Staff Writer

After generating strong efficacy in its first Phase III trial for resistant hypertension, Gilead Sciences Inc.'s darusentan failed to deliver a repeat performance in a second Phase III trial.

Analysts were puzzled by the failure, particularly because the successful trial (DORADO) and the unsuccessful trial (DORADO-AC) were similar in design. In a research note, Oppenheimer & Co. analyst Bret Holley predicted a "massive" placebo effect in the failed trial.

Gilead spokespersons weren't commenting beyond what was stated in the press release: that the randomized, double-blind, placebo- and active-controlled, 849-patient study failed to show a significant difference between darusentan and placebo in trough-sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) at week 14. The trial had been 95 percent powered to detect an 8 mm Hg improvement in SBP and DBP.

The first Phase III trial showed SBP improvements of 7.9 to 9.5 mm Hg and DBP improvements of 4.6 to 5.4 mm Hg over placebo (p < 0.001). (See BioWorld Today, April 6, 2009.)

Although the second trial met some secondary endpoints and showed superiority to active comparator guanfacine, Gilead indicated it would stop development of darusentan rather than pursue another trial.

Shares of Foster City, Calif.-based Gilead (NASDAQ:GILD) slipped $1.65 to close at $45.31 on Tuesday.

Yet analysts were not overly concerned about the decision to drop darusentan. The drug had turned up some questionable safety data in its first Phase III trial, and that, combined with the availability of generic hypertension drugs and uncertainty about the resistant hypertension market size, had caused some analysts to question the commercial opportunity.

Although expectations for darusentan weren't high, Credit Suisse Securities analyst Michael Aberman warned in a research note that the drug's failure will "likely re-energize criticism of Gilead's decision to enter into the cardiovascular markets."

Darusentan reflects poorly on Gilead's cardiovascular push in two ways.

First, it calls into question the $2.5 billion Gilead spent to acquire Myogen Inc. Darusentan was the headline asset in that deal, and it has now proven a bust. (See BioWorld Today, Oct. 3, 2006.)

Myogen also gave Gilead the marketed pulmonary arterial hypertension drug Letairis (ambrisentan), but sales have been slower than expected. The drug earned just $113 million last year and $132 million in the first nine months of this year - an impressive increase, but still far behind competing blockbuster Tracleer (bosentan, Actelion Ltd.).

Second, the darusentan failure raises questions about Gilead's $1.4 billion acquisition of CV Therapeutics Inc., which included the marketed chronic angina drug Ranexa (ranolazine extended-release tablets) and the marketed cardiac imaging agent Lexiscan (regadenoson), as well as the developmental atrial fibrillation drug tecadenoson. (See BioWorld Today, March 13, 2009.)

Ranexa and Lexiscan are not huge sellers Ranexa pulled in roughly $116 million in the first nine months of this year, and Lexiscan is marketed in the U.S. by Astellas Pharma Inc. Yet the Ranexa sales force could have been leveraged for darusentan, if things had gone as planned.

Gilead spokesman Nathan Kaiser confirmed that the company is still "absolutely" committed to cardiovascular disease, despite the loss of darusentan.

Kevin Young, executive vice president of commercial operations, said during Gilead's third-quarter earnings call that the company is making progress with Letairis thanks to an updated label, and that Ranexa commercialization has been revamped with new sales targets, new co-pay programs, new promotional efforts and more.

Gilead has time to work the kinks out of its cardiovascular system. For now, the big biotech's HIV franchise accounts for about 80 percent of its business, bringing in $4.3 billion in 2008. Much of that success is due to HIV drug Emtriva (emtricitabine), and in particular, Emtriva-containing HIV combination products Truvada (emtricitabine-tenofovir disoproxil fumarate) and Atripla (efavirenz-emtricitabine-tenofovir disoproxil fumarate).

Analysts like Holley predict continued "strong HIV franchise growth" in the short term. In the longer term, however, the HIV franchise will face patent expirations. The cardiovascular push and Gilead's similarly questionable move into pulmonary diseases are part of the plan to manage those patent expirations.

Yet as Gilead has sought to diversify, analysts have become increasingly focused on the company's next-generation HIV programs. At the top of their list is Gilead's once-daily quadruple combination product, dubbed "quad," which contains double-agent Truvada, integrase inhibitor elvitegravir and boosting agent GS 9350. (See BioWorld Today, Oct. 22, 2009.)