Becoming a master of the domain

Domainex breathes easier after lead compound in preclinical COPD model proves potent

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CAMBRIDGE, U.K.—Well on the road toward developing what it hopes to be a best-in-class anti-inflammatory oral drug to treat chronic obstructive pulmonary disease (COPD), U.K.-based drug discovery firm Domainex Ltd. recently reported its lead compound, DMX503433, has demonstrated it may be a more potent treatment for COPD than leading therapies, such as roflumulast and a p38 inhibitor.
 
Domainex also announced July 9 that it won a £1.4 million (approximately $2.3 million) Biomedical Catalyst Award to support further development toward Phase 1 clinical studies and continue its COPD research.
 
“These are very exciting results which suggest that our program could lead to an oral drug for the treatment of COPD with a much better anti-inflammatory effect than existing medicines,” Dr. Trevor Perrior, research director at Domainex, stated. “This could provide the first truly-effective disease-modifying treatment for COPD, which would have an enormous impact on the management of this debilitating condition.”
 
COPD is a serious respiratory disease in which patients suffer from a combination of chronic bronchitis, emphysema and small airway disease, and is a major and growing cause of illness and death worldwide.
 
A June 20 article in DDNews, written by Lloyd Dunlap, reported that Domainex 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, Domainex stated. 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. Domainex considers these results extremely promising in the search for new treatments of life-limiting diseases such as COPD.
 
Domainex CEO Dr. Eddy Littler stated at that time: “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 has shown that its inhibitors of TBK1 and IKKs can also inhibit signaling pathways activated by Toll-like receptors and IL-17, Littler said. This data suggests that these compounds may be an effective treatment for not only COPD, but other inflammatory diseases, such as rheumatoid arthritis, lupus and psoriasis.
 
The mechanism of Domainex’s TBK1/IKKe drug in COPD will be disease-modifying, unlike current treatments that merely provide symptomatic relief, he said.
 
Furthermore, Domainex’s TBK1/IKKε inhibitors are the most well-advanced in the industry and have several advantages over other TBK1/IKKε inhibitors, such as exhibiting high potency, being administered orally and containing excellent drug-like properties, he said.
 
In fact, Domainex’s project is aimed at oral therapy. With the exception of Rofluimast (PDE4 inhibitor), no oral/systemic agents are available for the treatment of COPD, Perrior said. Oral treatment has the advantage of delivering an anti-inflammatory effect to the lung and systemically.
 
Roflumilast is marketed by Takeda Pharmaceutical Co. Ltd. In the United States, the oral COPD drug is called Daliresp, and it is marketed by Forest Laboratories, he says. It is an inhibitor of PDE4. Most existing drugs for COPD are inhaled bronchodilators and give only symptomatic relief by making the patients’ breathing easier.
 
“Plus, it is likely that an oral treatment would be more convenient to use and improve patient compliance,” Perrior tells DDNews. “Our aim is to show superiority over these two drugs (Rofluimast and p38), and the preclinical data suggests that we are well along the road to doing so.”
 
 “Our objective is to achieve a disease-modifying effect that would slow or halt disease progression, and reduce the incidents of exacerbations,” he adds. “Other inflammatory diseases such as psoriasis, rheumatoid arthritis or neutrophilic asthma are also possible targets.”
 
In this respect, the $2.3-million Biomedical Catalyst Award is useful to the company, as it will allow Domainex to pursue further research.
 
“The grant (award) has been awarded to take the current project, of which DMX503433 is an exemplar lead molecule, and develop an IND-ready drug candidate, leading to proof-of-concept clinical trials relevant to the COPD setting,” Perrior says.
 
Eventually, a candidate drug will be selected from this lead series and “will be developed as an oral anti-inflammatory treatment for COPD,” he continues. “We are also pursuing a similar profile to Roflumilast, but with superior efficacy. We believe a compound with this profile would become the market-leading drug for treatment of COPD-associated inflammation.”
 
In the present study, Domainex compared the effect of oral doses of its compound with the same oral doses of either Roflumilast or a p38 inhibitor in a COPD model that is widely recognized to be the gold standard for preclinical study, according to Perrior. The Domainex compound reportedly showed more than twice the effect of the comparative drugs in reducing the cigarette smoke-induced influx of inflammatory cells, particularly neutrophils, into the lung.
 
“COPD is the fourth-largest cause of death, with over 70 million diagnosed patients,” Littler said in a news release. “The disease is increasing in prevalence, particularly in certain countries, including China. It is estimated that the market for an effective oral drug for COPD is currently worth around $20 billion. It is clear that an effective oral anti-inflammatory drug would not only achieve greater patient compliance, but would also treat the systemic inflammation which drives much of the morbidity and mortality caused by COPD, thereby addressing the major unmet medical need in this very important disease.”
 
Joanne McCudden, Domainex’s head of business development, says the company is targeting various pharmaceutical companies with its TBK1/IKKe program and hopes to partner this program later this year.
 
“We have held discussions with most of the top 20 global pharma companies, and the signs are good,” according to McCudden. “Domainex is poised for great things once our TBK1/IKKe is out-licensed.”
 
Keith Powell, chairman of Domainex stated: “We are very grateful for the £1.4 million awarded by the Technology Strategy Board via the Biomedical Catalyst, which will now enable Domainex to progress the COPD program to IND. In parallel with the company’s ongoing discussions with potential corporate partners, Domainex plans to seek funding to explore utility in other inflammatory diseases and take the program through to clinical proof of concept.”


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