Gilead Sciences Inc. and Bristol-Myers Squibb are heading back to the drawing board after the second formulation of their fixed-dose antiretroviral combination of Truvada and Sustiva failed to show bioequivalence to one of the HIV drugs dosed separately.

The companies formed a joint venture in December to develop and commercialize a triple-drug regimen that would be available to patients in a pill taken once-daily. The product is intended to combine Gilead's Truvada, which is in itself a combination of the drugs Emtriva (emtricitabine) and Viread (tenofovir disoproxil fumarate), with BMS's Sustiva (efavirenz). All three products have been approved to treat HIV.

The bioequivalency study showed that "the blood levels of efavirenz (Sustiva) were lower than when it was dosed separately," said Amy Flood, spokeswoman for Foster City, Calif.-based Gilead.

"So moving forward, we are using a different process," she told BioWorld Today. Instead of formulating all three drugs together, the companies will employ bi-layer technology, which will incorporate "two separate layers, one of the [Sustiva] formulation and one of the Truvada formulation, that are compressed together in one tablet."

The companies expect to evaluate up to three new formulations over the next several months.

Shares of Gilead (NASDAQ:GILD) lost $1.13 Wednesday to close at $41.55.

Under the joint venture, Gilead Sciences & Bristol-Myers Squibb LLC, the companies will share development costs and receive revenues based on the percentage of each product's contribution to the final drug formulation. (See BioWorld Today, Dec. 21, 2005.)

The companies initially anticipated filing a new drug application for the co-formulation during the last half of this year. But the missed bioequivalency study likely will set back regulatory filing about six months, to the first half of 2006, and delay possible approval until 2007.

Fixed-dose combinations are becoming the hottest trend in HIV treatment, offering patients simple and convenient dosing. In 1997, London-based GlaxoSmithKline plc launched Combivir, a combination of Retrovir (zidovudine) and Epivir (lamivudine). Last year, Gilead's Truvada entered the market, along with GSK's Epzicom (lamivudine plus abacavir). But there could be a downside to this rapid advancement.

A report issued this week by independent market analyst Datamonitor plc, of London, said the rates of new HIV infection, after years of decreasing numbers, is on the rise again, due in a large part to a "blasé attitude" by the public regarding HIV.

"The perception that HIV is no longer a death sentence but a manageable chronic condition, has led to a rise in risk behavior in some populations," stated the report, titled "HIV: An ever-changing epidemic."

According to Datamonitor's analysts, the rates of infection have changed over the last five or 10 years, both demographically - with older new HIV patients and a growing number of cases in heterosexual women - and geographically - with the regions of East Asia, Eastern Europe and Central Asia, along with the UK and Germany, seeing significant increases in their HIV populations.

Since it appeared on the market, Combivir has reported higher sales every year, with revenue of about $914 million in 2004, though Datamonitor expects Gilead's Truvada to become the leader in fixed-dose combinations by 2015.

If Gilead and BMS succeed in getting their joint formulation approved, it would be the first once-daily three-drug combination in HIV. Flood said the company has not given guidance on potential sales of that drug, but believes "the simplicity of having one pill a day" would be attractive to patients, particularly those who are treatment-na ve.

The product also could increase potential sales of Emtriva, one of Truvada's ingredients. Gilead entered a deal last month, along with New York-based Royalty Pharma, to buy out the royalty interest for Emtriva. The companies agreed to make a one-time cash payment of $525 million to Atlanta-based Emory University in exchange for all worldwide royalties. Gilead was responsible for about 65 percent of the cost, with its share totaling $341.25 million. (See BioWorld Today, July 20, 2005.)