About 18 months ago, South San Francisco-based Exelixis Inc. made a $25.7 million investment when it acquired three preclinical programs through its buyout of X-Ceptor Therapeutics Inc.

It proved to be a wise move for Exelixis - which since has secured partners for all three projects. The latest deal, announced Monday, gives Sankyo Co. rights to discover, develop and commercialize therapies targeted against the mineralocorticoid receptor (MR), which is implicated in several cardiovascular and metabolic diseases.

"If you look at these three deals and the relatively short period of time and total dollar figures, it represents a monetizing of the acquisition that we made in 2004," said Charles Butler, Exelixis’ director of corporate communications, "while at the same time, we maintain downstream [revenues]."

Sankyo, a wholly owned subsidiary of Tokyo-based Daiichi Sankyo Co. Ltd., is paying Exelixis $20 million up front, and could provide the company with a lot more in development, regulatory and commercialization milestone payments, as well as research funding and a double-digit royalty on potential sales. The exact figure of milestone payments is not disclosed, but Butler told BioWorld Today that the three deals combined provide Exelixis with "over $70 million in committed funding" from up-front payments and research and development funding, as well as "up to $1 billion in milestones."

Terms of the previous agreements, signed last September, put the company’s potential milestone payments for those two deals at up to $448 million.

Initially, Exelixis and Sankyo jointly will conduct and fund research together, and then Sankyo will take over all further preclinical and clinical development, regulatory, manufacturing and commercialization activities.

"It’s an initial 15-month research term," Butler said, "and there’s a possibility that, under mutual agreement, we could extend it."

Since acquiring the MR program from San Diego-based X-Ceptor in September 2004, Exelixis has developed a series of non-steroidal, small-molecule, receptor-specific MR antagonists that have shown good bioavailability and an excellent pharmacokinetic profile in preclinical studies. The antagonists may offer an advantage over existing therapies to treat hypertension, congestive heart failure and vascular damage.

"Currently, when we looked at these compounds preclinically, we think they look very favorable relative to the current compounds," Butler said. "We’ll continue to do the preclinical work that’s necessary and the clinical development work to actually prove that."

MR, a member of the NHR superfamily, is expressed in kidney, heart, brain and smooth muscle tissues. There are two FDA-approved MR antagonists on the market for hypertension and congestive heart failure due to their vascular protective effects, eplerenone and spironolactone, but their safety, tolerability and efficacy profiles could be improved upon with Exelixis’ compounds, the company said.

Butler could not say how soon a lead candidate could reach the clinic, but the Exelixis website said the company intends to file investigational new drug applications for its metabolic programs this year.

The other two preclinical programs acquired from X-Ceptor were for compounds that target the farnesoid X receptor (FXR) and the liver X receptor (LXR). The latter was partnered with Bristol-Myers Squibb Co., of New York, in early December for $17.5 million up front in a deal worth a potential $318 million, including milestone payments for up to two products to treat conditions such as atherosclerosis and coronary artery disease.

The deal for FXR-targeted compounds was signed later that same month with Madison, N.J.-based Wyeth. It included a $10 million up-front payment and up to $147.5 million in development and commercial milestone payments. Both agreements included royalties on potential sales. FXR is a nuclear hormone receptor implicated in a variety of metabolic and liver disorders. (See BioWorld Today, Dec. 7, 2005, and Dec. 23, 2005.)

Outside of those three preclinical programs, Exelixis’ pipeline includes XL119 (becatecarin), a product licensed to Helsinn Healthcare SA, of Lugano, Switzerland, that is in a Phase III trial in bile duct tumors; XL784, which is expected to enter Phase II early this year to treat renal disease; XL999, a cancer compound in Phase II trials for solid tumors; and several cancer compounds in Phase I trials.

The company has a deal with London-based GlaxoSmithKline plc that gives the pharmaceutical company options to develop a certain number of compounds, including XL784 and cancer compounds in clinical development, except for XL119. If GSK exercises its right to develop the compounds, once they have completed proof-of-concept studies, Exelixis would be entitled to milestone payments and royalties, as well as co-promotion rights.

Exelixis’ stock (NASDAQ:EXEL) rose 7 cents Monday to close at $11.85.