LONDON — Xenova Group plc has signed a deal with Eli Lilly and Co. for development of a new class of antithrombotic drugs for chronic use, based on small molecule inhibitors of plasminogen activator inhibitor (PAI-1) from Xenova's natural product library.

The headline value of the deal is $35 million, but Louis Nisbet, chief executive of Xenova Group, told BioWorld International he was unable to give any details of how this was divided among license fees, research funding and milestones.

If any product is commercialized as a result of the deal, Xenova also will be entitled to royalties.

"Unfortunately it is the usual thing. I can't say how the deal is structured," Nisbet said. "The project will last five years and I am thrilled because this is an excellent deal for the group." Xenova expects the deal to "have a significant positive impact" on its cash flow during 1998.

The collaboration will focus on PAI-1 inhibitors, which enhance the breakup of blood clots without the bleeding side effects of other antithrombotic drugs. The deal gives Lilly exclusive worldwide rights to the inhibitors and related technology for use in cardiovascular medicine. Xenova already has several compounds but it has not yet selected a clinical candidate.

Preclinical Work Done By US Subsidiary

"Over the next several months we will make the selection and then hand it over to Eli Lilly for clinical development and regulatory approval," said Nisbet. Most of the pre-clinical selection work will take place at the Xenova subsidiary MetaXen LLC, of Hayward, Calif.

Xenova, of Slough, U.K., specializes in discovery and development of new small molecule drugs derived from microorganisms. Its MetaXen subsidiary specializes in transformation of leads into drug candidates. Xenova has focused primarily on oncology as its main platform.

"Once we had proven the action in vitro and in vivo, we put significant effort into scoping out the chemistry and exploring the structure activity relationship," Nesbit said, referring to the PAI-1 blockers. The company developed a pharmacological model of PAI-1 inhibition and used combinatorial and medicinal chemistry, along with high-throughput screening, to identify and optimize leads.

Patients who have heart attacks or major surgery remain at risk for some months of developing life-threatening blood clots. Current treatments to prevent clots, such as warfarin and heparin, can cause bleeding, making dosing difficult and meaning patients must be closely monitored.

PAI-1 is a protein secreted at sites of disease by the red blood cells and platelet-forming cells. Its role is to inactivate the clot-busting enzyme tPA once it has broken down a blood clot. When PAI-1 activity is inhibited, tPA activity is increased, reducing the body's tendency to form clots, but without a corresponding increase in spontaneous or delayed bleeding.

Michael Clayman, Lilly vice president of cardiovascular research, said, "PAI-1 inhibitors have the potential to make a positive impact in the very large market for antithrombotic drugs, where products suitable for chronic use without the bleeding complications or costly monitoring requirements of current therapies are greatly needed."

Xenova's share price rose by 31 pence to £2.25 when the deal was announced last week.

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