Gilead, of course, is a company we’ve long been watching with interest. Here, for example, is Bill Trombetta’s look at the company in last year’s “Stealth Pharma” analysis.

Other pharma related companies in the top 50 include lab giant Waters and PBM Express Scripts.

Gilead, the Foster City, CA, powerhouse will pay cash for the deal.

In A conference call, Gilead CEO John Martin, COO John Mulligan, and R&D wizard Norbert Bischogberger had to deal with a fair amount of skepticism from industry analysts, who poked and prodded with questions about the deal, aiming to find its vulnerable spots. And there are several.

From CV Therapeutics, Gilead gets two marketed products: Ranexa, a $100 million seller in chronic angina; and Lexiscan, a $50 million drug for mycocardial perfusion imaging—plus a pipeline including two Phase III molecules for atrial-fibrillation molecule and heart failure.

Analysts asked whether Gilead was placing too big a bet on two hopes: that Ranexa, with a new label for first line treatment, will grab a major piece of the angio market; and that the platform will indeed deliver. The biotech is also banking on its own Phase III compound, darusentan, for persistent hypertension. In addition, CV Therapeutics sales force nicely expands Gilead’s access to cardio specialists. If everything works out as planned, the innovative specialty drugmaker could find itself leading in the blockbuster-making primary-care market. That would be a truly remarkable accomplishment.

Under tough questioning, the Gilead team stuck to their guns, proclaiming complete confidence in both their planned relaunch of Ranexa and the approval of darusentan in the competitive hypertension field, where other brave new molecules have failed.

Is it all a bridge too far, analysts wondered. Based on Gilead’s track record, maybe not. Martin reminded them that “we didn’t have to do this acquisition” (unlike some pharmas, hint, hint). But rather than sit on their cash pile, Gilead chose to roll the dice in a new game. That’s biotech talking.

Update 3/16/09: Astellas announced Monday morning that it would not engage in a bidding war with Gilead and terminated its $16 per share offer.

“Astellas also intends to withdraw a related lawsuit in the Delaware Chancery Court against CV Therapeutics and its directors,” the company stated in a release. “Astellas is a disciplined acquirer and does not see value for Astellas stockholders in CV Therapeutics at the price level ofthe sale announced on March 12.”

If approved, the Quad would likely improve patient adherence to HIV treatment, which typically calls for a “cocktail” of three drugs, each with its own dosing requirements. Better adherence, in turn, decreases the risk of viral resistance and drug failure. The Quad would also likely shake up the market—not a first for the Foster City, CA, biotech, which was founded in 1987 during the darkest days of the AIDS epidemic.

After launching Viread (tenofovir) and Emtriva (emtricitabine)—two nucleoside/nucleotide reverse transcription inhibitors—Gilead pioneered fixed-dose HIV combinations in 2004 by combining the two molecules, and called it Truvada. Two years later, in a rare melding of two pharma competitors, the biotech partnered with Bristol-Myers Squibb to produce the first-ever three-drug HIV regimen in a one-a-day pill—a medical advance that was unimaginable a decade earlier. Atripla, which combines Truvada with BMS’s Sustiva (efavirenz), a non-nucleoside reverse transcriptase inhibitor, became the new gold standard for first time patients, with 2008 sales of $1.6 billion, up 74 percent from 2007. Truvada remains the market leader for the third year in a row, with sales up 33 percent to $2.1 billion.

The Quad appears to be the first-ever four-drug combo in any category. (There are three-drug fixed-doses in TB and malaria.) The product builds on the success of Truvada by adding to it Gilead’s two newest experimental drugs: elvitegravir, a second-in-class integrase inhibitor, and GS 9350, a compound with the ability to boost levels of integrase inhibitors (and probably protease inhibitors, still the most widely used class in HIV cocktails).

The simultaneous development of all three drugs may lead to interesting clinical and commercialization challenges. Elvitegravir is currently going head-to-head with Isentress, Merck’s breakthrough integrase inhibitor, in a Phase III non-inferiority trial in treatment-experienced patients. The Quad must pass the Phase II non-inferiority test against Atripla, which will position either the Truvada/boosted elvitegravir or the Truvada/Sustiva combo to lead the market in a few years. It’s worth noting that data suggest that black patients are at greater risk of Sustiva’s notorious central nervous system side-effects because they metabolize the drug more slowly. The right clinical results could give integrase inhibitors the edge over this first-line non-nucleoside, making the Quad a must-have for millions of Africans with HIV.

But at what price? That question will test Gilead’s talent at mixing—and mixing it up—with the feisty global AIDS treatment movement. Meanwhile, the biotech continues to enjoy outlandish sales growth (36 percent in 2008, to $5 billion), elevating this Bay Area dynamo to the top of the list of biotechs in this season of Big Pharma takeovers.