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Therapeutic Targets
Targeting inflammation at its source
Idiopathic Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic disease, associated with genetic and environmental risk factors (eg smoking and pollution).
The IPF market is growing at a rate of more than 5% per annum and is expected to reach a global market value of approximately $9 billion by 2027.
This is expected to be at least matched by the marked unmet clinical needs emerging from the post-COVID19 pandemic, where lung fibrosis is expected to be an emerging problem of substantial magnitude. Not only is there increased incidence of fibrosis in patients with no prior diagnosis of IPF or interstitial lung disease (ILD), but also worsening of symptoms and disease progression within the population with such previous diagnoses.
Audax is addressing this critical need to develop novel pharmaceuticals designed to combat both chronic inflammation and fibrosis.
Why EPAC1 Agonists?
In IPF, continuous injury to the lung epithelium promotes inflammation, loss of epithelial cells, and excessive recruitment of fibroblasts and myofibroblasts. This causes accumulation of extracellular matrix components (eg collagen), abnormal tissue repair and deformation of the lung architecture.
Inhaled EPAC1 agonists are predicted to counteract this by inhibiting fibroblast activation and regulating the responses of a range of different cell types, including airway smooth muscle cells, vascular endothelial cells, lung epithelial cells mesenchymal stem cells, and immune cells (eg macrophages), with therapeutic benefit in combating the fibrotic pathway.
Inhaled EPAC1 agonists are differentiated from existing therapies in the disease space in that they promote activation of pre-existing anti-inflammatory/antifibrotic mechanisms as opposed to the commonly used “inhibitor” approach that exert a blanket blockade on pro-inflammatory mechanisms, as well as potentially desirable off-target control mechanisms.
By directly inhibiting the excessive inflammatory and hence fibrotic response within the lung, EPAC1 agonists are predicted to normalise the rate of loss in lung function seen in IPF patients.
Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) describes a group of severe pulmonary vascular disorders, with 1 - 2 million new cases reported annually in the United States.
PAH is a complex and devastating disease that causes progressive vasoconstriction and vascular remodeling of the distal pulmonary arteries. Currently, there is no cure, and the majority of patients with PAH go on to develop many serious conditions such as right-sided heart failure and premature death.
The level of unmet need in the PAH remains high, and the greatest need is for novel drugs with curative or disease-stabilizing properties. There are still significant limitations to marketed and pipeline agents.
Currently available drugs work to slow the disease progression, but there is no marketed drug that addresses the underlying disease mechanism and is targeted at curing patients.
Why EPAC1 Agonists?
Inhaled EPAC1 agonists provide an exciting and valuable opportunity for drug development to PAH.
EPAC1 agonists inhibit NLRP3 inflammasome, TGFβ signalling, JAK/STAT activation and disrupt pro-inflammatory communication between macrophages and vascular endothelial cells.
These unique actions highlight the importance for EPAC1 in coordinating key responses involved in the progression of vascular inflammation and identifies a new, druggable route to treat PAH.