Investigational drugs for idiopathic pulmonary fibrosis

ABSTRACT

Introduction: IPF is a specific form of chronic fibrosing interstitial pneumonia of unknown cause, characterized by progressive worsening in lung function and an unfavorable prognosis. Current concepts on IPF pathogenesis are based on a dysregulated wound healing response, leading to an over production of extracellular matrix. Based on recent research however, several other mechanisms are now proposed as potential targets for novel therapeutic strategies.

Areas covered: This review analyzes the current investigational strategies targeting extracellular matrix deposition, tyrosine-kinase antagonism, immune and autoimmune response, and cell-based therapy. A description of the pathogenic rationale implied in each novel therapeutic approach is summarized.

Expert opinion: New IPF drugs are being evaluated in the context of phase 1 and 2 clinical trials. Nevertheless, many drugs that have shown efficacy in preclinical studies, failed to exhibit the same positive effect when translated to humans. A possible explanation for these failures might be related to the known limitations of animal models of the disease. The recent development of 3D systems composed of cells from individual patients that recreate an ex-vivo model of IPF, could lead to significant improvements in disease pathogenesis and treatment. New drugs could be tested on more genuine models and clinicians could tailor therapy based on patient’s response.

KEYWORDS:

• Alveolar epithelial cell
• autoimmunity
• idiopathic pulmonary fibrosis
• immunity
• mesenchyme
• novel targets
• precision medicine
• pulmospheres
• stem cell
• tyrosine-kinase antagonists

Article highlights

• The improvements in the understanding of IPF pathogenetic pathways generated different novel potential therapeutic targets; as a consequence, several phase 1 and 2 trials are currently in progress.

• The concept of lung fibrosis in IPF should be seen as a dynamic and plastic process, with significant repercussions on the development of new therapies and design of future trials.

• The main aim of pharmacological treatment in IPF should be the interruption of the aberrant mesenchymal deposition.

• The dissimilarities between animal models and human IPF features could delay the development of new therapies.

• Regenerative cell therapy represents an attractive approach to IPF therapy, but the long-term safety and the efficacy are still unknown.

• The recent development of 3D culture systems could greatly help the understanding of IPF pathogenesis.

This box summarizes key points contained in the article.

Acknowledgments

We thank the architect Leonardo Giuzio for drawing the figure.

Declaration of interest

L Richeldi discloses relationships with Medimmune, Biogen, Sanofi-Aventis, Takeda, ImmuneWorks, Shionogi, Cipla, Pliant Therapeutics, Boehringer Ingelheim and Roche. 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 apart from those disclosed.

Additional information

Funding

This paper was not funding.