An Official American Thoracic Society Workshop Report: Use of Animal Models for the Preclinical Assessment of Potential Therapies for Pulmonary Fibrosis

Abstract

Numerous compounds have shown efficacy in limiting development of pulmonary fibrosis using animal models, yet few of these compounds have replicated these beneficial effects in clinical trials. Given the challenges associated with performing clinical trials in patients with idiopathic pulmonary fibrosis (IPF), it is imperative that preclinical data packages be robust in their analyses and interpretations to have the best chance of selecting promising drug candidates to advance to clinical trials. The American Thoracic Society has convened a group of experts in lung fibrosis to discuss and formalize recommendations for preclinical assessment of antifibrotic compounds. The panel considered three major themes (choice of animal, practical considerations of fibrosis modeling, and fibrotic endpoints for evaluation). Recognizing the need for practical considerations, we have taken a pragmatic approach. The consensus view is that use of the murine intratracheal bleomycin model in animals of both genders, using hydroxyproline measurements for collagen accumulation along with histologic assessments, is the best-characterized animal model available for preclinical testing. Testing of antifibrotic compounds in this model is recommended to occur after the acute inflammatory phase has subsided (generally after Day 7). Robust analyses may also include confirmatory studies in human IPF specimens and validation of results in a second system using in vivo or in vitro approaches. The panel also strongly encourages the publication of negative results to inform the lung fibrosis community. These recommendations are for preclinical therapeutic evaluation only and are not intended to dissuade development of emerging technologies to better understand IPF pathogenesis.

Figure 1.

Integrating human disease data with preclinical animal studies. Preclinical assessment of drug candidates should make judicious use of animal models, such as the bleomycin model in mice, with strong biochemical and histologic assessments of collagen deposition. In addition, animal models and culture systems can be used for efficacy, safety, and imaging studies. Target validation should involve annotated human specimens. An integrated approach that tests effects of compounds on established fibrosis should help move promising targets to clinical trials. iPSCs, inducible pluripotent stem cells; PD, pharmacodynamics; PK, pharmacokinetics. Figure adapted from a slide shown by Dr. Shelia Violette, who presented this at the American Thoracic Society Conference in May 2015.