), compared with the maximally efficacious doses of AM152 (once daily P.O.…”

An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial

“…Pirfenidone is an antifibrotic agent 13 with antiinflammatory properties, including inhibition of proinflammatory cytokines 14 and inhibition of inflammatory cell proliferation 15 . Pirfenidone was approved by European and US regulatory agencies in 2011 and 2014, respectively, for the treatment of patients with idiopathic pulmonary fibrosis (IPF) 16,17,18,19 , a chronic, progressive, and almost invariably fatal disease 20 .…”