The decision by Merck & Co. Inc. to end its Phase III program with preladenant based on three studies that failed to show efficacy in Parkinson's disease put the spotlight on adenosine A2A receptor antagonists as a class, which has been explored by a handful of other companies, some of them with work still under way.

Merck, of Whitehouse Station, N.J., said last week that the company is "taking steps to discontinue" the extension phases of the studies and will abandon bids for regulatory findings.

Results from the research will be offered at an upcoming scientific meeting, and will be submitted for publication in a peer-reviewed journal.

Mark Schoenebaum, analyst with ISI Group, noted in an alert to investors that consensus estimates pegged peak sales of preladenant of only about $200 million in 2018, the last year for which figures were available, and called the impact to Merck "quite small."

The preladenant news was dwarfed by happier developments, such as the company's accelerated share repurchase valued at about $5 billion, the scheduling at an analyst meeting at the American Society of Clinical Oncology, and a favorable vote by an FDA advisory panel for suvorexant a first-in-class dual orexin receptor antagonist (DORA) for insomnia. DORAs have made something of a splash lately, seeming to promise a solid night of sleep without the daytime drowsiness that besets users of other, generic sleep medications. (See BioWorld Today, April 16, 2013.)

Adenosine A2A receptor antagonists – members of the G-protein-coupled receptor (GPCR) family, and believed useful in central nervous system disorders other than Parkinson's – may fare less well. Investors likely are looking askance at Biotie Therapies Corp., of Turku, Finland, which in December reported Phase IIb data with tozadenant, also targeting Parkinson's.

Data showed the study met its primary endpoint of decreasing the "off" time in patients experiencing levodopa-related end-of-dose wearing off vs. placebo, with efficacy across multiple secondary endpoints, too.

Biotie ended up with tozadenant by way of its early 2011 buyout of Synosia Therapeutics AG, in an all-share deal valued at €93.6 million (then US$121 million). The takeover, three months after Biotie underwent a restructuring that cut staff by about 75 percent, brought aboard six clinical stage central nervous system products, including treatments for Parkinson's and Alzheimer's diseases, and for bipolar disorder. (See BioWorld Today, Jan. 12, 2011.)

Another player in the adenosine A2A antagonist field, Montreal-based Valeant Pharmaceuticals International Inc., holds North American rights to istradefylline – once again, for Parkinson's – which was the first compound in the class to enter the clinic. Its fate may have foreshadowed the failure of the Merck candidate: istradefylline received a not-approvable letter from the FDA in 2008.

Regulators made known their concerns about the drug's efficacy and requested additional nonclinical mineralization data and clinical pharmacology data.

In 2010, though, Valeant's subsidiary Biovail Corp. disclosed a license deal with Kyowa Hakko Kirin Co. Ltd., of Tokyo, for U.S. and Canadian rights to commercialize products containing istradefylline.

Biovail provided $10 million up front, and pledged as much as $20 million in potential development milestone payments that would come along the path through FDA approval, plus $35 million if certain sales-based milestones are met.

The space, at least for now, remains active. In March, Addex Therapeutics SA, of Geneva, and Viva Biotech Ltd., of Shanghai, China, entered a deal to advance oral small-molecule adenosine 2A receptor positive allosteric modulators, not disclosing terms.

Another player is Heptares Therapeutics Ltd., of Welwyn Garden City, UK, which in early 2012 reported what it called the first use of structure-based design to discover a GPCR-targeted drug candidate.

In the Journal of Medicinal Chemistry, company scientists described how they identified antagonists to the adenosine A2A receptor using stabilized receptors and a virtual screening approach. Heptares signed a $106.3 million schizophrenia deal with Takeda Pharmaceutical Co. Ltd., of Osaka, Japan, and a $200 million deal with Novartis Option Fund to generate leads against an unspecified target of interest to parent company Novartis AG, of Basel, Switzerland. Also, in May 2011, Heptares outlicensed an adenosine A2A antagonist, discovered in-house, to UK-based Shire Pharmaceuticals plc, for potential development in Parkinson's. (See BioWorld Today, Oct. 13, 2009, and April 12, 2011.)

Strasbourg, France-based Domain Therapeutics SA has a different approach with DT1133 and its analogs, new chemical entities with adenosine A2A-antagonist potency, discovered by way of the firm's DTect-All assay technology. The molecules, Domain said, belong to a chemical family distinct from the known xanthines or furan-containing A2A-antagonists, with their metabolism issues. Domain's main candidate has shown oral bioavailability in rodents and no clinical toxicology sign in a 14-day rat study.