Novel drug targets in idiopathic pulmonary fibrosis

ABSTRACT

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fatal, fibrosing interstitial pneumonia of unknown cause, that arises with progressive worsening in lung function. Several pathways were assumed to be involved in its pathogenesis and various molecules, targeting the differing mechanisms, have been investigated. To date, the most likely scenario is that the driving process is an aberrant wound healing response as a result of repeated alveolar epithelial cell (AEC) micro-injuries, that lead to lung remodeling. Thus, the only drugs approved for the treatment of IPF are two disease-modifying, anti-fibrotic molecules.

Areas covered: This review provides a comprehensive summary of the current investigational drugs targeting pro-fibrotic and immune pathways, and cell-based therapy. Ongoing and completed trials are purposed through updated data.

Expert opinion: Novel phase I and II trial results promote the paradigm of fibrosis-driven process against the inflammatory-based model previously proposed. The anti-fibrotic approved drugs, nintedanib and pirfenidone, are still an intriguing research topic. Meanwhile, multiple novel therapies, with more precise anti-fibrotic mechanisms than in the past, are under evaluation. Given the heterogeneity of IPF, multi-target therapies are likely to be most effective and validation of biomarkers of treatment is needed. At the moment, enrolment in a clinical trial may be the best chance for IPF patients to cure the disease.

KEYWORDS:

• Idiopathic pulmonary fibrosis
• novel targets
• precision medicine
• anti-fibrotic
• immunity

Acknowledgement

We thank the architect Leonardo Giuzio for drawing the figure.

Article highlights

• A wide range of Phase 1 and Phase 2 trials are being continued and intensified, together with the progress in the understanding of IPF pathogenetic pathways.

• The main purpose of IPF treatment should be the discontinuation of aberrant mesenchymal deposition.

• The lack of validate pre-clinical model that faithfully mimics human disease is one of the biggest limitations of IPF research.

• The fibrotic process in IPF lungs is dynamic and plastic, with different involved pathways. Further research on multi-target therapies should be encouraged.

• Validation of biomarkers of treatment efficacy would enable stratification of the disease and increase the strength of clinical trials.

This box summarizes key points contained in the article.

Declaration of interest

L Richeldi reports personal fees from Sanofi-Aventis, Roche, ImmuneWorks, Boehringer Ingelheim, Celgene, Nitto, Fibrogen, Promedior, Bristol Myers Squibb and DynaMed, outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript other than those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.