Development of a novel therapeutic for inflammatory lung diseases
Professor’s Chris Corrigan and Jeremy Ward
Dr Barry Porter
Inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) represent a substantial medical need which, despite existing medicines, are insufficiently treated. Inhaled steroids do not work in 10% of asthmatics (such patients draw 90% of the asthma healthcare resources), and have been questioned in COPD; moreover, the Inhaled steroids and fibrotic aspects represent significant unmet medical needs.
Current therapies are directed at increasing bronchodilatation and reducing airways inflammation, often with combination products. This technology takes an entirely different approach, addressing the root cause of asthma and COPD, as well as remodelling/fibrosis, through a single mechanism of action.
At the centre of these diseases, there are two cell types, eosinophils and airway smooth muscle cells, responsible for inflammation and airway constriction, respectively.
Fig1: A treatment that has the potential to address the root cause of inflammatory lung disease
From a plethora of in vitro and in vivo data, we now have compelling evidence that the Calcium Sensing Receptor (CaSR) is present on both key cell types and links these two processes. This would imply that a CaSR antagonist (calcilytic) would be useful in treating inflammatory lung conditions.
What is interesting is that several pharmaceutical companies have developed systemic calcilytics for the treatment of osteoporosis. Although relatively safe, their development was terminated because of lack of efficacy for this indication. Our aim is to repurpose one of these calcilytics, delivering it directly to the lungs to improve further its tolerability, as a revolutionary treatment for severe asthma and other inflammatory lung disorders.
If pre-clinical findings hold true in humans, calcilytics could target bronchial hyperreactivity, inflammation and fibrosis with one agent. No other existing or developmental therapy for asthma or COPD addresses all of these at once. Furthermore, by antagonising the CaSR, we address an upstream mediator linked to the disease cause, rather than downstream intracellular pathways common to many other biological functions, a strategy which is inevitably associated with undesired effects.
An important feature is that oral calcilytics have been shown to be safe and well tolerated in human clinical trials. Although their development was halted because of lack of efficacy in osteoporosis, such information will expedite the development of a drug for treating asthma and COPD.
The Project is currently seeking licensees or partners to fund and support development of a calcilytic through bridging toxicology and formulation to achieve POC in man.
We are also considering seeking investment to create a company that could support activities through to POC in man.
WO2014049351 filed 23/09/2013, priority date 28/09/2012, is granted in US, AU and JP and pending in EU, CA and CN
Yarova et al, Sci Transl Med, 2015-284ra60