Disease-modifying treatment for COPD, Drug Discovery News
Domainex Ltd. has successfully completed a series of laboratory studies examining the in-vivo effects of its proprietary selective inhibitors of IKK-epsilon and TBK1 in inflammation models. In four separate studies, a lipopolysaccharide challenge was delivered either to the lungs or systemically to mimic the effect of inflammatory disease. In these experiments, Domainex showed that its orally delivered compounds can inhibit the expression of a number of pro-inflammatory cytokines, including TNF-alpha, RANTES, IL-1-beta and IL-6, and maintain prolonged activity against many of the cytokines for at least 20 hours. No side effects were evident in these studies. The company considers these results extremely promising in the search for new treatments of life-limiting diseases such as chronic obstructive pulmonary disease (COPD).
Domainex’s TBK1/IKKe program is first-in-class and promises to offer a disease-modifying treatment for COPD patients, whereas existing treatments merely provide them with symptomatic relief, the company stated in the press release announcing the results.
Domainex’s Director of Research Dr. Trevor Perrior states that “These exciting results clearly show that Domainex’s program on TBK1/IKKe offers the prospect of new treatments for a number of inflammatory diseases, including psoriasis, rheumatoid arthritis and COPD. It’s also very significant that the compounds can be delivered orally, because in many of these diseases—such as psoriasis and COPD—patients are in great need of effective oral medicines.”
Domainex’s CEO Dr. Eddy Littler said: “This is a major achievement by Domainex, and we will build upon this success with further in-vivo models of inflammatory diseases. Our first disease model will be for COPD, a disease which has high medical need and enormous commercial potential. Our compounds are likely to achieve the highly attractive profile of being safe, effective and orally delivered anti-inflammatory compounds.”
Domainex will continue to study the utility of these compounds as treatments for COPD and other inflammatory diseases, and it hopes to partner the program soon and proceed to Phase 1 clinical trials.
“Domainex is targeting mid-large pharma with its TBK1/IKKe program and hopes to partner this program later in 2014,” Joanne McCudden, head of business development, tells DDNews. “We have held discussions with most top 20 global pharma companies and the signs are good. Unfortunately I can’t tell you much more at the moment, except that Domainex is poised for great things once our TBK1/IKKe is out-licensed.”
“Domainex is very much ‘discovery-focused’ and currently does not have the expertise or the resources to progress to the clinic itself. Its strategy is therefore to be a drug discovery powerhouse, delivering exciting new drugs which it will partner in order to maintain this focus,” McCudden continues. “Domainex’s approach seems to fit in well with the current strategy of many big pharma companies, who have found it difficult to be successful in the efficient discovery of new drugs, especially against very novel drug targets.”
Domainex’s technology platform is based on its Combinatorial Domain Hunting (CDH) and LeadBuilder technologies. CDH is a patented approach to the exhaustive screening of all possible constructs of a target protein using E. coli expression. The purpose is to identify protein constructs that are stable, soluble and easily produced for use in screening assay development and structural studies. In practice, this means the screening of 100,000-plus gene constructs with different start and end points across a protein domain within a mere three-month period, McCudden notes.
LeadBuilder is a virtual screening tool, which Domainex uses to identify focused screening sets of around 1,000 to 2,000 small-molecule compounds, predicted to bind to the drug target of interest. The key thing here, McCudden explains, is that Domainex has built-in algorithms that enable it to select for “developable” hit compounds—i.e. the Lipinski Rule of 3. This means that any inhibitors identified using this approach are useful and can be quickly developed into leads. Or bluntly put, “no more ‘rubbish in, rubbish out’ scenarios,” says McCudden.
Domainex uses this CDH and LeadBuilder approach to enable it to work on a wider range of more challenging but well-validated drug targets, which other pharma and biotech companies may balk at attempting. This has indeed enabled Domainex to be extremely successful in approaching novel drug targets such as the dual kinases TBK1/IKKe and a range of lysine methyl transferase targets that are involved in epigenetics.
“Epigenetics is clearly a ‘hot’ area in drug discovery right now,” she notes, “which we think will position Domainex as a force to be reckoned with as candidate drugs start to emerge.”
“Domainex understands its strengths and plays to these well,” McCudden summarizes.