DUBLIN – Heptares Therapeutics, a subsidiary of Tokyo-based Sosei Group Corp., is getting $10 million up front and potentially more than $500 million in milestones by out-licensing to Astrazeneca plc its A2A adenosine receptor (A2AR) antagonist HTL-1071 for development in immuno-oncology indications. It would also receive tiered double-digit royalties on product sales.

It's the same compound that Heptares, of Welwyn Garden City, UK, licensed to Dublin-based Shire plc back in 2012 for disorders of the central nervous system (CNS), in a deal worth up to $190 million in milestone payments. (See BioWorld Today, March 21, 2012.)

However, Shire subsequently exited from early stage development in areas such as attention deficit hyperactivity disorder and handed the program back about a year ago, Heptares CEO Malcolm Weir told BioWorld Today. The company has touted its potential in cancer to a number of companies since then.

"It's ready to go into humans," he said.

Michail Sitkovsky, of Northeastern University in Boston, was first to recognize an association between adenosine signaling through the A2AR – a member of the G protein-coupled receptor family – and tumor immune evasion. Back in 2006, Sitkovsky and colleagues reported, in the Aug. 29 issue of Proceedings of the National Academy of Sciences, that 60 percent of knockout mice lacking A2AR rejected established immunogenic tumors, whereas no wild-type mice did.

"It's become a very interesting target in immuno-oncology," Weir said.

The hypoxic tumor microenvironment results in the extracellular release of adenosine, which binds A2ARs expressed on the surface of regulatory T-cells (Treg), leading to down-regulation of cytotoxic T-cells directed against the cancer.

"What you want to do is block adenosine binding the A2AR on the T cells," Weir said.

Being able to target the receptor with an orally available small molecule makes it an ideal candidate for combining with other therapeutic modalities, such as chemotherapy, cancer vaccines or checkpoint modulators.

Although still playing catch-up to New York-based Bristol-Myers Squibb Co. and Kenilworth, N.J.-based Merck & Co. Inc., London-based Astrazeneca is shaping up to be one of the main players in immuno-oncology – and it already had an existing alliance with Heptares in inflammatory pain.

"We thought they were a partner of choice," Weir said.

A2AR has long been targeted in CNS indications, most notably Parkinson's disease, because of the inhibitory effect of adenosine on dopamine signaling. Success has been largely elusive, however. Merck terminated development of preladenant after phase III trials showed no efficacy. Cambridge, Mass.-based Biogen Inc. and Winnersh, UK-based Vernalis plc halted development of vipadenant before phase III trials.

"The issue is partly related to the compounds that have been trialed and, in some cases, to the way in which the trials have been carried out," Weir said.

Turku, Finland-based Biotie Therapies Oyj is still in the game – it moved tozadenant into a phase III trial in Parkinson's last month. In 2013, Tokyo-based Kyowa Hakko Kirin Co. Ltd. gained approval in Japan for Nouriast (istradefylline) for treating Parkinson's. The same drug is now undergoing a phase III trial in the U.S. under an FDA special protocol assessment, despite the agency having deemed it not approvable in 2008.

In cancer, the class is less developed, and most programs are still operating under the radar. Palobiofarma SL, of Barcelona, Spain, has submitted an investigational new drug application for PBF-509, with a view to conducting a phase I trial in patients with advanced non-small-cell lung cancer, in collaboration with the H. Lee Moffitt Cancer Center, of Tampa, Fla.

The side effect profile of the drug class is clean, Weir said, with little mechanism-based toxicity. "If you look at the side effect profile of A2AR antagonists in Parkinson's disease, there is very little evidence of side effects that are not related to the chemical structures."

HTL-1071 emerged from Heptares' structure-based drug design process, which is informed by X-ray crystallographic studies of the A2AR complexed with small molecules. It is highly selective, Weir said, and lacks a toxophore moiety that has limited the utility of some of the previous drugs.