Inhaled EP4 receptor agonists for the treatment of idiopathic pulmonary fibrosis

This project aims to deliver a novel drug candidate for the treatment of idiopathic pulmonary fibrosis (IPF), a debilitating and fatal disease for which few treatment options are available.

IPF is a chronic and progressive lung disease where excessive scarring occurs in the lung. This leads to stiffening of the airways, making it harder for the lungs to inflate and function normally, which causes severe shortness of breath. Patients with IPF experience worsening symptoms over time that prevent them performing activities that many of us take for granted, including daily tasks such as washing and dressing. For many people this progression is rapid, and people die early. In fact, with an average survival time of only 3 years from diagnosis, IPF is worse than most cancers. Diagnosis of IPF is a complex and lengthy process, but current estimates suggest that 18 people in every 100,000 suffer from it in the UK.

Wound healing is a normal process where naturally occurring substances (or growth factors) in the lung stimulate regrowth of cells to repair the damaged area. For some reason, in IPF this process is not properly regulated, so cell growth continues unchecked resulting in the characteristic scarring of the lungs. Currently two anti-cancer drugs are used in IPF in an attempt to prevent this cell growth, but they only inhibit some of the growth factors that stimulate repair, so are not very effective. They are also swallowed drugs and have unwanted effects on other parts of the body. This is particularly bad in the gut where they can cause diarrhoea that is so severe that many patients chose to stop taking their medicines. Despite ongoing research in this area, effective medicines to treat IPF remain elusive, highlighting the need to explore new ways of treating this disease.

We have identified a novel approach to treat IPF. By specifically activating beneficial pathways in lung cells we will counteract the unregulated wound healing stimulated by all growth factors involved in IPF. We will do this by switching on a particular protein on the surface of lung cells known as the EP4 receptor. We have already shown that activation of this receptor is able to robustly inhibit several key processes involved in scarring, and therefore has the potential to treat this debilitating disease.

In addition to improving the effectiveness of existing IPF medicines, we also want to make them safer by reducing the severe side effects linked to them. To do this, we plan to develop a medicine that can be taken using an inhaler, similar to other lung diseases like asthma. This will allow us to deliver our medicine directly to the lung where they are needed, without reaching the rest of the body where they may cause unwanted effects.

This project has been designed and submitted by researchers at the University of Nottingham who have significant expertise in making drugs for lung diseases, having successfully brought new drugs to market for asthma and chronic obstructive pulmonary disease (COPD). Our aim is to build on these successes and develop a novel, effective and safe medicine for IPF patients.

Idiopathic pulmonary fibrosis (IPF) is a fatal chronic fibrosing interstitial lung disease with a median survival of just 3 years. IPF is characterised by the formation of fibroblast and myofibroblast foci that excrete excessive amounts of extracellular matrix resulting in airway stiffening and loss of pulmonary function. Recent work has demonstrated a link between a decrease in prostaglandin E2 (PGE2) signalling and fibrotic diseases, and restoration of this pathway can inhibit, and in some cases reverse, remodelling processes associated with fibrosis. Studies in our lab have shown that EP4 receptor agonism potently inhibits fibroblast migration, proliferation and differentiation to a variety of disease-associated stimuli. This demonstrates that the PGE2-EP4 signalling axis has the potential to prevent further structural changes in the lungs, making EP4 an attractive target to treat IPF. EP4 receptor expression is not restricted to the lung, so we propose inhaled delivery to minimise systemic exposure and mitigate anticipated on-target side effects, such as hypotension and inflammatory pain. The immediate goal of this project is to develop lead compounds with anti-remodelling efficacy and appropriate inhaled pharmacokinetic (PK) and lung coverage. Efficacy will be assessed through inhibition of primary human lung fibroblast proliferation and fibroblast to myofibroblast transdifferentiation (FMT). Duration of lung action will be evaluated using in vitro PK and cell membrane wash-out assays, followed by in vivo lung PK studies. This design strategy is based on our previous experience developing successful long-acting inhaled GPCR agonists (e.g. indacaterol). Compounds will be developed from 2 distinct chemical series, one disclosed in literature and one novel class from which we have synthesized preliminary active examples. Selected compounds will form the basis of a future lead optimisation MRC DPFS application to deliver novel, clinical candidates to treat IPF.

We are proposing an innovative research programme to explore a novel target and mechanism to treat idiopathic pulmonary fibrosis (IPF). This has the potential to have a high impact on society, in terms of significant health improvements, commercial opportunities and economic growth. We have already mapped out options for alternative routes to funding the next stages of development (i.e. lead optimisation) and will continue to explore and develop these options as the project progresses.

This project will also increase our understanding of strategies to develop long-acting, inhaled medicines, with reach into other debilitating and fatal lung diseases. In order to ensure that this impact is delivered, our research will be disseminated through seminar presentations at the University of Nottingham and other academic institutions, lecture and conference presentations (e.g. European Respiratory Society and American Thoracic Society meetings), and publications in internationally recognised journals.

In addition we will deliver a highly trained postdoctoral researcher assistant (PDRA), with the potential to impact on any Masters and Undergraduate students who undertake projects in the laboratory, contributing to the UK Pharmacology talent base. The PDRA will be mentored by the PI and CoI's, who have an established track record of training young scientists. The PDRA will also be responsible for analysis, interpretation and dissemination of results, as well as working closely with medicinal chemists in industry. This will give them invaluable insight into working across the academia:industry interface and will enhance their skills in team work and communication as well as problem solving and critical thinking.