New therapeutic targets in idiopathic pulmonary fibrosis. Aiming to rein in runaway wound-healing responses

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating disease, with a median survival as short as 3 years from the time of diagnosis and no pharmacological therapies yet approved by the U.S. Food and Drug Administration. To address the great unmet need for effective IPF therapy, a number of new drugs have recently been, or are now being, evaluated in clinical trials. The rationales for most of these therapeutic candidates are based on the current paradigm of IPF pathogenesis, in which recurrent injury to the alveolar epithelium is believed to drive aberrant wound healing responses, resulting in fibrosis rather than repair. Here we discuss drugs in recently completed or currently ongoing phase II and III IPF clinical trials in the context of their putative mechanisms of action and the aberrant repair processes they are believed to target: innate immune activation and polarization, fibroblast accumulation and myofibroblast differentiation, or extracellular matrix deposition and stiffening. Placed in this context, the positive results of recently completed trials of pirfenidone and nintedanib, and results that will come from ongoing trials of other agents, should provide valuable insights into the still-enigmatic pathogenesis of this disease, in addition to providing benefits to patients with IPF.

Keywords: idiopathic pulmonary fibrosis; investigational treatments; pathogenesis.

Figure 1.

Investigational therapies for idiopathic pulmonary fibrosis (IPF): targeting aberrant responses to injury. This schematic indicates the sequential profibrotic processes implicated in the currently prevailing paradigm of IPF pathogenesis, in which recurrent or persistent injury to the alveolar epithelium is believed to drive aberrant wound-healing responses, resulting in fibrosis rather than repair. Drug candidates evaluated in recently completed or ongoing phase II and III clinical trials in IPF are placed in the context of the profibrotic process(es) they are believed to target. Although fibrosis in IPF appears to predominantly expand the interstitial compartment, the aberrant repair processes driving IPF progression, and the fibrosis they produce, may occur in both the interstitium and the airspaces. For purposes of figure clarity, we have depicted the development of fibrosis in the airspaces in this figure. NAC = N-acetylcysteine. Inspired by Reference .