Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by uncontrolled deposition of extracellular matrix leading to progressive loss of lung function. Patients diagnosed with IPF experience progressive pulmonary insufficiency with a variable course and ultimately die of respiratory failure. The median survival upon diagnosis is ~3 years, similar to the most deadly of cancers. Until 2014, there were no FDA approved therapies for IPF. Several years ago, pirfenidone became the first agent approved to treat IPF in the EU, Canada and certain territories in Asia. In 2014, pirfenidone was approved to treat IPF by the US FDA. Pirfenidone is an orally bioavailable small molecule comprising a modified phenyl pyridone. It was initially identified as having anti-inflammatory activity in animal models. The unexpected identification of anti-fibrotic effects redefined interest in the compound. Subsequently, pirfenidone has been shown to attenuate fibrosis in numerous animal models across organ systems, including lung, liver, heart and kidney. Clinical investigation of pirfenidone in IPF was initiated based on the broad anti-fibrotic activity observed in animal models. Pirfenidone’s activity in IPF has been demonstrated by InterMune’s CAPACITY and ASCEND, and Shionogi’s Phase 2 and Phase 3 programs. Despite its unknown molecular target, clinical validation of the pirfenidone chemotype represents a watershed moment in the treatment of fibrotic conditions. Starting from an understanding of pirfenidone’s clinical safety and efficacy, optimization was undertaken to improve the profile of molecules based on the pirfenidone chemotype. Pirfenidone analogues have been developed that show activity in animal models of pulmonary and liver fibrosis and minimal effects in nonclinical safety models

Pirfenidone and optimized pirfenidone analogs for antifibrotic indications

249th National Meeting (2015)

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