Staff Writer

Barely two weeks after inking a deal with Bristol-Myers Squibb Co. for liver X receptor (LXR) agonists, Exelixis Inc. signed a similar agreement with Wyeth Pharmaceuticals - this time for compounds that target the farnesoid X receptor (FXR).

South San Francisco-based Exelixis now has major pharmaceutical companies advancing two of the three main preclinical programs acquired in September 2004 through the buyout of San Diego-based X-Ceptor Therapeutics Inc. for $22.3 million. (See BioWorld Today, Sept. 29, 2004.)

Exelixis has already made back that money with the up-front payments from BMS and Wyeth.

"We haven't discussed how much we've invested in the programs," said Charles Butler, Exelixis' director of corporate communications, but the acquisition "has paid off and allowed us to sign" deals with significant cash, as well as downstream revenues.

"It's a real testament to the quality of the science that exists at X-Ceptor," he added, "and then our drug development capabilities really brought these compounds to a position where we could generate [the deals]."

In early December, BMS made a $17.5 million up-front payment in a deal worth a potential $318 million, including milestone payments for up to two products that would treat conditions such as atherosclerosis and coronary artery disease. (See BioWorld Today, Dec. 7, 2005.)

The up-front payment from Wyeth stands at $10 million, which, when added to the promise of up to $147.5 million in development and commercial milestone payments, brings the deal's total value to $157.5 million. Similar to the agreement with BMY, Exelixis also is entitled to receive royalties on the sale of products commercialized by Wyeth Pharmaceuticals, a division of Madison, N.J.-based Wyeth.

"The royalties will allow us to have a meaningful participation in the economics of any drug that is commercialized," Butler told BioWorld Today.

Wyeth will take on all further preclinical and clinical development, as well as regulatory, manufacturing and commercialization activities for several small-molecule compounds that have demonstrated their ability to modulate the activity of FXR in preclinical studies. The pharmaceutical company has a growing pipeline of drugs focused on abnormal lipid metabolism associated with metabolic and cardiovascular diseases. Wyeth said it plans to move the FXR program into the clinic in the near future.

"There is sort of a general timeline in mind," Butler said, "but with this program, unlike the BMS deal, it is solely Wyeth's decision."

FXR is a nuclear hormone receptor that is implicated in a variety of metabolic and liver disorders. It is involved in maintaining the balance of various lipids. By using endogenous ligands, such as chenodeoxycholic acid, FXR is regulated, leading to transcriptional responses that, in turn, regulate triglyceride, cholesterol and bile acid metabolism. Exelixis' synthetic FXR ligands have shown in animal models their ability to lower triglycerides and improve cholesterol profile. In animal models of liver disorders, the compounds have shown efficacy in blocking disease progression. With favorable pharmacokinetic and safety profiles, the lead compounds might offer patients with metabolic syndrome and liver disease a better option for therapy.

"We've yet to see [the positive benefits] in humans, but obviously, we and Wyeth both are hopeful of their promise," Butler said.

Exelixis plans to use the $10 million up-front payment from Wyeth to advance its pipeline of cancer therapies. The company is studying XL999 in Phase II trials for a variety of solid tumors, as well as several other cancer compounds - XL647, XL880, XL820, XL844 and XL184 - in Phase I trials. London-based GlaxoSmithKline plc has an option to develop any of those compounds once they complete Phase IIa trials.

Exelixis' lead product, XL119 (becatecarin), which is exclusively licensed to Helsinn Healthcare SA, of Lugano, Switzerland, is in a multinational Phase III trial in bile duct tumors, scheduled for completion in mid-2007. Another product, XL784, is set to enter Phase II development in early 2006 for renal disease. In addition to the cancer compounds, GSK also has an option to develop XL784.

A third preclinical program acquired from X-Ceptor in 2004 is focused on mineralocorticoid receptors (MRs) and remains under Exelixis' realm.

"We have nothing that we're ready to announce, but all of these metabolism programs, as we've said in the past, have gained a lot of interest by big pharma companies," Butler said.

Exelixis' stock (NASDAQ:EXEL) climbed 44 cents Thursday to close at $9.58.