Established a dozen years ago, Domainex Ltd. is familiar to drug developers – especially in the UK, where the company spun out of University College London – as a contract research organization.

Initially, Domainex operated in partnership with sister organization NCE Discovery, with the two entities sharing a similar shareholder base.

That relationship changed in 2006, when the companies were combined "to give a more critical mass" and to bring the chemistry and advanced biology assets at NCE Discovery into the Domainex fold, explained CEO Eddy Littler.

"In some ways, that's where the company that we have today really started," said Littler, who joined Domainex shortly after the merger.

Although Cambridge-based Domainex continues to provide contract research services, the integration of NCE Discovery also served as "the trigger point" to launch an internal pipeline.

"I'm a big believer that a lot of companies succeed or fail in biotech on the very early decisions they made about which targets to choose," Littler told BioWorld Today. "We spent quite a lot of time on that process."

Banking on its experience in drug discovery, Domainex examined targets "that were known by the pharma community but regarded as being challenging," Littler explained. The company refined the process to focus on programs whose specific problems could be solved by applying its platform, known as combinatorial domain hunting (CDH). The technology is designed to clone and express difficult genes and to produce protein at the requisite levels by screening all possible protein constructs, in rapid fashion.

Domainex started with a group of targets that included the closely related pro-inflammatory kinases TANK-binding kinase 1 (TBK1) and IkappaB kinase epsilon (IKKε). In July, the company reported that its lead program, encompassing small-molecule inhibitors of TBK1/IKKε, demonstrated a more potent effect in a model of chronic obstructive pulmonary disease (COPD) than the PDE4 inhibitor Daliresp (roflumilast, Forest Laboratories Inc.) or a p38 inhibitor. The Domainex compound showed at least three times the effectiveness of roflumilast "and was many more times effective than the p38 inhibitor" in reducing the cigarette smoke-induced influx of inflammatory cells, particularly neutrophils, into the lung, Littler said.

Daliresp was approved by the FDA in 2011 to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of such flare-ups. Forest Labs, now part of Actavis plc, had licensed the drug – marketed as Daxas in the European Union and Canada – from privately held Nycomed GmbH, of Zurich, Switzerland, in a deal potentially worth more than $500 million. (See BioWorld Today, Aug. 11, 2009, and March 2, 2011.)

Domainex is exploring the TBK1/IKKε inhibitors in a number of inflammatory disease models, including rheumatoid arthritis, lupus and psoriasis, and said they also have applications in a range of cancers, including colorectal, breast and lung cancers. Domainex has filed multiple patents on the lead series to treat COPD and on the use of TBK1 in cancer.

"COPD is a huge medical need and a very attractive marketplace, so we chose that as our first disease model," Littler pointed out.

The company's real coup was to solve the problem of oral bioavailability for the drug class. "We spent about a year solving that problem, and it was probably the worst one I've ever seen," Littler said. "But we got there. We had to. We're a small biotech company, and that was our program. We had to be successful, or the company would have failed."

ORGANIZATIONAL CHANGE BEST APPROACHED FROM A POSITION OF STRENGTH

In the process of working on the TBK1/IKKε inhibitors, Domainex discovered targets involved in epigenetic gene regulation known as lysine methyltransferase, or KMTs. Scientific evidence suggests those enzymes play a significant role in many diseases, Littler said, with a number of the enzymes known to have relevance in mechanisms of carcinogenesis. Using its CDH technology, the company subsequently cloned and expressed a number of KMT enzymes, with the design of inhibitors representing the second program in its pipeline.

"It's a very hot area, and we have some novel chemistry in that area that looks very much like drug-like molecules," Littler said, describing the company's molecules as "very, very clean."

Findings on the TBK1/IKKε inhibitors won Domainex a £1.4 million (US$2.4 million) Biomedical Catalyst Award from the UK's Technology Strategy Board to advance the program into phase I studies. The company also secured early funding from the Bloomsbury Bioseed Fund and two small rounds from Longbow Capital. Revenues from its drug discovery services, which represent about 70 percent of the company's operations, make it less focused on fundraising than most small biotechs.

"The service business has been quite successful and is profitable," Littler said, noting that Domainex expects to expand from 32 to approximately 40 employees by year-end. "Our priority now is to take the service business forward and grow it organically or through some sort of M&A to increase the critical mass of the technologies."

Littler, whose resume includes tenure at Wellcome Research Laboratories and Glaxo Wellcome plc – now part of Glaxosmithkline plc, of London – as well as Sweden's Medivir AB, maintained that just as most biotechs are more efficient organizations than large pharmas, most life science service organizations are similarly more efficient than biotechs.

"You're working for a client, and the relationship is usually fairly straightforward," he observed. "They give you cash, and you deliver the goods on time, as they expect. That relationship drives you to be extremely efficient, and that efficiency spins over directly to the approach to internal programs."

The company's ongoing service work with pharmas – including more than 40 collaborations, to date, on its CDH platform – has served as a springboard to its pipeline by increasing the company's understanding of a variety of targets while providing opportunities to discuss its internal projects with clients. The hybrid approach "is a very effective model, both on a technical level and from a commercial standpoint," Littler said.

By year-end, Domainex expects to establish a separate intellectual property company (IPCO) that will serve as a repository for its patents and enable its internal drug pipeline to move forward with its own set of goals, targets, budgets and timelines. At that point, Domainex will seek to raise additional funding.

"That work is getting off the ground," Littler said. "By the end of the year, we'll have established the IPCO and we hope to be in discussions with a couple of investors about taking these projects through to clinical proof of concept."

Organizational change is best approached from a position of strength, he added. With the company's service business running smoothly and its nascent drug pipeline now at an inflection point, "that's the right time to make these changes and move the company forward," Littler said.