Idiopathic pulmonary Fibrosis (IPF) is described clinically as a chronic and progressive interstitial lung disease.
Patients are faced with limited treatment options and poor prognosis, with figures showing only a 31% survival rate at 5-years post-diagnosis.1 The recent FDA approval of Nerandomilast, a small molecule inhibitor of phosphodiesterase 4B (PDE4B), is the first novel therapy for IPF in over a decade.2 This now joins Nintedanib and
Pirfenidone, which until recently were the only treatment options for patients living with IPF. However, treatment with Nintedanib and Pirfenidone is associated with tolerability issues and debilitating side effects. In addition, these drugs mainly function to slow the progression of the disease without offering a cure. This highlights the significant need to bridge the gap and accelerate the discovery process to progress more therapeutic candidates towards the clinic.

Molecular Mechanism of Fibrosis

Multiple factors have been implicated in the aetiology of Lung fibrosis. Owing to their physiological function as the body’s initial interface with the external environment to facilitate gas exchange, the lungs are continually exposed to a variety of environmental insults such as toxins, dust particles, smoke inhalation and microorganisms. Off-target therapeutic effects, autoinflammatory and genetic factors are also linked with disease. However, the causative insult leading to the development of IPF remains largely undefined.

The pathological phenotype of IPF includes unresolving scarring of the lung parenchyma, which is thought to arise following repetitive epithelial injury and dysregulated repair mechanisms. The physiological response to damage and the resultant release of pro-inflammatory and pro-fibrotic mediators drives cellular response pathways to promote wound healing. Prolonged and unresolved activation of these signalling pathways can result in the development of disease. Excessive extracellular matrix (ECM) deposition ultimately leads to stiffening of the lung tissue and distortion of normal architecture, which in turn significantly reduces lung compliance and leads to an irreversible loss of function.