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Improving the translational relevance of preclinical models for pulmonary fibrosis

Preclinical models play a vital role in understanding the potency, efficacy and safety of new pharmaceutical products, allowing developers to make timely decisions on the progression of drug candidates. Improving the translational relevance of preclinical models for pulmonary fibrosis

Given their importance for de-risking development programs, it’s essential preclinical models are as translational to human pathology as possible. After all, unreliable information on the efficacy or safety of candidates can lead to ineffective or potentially unsafe molecules being progressed towards the clinical stage, with associated risk to investment and, most importantly, human health. Improving the quality of information these models provide is therefore an important goal in drug development across many therapeutic areas.

Translationally relevant preclinical models of IPF

One disease area where calls for more translationally useful preclinical models are being met with innovative solutions is Idiopathic Pulmonary Fibrosis (IPF), a chronic and irreversible respiratory disease characterized by collagen-based scar tissue formation (fibrosis) in the lungs.

While a large number of anti-fibrotics have shown promise in preclinical studies, when it comes to translating this activity into effective treatments, development efforts have met with limited success. Currently, just two approved IPF drug treatments, nintedanib and pirfenidone, are available. Although these drugs have been shown to slow progression of the disease in some patients, there remains a need for more effective and better tolerated alternatives.

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Some experts believe that the disappointing pace of development in this area is due to limitations with existing preclinical models. Currently, the most commonly used and well-characterized model for IPF research is the mouse bleomycin model, with the measurement of hydroxyproline content (a suitable surrogate for collagen) acting as the recommended endpoint for quantifying fibrosis.

Despite advantages around the relatively short time to the manifestation of fibrosis, the model suffers from a number of limitations including rapid tissue recovery following bleomycin administration. As a result, distinguishing the benefits of test compounds from normal lung repair can therefore be challenging.

The search for better IPF preclinical model endpoints

So how can we improve the translational capacity of preclinical IPF models? Well, ongoing research suggests the answer may lie in the study of similar endpoints across the animal model and human patient.

Models based on the analysis of blood biomarkers, for example, could better enable the identification of the early changes associated with the development of fibrosis, rather than inflammation. Recent studies highlight how biomarkers such as neo-antigens may be used to characterize fibrosis in humans. By measuring similar antigens in mouse models, the translational effectiveness of these preclinical studies could be improved.

Similarly, advances in the capability of non-invasive imaging technologies could also strengthen the link between model and patient. The use of imaging technologies such as micro-computed tomography, for example, across both animal models and human patients has the potential to improve the quality and relevance of the information collected, ultimately leading to more reliable development decisions.

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To learn more about how innovative end points are helping to improve the translational relevance of preclinical IPF models, read the article in full here.

Topics: Drug Development