Targeted Therapy for Idiopathic Pulmonary Fibrosis: Where To Now?

Abstract

Idiopathic pulmonary fibrosis (IPF) is an aging-associated, recalcitrant lung disease with historically limited therapeutic options. The recent approval of two drugs, pirfenidone and nintedanib, by the US Food and Drug Administration in 2014 has heralded a new era in its management. Both drugs have demonstrated efficacy in phase III clinical trials by retarding the rate of progression of IPF; neither drug appears to be able to completely arrest disease progression. Advances in the understanding of IPF pathobiology have led to an unprecedented expansion in the number of potential therapeutic targets. Drugs targeting several of these are under investigation in various stages of clinical development. Here, we provide a brief overview of the drugs that are currently approved and others in phase II clinical trials. Future therapeutic opportunities that target novel pathways, including some that are associated with the biology of aging, are examined. A multi-targeted approach, potentially with combination therapies, and identification of individual patients (or subsets of patients) who may respond more favourably to specific agents are likely to be more effective.

Figure 1. Proposed mechanisms for the predilection of fibrosis with aging

Aging may result in “immunosenescence” that results in impaired antigen clearance and autoimmunity; additionally, senescence of epithelial cells and fibroblasts result in impaired regeneration and aberrant recapitulation of developmental genes. These processes may perpetuate epithelial injury/apoptosis and fibroblast activation that results in failed re-epithelialization, fibroblast persistence and progressive fibrosis.