Development of inhaled, dual EP2/4 receptor agonists for the treatment of idiopathic pulmonary fibrosis
Lead Research Organisation:
University of Nottingham
Department Name: School of Life Sciences
Abstract
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.
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.
Technical Summary
Idiopathic pulmonary fibrosis (IPF) is a fatal chronic fibrosing interstitial lung disease with median survival of 3 years. IPF is characterised by formation of fibroblast/myofibroblast foci that excrete excessive extracellular matrix resulting in airway stiffening and loss of pulmonary function. Recent work demonstrated a link between a decrease in prostaglandin E2 (PGE2) signalling and fibrotic disease. Restoration of this pathway via activation of EP2 and EP4 receptors can inhibit, and in some cases reverse, remodelling processes associated with fibrosis. Through an MRC DPFS-funded hit to lead campaign we have identified novel, dual EP2/4 receptor agonists that inhibit fibroblast migration, proliferation and differentiation to a variety of IPF-associated growth factors. We now propose a full Lead Optimisation project to further develop these leads, consisting of chemistry to explore core modification, side chain optimisation and improvement of compound physicochemical properties. As EP2 and EP4 receptors are not restricted to lung we will pursue an inhaled delivery approach to facilitate targeting of compounds directly to their site of action, minimising systemic exposure. We will conduct in vitro characterization against human lung fibroblasts to optimise efficacy against a range of phenotypic responses important in IPF. We will perform detailed pharmacokinetic studies to confirm compound suitability for inhaled delivery. Finally, we will perform pharmacokinetic/pharmacodynamic profiling in the murine bleomycin model to determine efficacy against a chronic pulmonary fibrosis and remodelling response. The ultimate goal is selection of a candidate suitable for progression to GLP long-term inhaled non-human toxicology studies.