LONDON – Heptares Therapeutics Ltd. convinced another partner of the power of its G protein-coupled receptor (GPCR) technology, sealing a deal with Cubist Pharmaceuticals Inc. around one – or possibly two – targets to be nominated by the quoted U.S. biotech.

The full terms of the deal were not made public, but Heptares will receive $5.5 million up front and about $4 million in research funding for the first target, with milestones and royalties to follow if a program moves forward. Malcolm Weir, CEO, said the same terms will apply if Cubist subsequently decides to bring a second target into the collaboration.

"Although we are not disclosing details on the overall biodollars, I'm happy with the deal, which is significant for Heptares," he told BioWorld International.

The initial target chosen by Lexington, Mass-based Cubist was not disclosed. However, Weir said Cubist's focus on hospital acute care means "we will be working in an area where there are some interesting GPCR targets that are yet to be exploited." The indications include pain, inflammation and cardiovascular disease.

The partnership will see Welwyn Garden City, UK-based Heptares applying its structure-based GPCR technology to find novel leads. "Cubist brings existing knowledge of these targets and the ability to develop molecules we help discover," Weir said. "We will be working as true collaborators, with Cubist inputting expertise and resources from the start."

Having secured the deal, Weir is attending the J.P. Morgan meeting in San Francisco this week on further business development duties. "While I'm looking for potential partnerships, our strategy is not to do lots of deals. We've just got Cubist, and now I'm looking ahead to the next couple of years when our existing partnership with AstraZeneca [plc] expires," Weir said.

Heptares also has partnerships with Takeda Pharmaceutical Co. Ltd. and Shire plc, and although those are important validations of the GPCR platform, the ambition is to become a profitable standalone company based on developing and commercializing the in-house portfolio. Weir said he expects progress on that front over the next year as the lead program advances through preclinical development.

The lead product is the first selective muscarinic M1 receptor agonist, which is being developed for the treatment of Alzheimer's disease and schizophrenia. Heptares said that will offer an advance over currently marketed nonselective cholinesterase inhibitors, which show limited and transient efficacy and dose-limiting side effects. "This is going really well; it is highly selective compared to other muscarinic agonists, and it may possibly advance into Phase I before the end of the year," Weir said.

Following behind is the first selective Orexin 1 subtype receptor antagonist, for the treatment of addiction and compulsive disorders. Heptares said Orexin 1 antagonism is a new mechanism to directly inhibit craving, the leading cause of relapse in addicts. The mechanism has broad applications in substance addiction, including nicotine and alcohol, and in compulsive disorders, including binge eating and gambling. Other compounds are in the works for treating Type II diabetes, autism, dyskinesia and migraine, among other disorders. The wide range of indications is illustrative of the fact that the GPCR superfamily is the largest and single most important family of drug targets in humans.

The Heptares technology platform is designed to overcome the difficulties in handling GPCR targets by making it possible to engineer stabilized GPCRs in their natural pharmacological conformations and then determine the 3-D structures by X-ray crystallography.

That forms the basis for using fragment-based approaches to discover new small-molecule leads. The stabilized GPCRs also can be applied to antibody discovery, providing a purified protein for use as an antigen against which antibodies can be raised. The instability of native GPCRs means that to date there is only one marketed antibody against a GPCR target.

Heptares said its stabilized GPCRs preserve all biologically relevant epitopes and allow a diverse panel of functional antibodies to be obtained when they are used as an antigen for in vivo immunization.