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Where no pharma has gone before
LONDON—AstraZeneca PLC has taken the wraps off a four-year collaboration with Heptares Therapeutics Ltd. to find and develop new medicines from difficult-to-access proteins in the human body.
The collaboration will target G-protein coupled receptors, or GPCRs, which are among the largest and most important family of proteins, but which become highly unstable when removed from their natural membrane-bound environments. This instability has prevented pharmaceutical researchers from understanding GPCR structures and hampered efforts to design medicines that work on GPCR targets.
As part of a joint discovery effort, Heptares and AstraZeneca will engage their respective discovery teams, compound libraries and other discovery technologies for the purposes of initial screening and lead identification. Results will be combined into a common pool, and the best leads will be further optimized collaboratively. AstraZeneca will then select preclinical, small- and large-molecule candidates and will be solely responsible for preclinical and clinical development.
Under the terms of the agreement, AstraZeneca has worldwide commercial rights to product candidates emerging from the collaboration. Heptares will receive an upfront $6.25 million cash payment fee plus committed research funding, and also qualifies for significant future payments depending on delivery of agreed-upon milestones. Heptares will also receive royalties on sales of all products discovered through the joint research.
The companies say the collaboration will focus on specific GPCR targets linked to the human central nervous system, pain, heart conditions, metabolic and inflammatory disorders from candidate medicines in AstraZeneca's small- and large-molecule portfolio, including projects from its biologics unit, MedImmune.
According to Mike Snowden, vice president and head of Discovery Enabling Capabilities and Science at AstraZeneca, its innovative approach to GPCR discovery made Heptares an attractive partner for this collaboration.
"They have a stabilizing technique to enable in-vitro lead discovery on purified proteins, enabling crystallography on receptor to support SAR, integrated platform of structure, biophysical affinity-based fragment screening, mutant analysis to infer binding modes, molecular modeling and biology," he says. "They have expertise in medicinal chemistry to handle fragment information to develop lead series."
The collaboration also brings together Heptares' GPCR discovery expertise and proprietary technologies—including its StaR technology, which engineers stabilized receptors and allows GPCRs to be investigated—with AstraZeneca's biopharmaceutical discovery, development and commercial capabilities.
Malcolm Weir, CEO of Heptares, says the targets that the company is working on are major industry challenges—and many groups have tried and failed to get good lead compounds to them.
"Our StaR technology enables for the first time the application of fragment and structure-based approaches to cracking such intractable targets, whose biology is great but against which chemistry is poor or non-existent," he says. "We have shown via our in-house platform-derived pipeline (which includes a number of leads and a clinical candidate to adenosine A2a receptor recently partnered with Shire) that we can discover radically new chemistries to much-studied targets."
Weir maintains that researchers are gaining a better understanding of GPCR structures, with "some exciting new structures published in the last couple of years, including agonist and antagonist receptor conformations from us and our colleagues and founders at the MRC Laboratory of Molecular Biology at Cambridge."
Snowden notes that a goal of the collaboration is to be successful in early discovery to develop lead series on high-value GPCR targets that have proved "intractable" in the past using traditional (cell-based) discovery approaches.
"We certainly hope to use crystallography during lead generation to understand SAR, drive potency and selectivity," he says. "In addition, any further GPCR structures will enable general scientific understanding of this important class of drug targets."
Moreover, Snowden notes that in the collaboration, AstraZeneca and Heptares will progress a number of GPCR targets where traditionally pharma has failed to discover new drugs.
"We now hope to successfully discover and develop new drugs on these well-validated targets," he says. "The novel technology developed at Heptares and the discovery expertise and capabilities at AstraZeneca will be a powerful combination to deliver a strong output."
Going forward, Snowden says the partners expect to be successful in the generation of chemical assets and lead series, which will be further optimized and developed at AstraZeneca.
"We expect at least one, but hope for several successful projects that will deliver new candidate drugs," he concludes.
AstraZeneca, Daiichi Sankyo to co-promote denosumab for cancer
LONDON—AstraZeneca PLC also announced last month that it has entered into a co-promotion agreement in Japan with Daiichi Sankyo for denosumab for the treatment of bone disorders stemming from bone metastasis.
AstraZeneca and Daiichi Sankyo will co-promote denosumab after it is approved for use in Japan. Bone metastasis, one of the most frequent causes of pain for cancer patients, can cause bone fractures and reduce the ability to maintain normal quality of life including day-to-day activities. Denosumab, with its novel mode of action and targeted delivery via a monthly subcutaneous injection, represents a new treatment option in Japan for the management of bone metastasis across a broad range of cancer types.
In Japan, Daiichi Sankyo acquired denosumab rights in 2007 from Amgen Inc. The company filed a Japanese New Drug Application (JNDA) in August 2010.
"Collaborations like this are a key part of our strategy to bring innovative medicines to patients," says Tony Zook, executive vice president of AstraZeneca's global commercial organization. "This partnership leverages our long-standing commitment to oncology in Japan, and we look forward to contributing our expertise in this area to bring this novel cancer treatment to patients upon approval."
Financial terms of this agreement were not disclosed.