COPD is a serious respiratory disease in which patients suffer from a combination of chronic bronchitis, emphysema and small airway disease. It is a major and growing cause of illness and death in the UK and worldwide. Importantly, the mechanism of Domainex's TBK1/IKKe drug in COPD will be disease-modifying, unlike current treatments that merely provide symptomatic relief.
It is anticipated that inhibition of IKKε/TBK1 will lead to a more potent and profound effect on both the symptoms and progression of COPD. Fundamentally the basis of this expectation is based upon the observations that these kinases are at the nexus of several pathways each of which is known to be a driver of the pathology of COPD. For example it has been clearly shown that IKKε is a key player in IL-17 signalling, through phosphorylation of Act1 which leads to the formation of a complex between the activated Act1 and TRAF 2 and 5 thus leading to both increased levels and increased stabilisation of the mRNA of key pathogenic cytokines such as MAPK kinases and IL-6.
Similarly it is well established that IKKε also lies on the same pathway as p38 MAPK. This pro-inflammatory kinase is already an established target for COPD with several inhibitor programmes in development. Thus inhibition of IKKε/TBK1, unlike other targets such as p38, will down-regulate numerous pathways that are involved in induction of pro- inflammatory cytokines. It is expected that such a unique spectrum of anti-inflammatory changes will have a profound effect on the pathology of COPD.
Finally Domainex’s project is aimed at oral therapy. With the exception of Rofluimast (PDE4 inhibitor), no oral/systemic agents are available for treatment of COPD. Oral treatment has the advantage of delivering an anti-inflammatory effect to the lung and systemically.