Development of inhaled, dual EP2/4 receptor agonists for the treatment of idiopathic pulmonary fibrosis

This project aims to deliver novel drug candidates for the treatment of Idiopathic Pulmonary Fibrosis (IPF), a debilitating and fatal disease for which few treatment options are available. IPF is a chronic, progressive and fatal lung disease that is characterised by excessive scarring of the lung, a process known as fibrosis. Fibrosis leads to stiffening of the airways and makes it harder for the lungs to inflate and function normally, resulting in shortness of breath. Patients with IPF experience worsening symptoms over time that lead to the inability to undertake activities that many of us take for granted, including daily tasks such as washing and dressing, and ultimately death through suffocation. We do not currently understand the processes that lead to fibrosis, therefore the development of highly effective medicines to treat IPF remains elusive. IPF is a complex disease and accurate diagnosis is challenging. Current estimates state that approximately 50 per 100,000 people in the UK have an IPF diagnosis, with about 40,000 patients dying per year. The average survival time of patients is only 3 years from time of diagnosis, however rate of progression varies greatly amongst patients meaning about 20% of people with the disease survive for more than 5 years. Although we don't understand exactly what causes IPF, it is likely to be the result of damage to the lining of the lung, either by chemical, particulate or viral insults. This leads to a cascade of events in the lungs which are caused by the over-production of naturally occurring substances in the lung, which would normally be responsible for stimulating growth. The unnaturally occurring levels of these substances results in out of control wound healing that leads to the scarring of the lungs. Current medicines for IPF have been repurposed from cancer treatments. They are poor at reducing symptoms and have debilitating side effects. These oral medications dose the whole body, causing widespread side effects such as intolerable diarrhoea. These symptoms are so severe that many patients choose to stop taking these medicines, as the benefits to their health are outweighed by the devastating side effects they experience. There is clearly a need for new, more effective and safer medicines to treat IPF. We have identified a novel approach to treat IPF. Firstly, we wish to activate a pathway that will counteract many of the processes involved in IPF, regardless of which substance is causing the underlying problem. The targets we are interested in are the prostaglandin E2 receptor subtypes 2 and 4 (EP2 and EP4 receptors). We have identified novel compounds that activate these receptors, and generated data demonstrating these compounds are able to robustly inhibit key cellular processes involved in IPF, and therefore have the potential to treat this debilitating disease. We are developing these medicines to be taken using a nebuliser, similar to other lung diseases like asthma. This will allow us to deliver our medicines directly to the lung where they are needed, without reaching the rest of the body where they may cause unwanted effects. Although nebulising current therapies would improve their whole body side effect profiles, this won't improve the poor clinical effect of existing medicines. 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), and have previously identified early drug-like candidates from existing MRC-DPFS funding. Our aim is to build on these successes and develop a novel, safe and effective therapy for IPF patients.