Pirfenidone is the company’s small molecule drug candidate that is being developed for the treatment of patients with idiopathic pulmonary fibrosis (IPF) in its phase III program, named CAPACITY. The in vitro studies demonstrate that pirfenidone suppresses fibrogenesis through selective inhibition of the p38-gamma mitogen-activated protein kinase (MAPK).
In IPF, fibrosis occurs when wound healing cells deposit collagen, which leads to abnormal scarring of the lung tissues. Previous research demonstrates that pirfenidone reduces blood plasma levels in vivo of TGF-beta and Interleukin-4, two pro-fibrotic signaling molecules, and significantly inhibits TGF-beta-induced collagen synthesis in vitro. Pirfenidone was also shown to inhibit production of TNF-alpha, a molecule involved with inflammation.
In this new work, InterMune scientists have shown a principal anti-fibrotic mechanism of action of pirfenidone as the inhibition of the p38- gamma kinase. In support of this, InterMune studies have demonstrated specificity of pirfenidone for the p38-gamma isoforms in biochemical kinase assays as well as the attenuation of TGF-beta induced collagen synthesis following treatment of cells with pirfenidone. These new studies demonstrate a link between inhibition of p38-gamma and a specific marker of fibrogenesis.
“Extensive industry-wide research has demonstrated that the p38-alpha isoform regulates numerous biological processes that play an important role in inflammatory diseases,” said Dr Lawrence Blatt, chief scientific officer of InterMune.
“The anti-fibrotic mechanism of action of pirfenidone involving selective inhibition of p38-gamma and its associated inhibition of collagen synthesis may prove to be an important element in the treatment of fibrotic lung diseases.”