New once-a-day pill submitted to FDA

First complete regimen in single tablet

HIV antiretroviral therapy treatment soon will become a whole lot simpler than most antibiotic regimens when the FDA approves the combination pill of efavirenz/emtricitabine/ tenofovir (Truvada/Sustiva).

The combination drug which will be taken in one pill, once daily, was submitted to the FDA in a new drug application by Gilead Sciences of Foster City, CA, and Bristol-Myers Squibb of Princeton, NJ.

"It's the first complete regimen in a single tablet, once a day," says Calvin Cohen, MD, MSc, research director of CRI New England in Boston. Cohen also is the research director for Harvard Vanguard Medical Associates in Boston and is a clinical instructor at the Harvard Medical School in Boston.

Previous combination regimens have combined three drugs in a twice-a-day pill or two medications in a single tablet, Cohen notes. The new combination puts two nucleoside reverse transcriptase inhibitors with one non-nucleoside reverse transcriptase inhibitor.

The combined three-drug pill has been studied in a large clinical, randomized study of treatment-naïve patients, Cohen says.

"We have existing data about the benefits and side effects profile of this three-drug regimen," Cohen says. "That the tablet can be created that puts all of these together and has similar absorption allows us to say it has the characteristics of the regimen when it is given in three separate tablets."

The three tablets have the same absorption as the single tablet, he adds.

So while the new combined single tablet has not been studied as its own entity, once investigators could show that it has the same absorption, the data available about the three separate pills given in combination is relevant, Cohen explains.

Efavirenz's safety profile shows that it generally is tolerated by 95% of the people who take the drug, Cohen says. "The 4% to 5% who has to come off Sustiva does so because of side effects, which include disequilibrium because of dizziness or altered dreaming," Cohen says.

"In 95% of the people it's either well-tolerated from the beginning, or they'll have side effects and then it wanes; but in some people it does not resolve," Cohen explains. "Somewhere between 25% to 50% will notice something, but in the majority of people it resolves in the first week."

Among some others it will resolve after a few weeks, but after continued dosing, about 5% of the people taking efavirenz find it's not for them, Cohen adds.

"Tenofovir and FTC have, in some ways, even more attractive or just as attractive safety profiles in that over 95% of the people who take those two drugs find they can tolerate them," Cohen says.

"So the regimen of the three drugs roughly is tolerated in more than 90% of the people who start it," Cohen adds.

The three-drug regimen hasn't been studied fully in a randomized trial versus a protease inhibitor (PI) therapy, Cohen says.

"Those studies are underway now," he says. "What we would be able to conclude is based on other studies done in the past, efavirenz has gone up head-to-head against several PIs and has either come up with superior results or equal efficacy."

But it has never lost in a head-to-head comparison yet, Cohen says. "In fact, it's one of the major reasons why efavirenz is a popular drug in the United States — it's either tied or won, but never lost," Cohen adds.

Adherence studies would suggest that the new once-a-day pill will be more acceptable to patients than regimens requiring two or more pills daily, Cohen says.

When patients are asked if a once-a-day pill regimen fits into their schedule, virtually all of them say it does, while only 80% of people asked about a twice-a-day pill will say that it fits into their schedule, Cohen says.

"In every single measure, once-a-day pill had superior adherence with two years of monitoring," Cohen says.

Resistance also is not a major problem for this combination regimen, Cohen says.

"In the long-term studies of regimens very similar to this one, when drugs were given as separate components, only 4% of people developed resistance after a year to any of the drugs," Cohen says. "Part of what we hope is and, in some ways, expect is as we improve the simplicity of going from three pills to one pill a day that people will find the regimen more attractive and less burdensome, and the resistance levels will decrease."

Already, the combination therapy has a 95% success rate without resistance at one year, and the expectation is that as the simpler combination is used, the resistance will remain at a low level past year one, Cohen explains.

"Resistance is a product of erratic drug taking," he says.

Truvada/Sustiva has gained a lot of interest among clinicians both because of its simplicity and its efficacy, Cohen says.

"This doesn't mean it's perfect, but among our choices it is one of the best combinations," Cohen says. "Clinicians are enthusiastic to prescribe a regimen that is more attractive to people with HIV and which also is less burdensome and intrusive."

Treatment-naïve patients also find this one-pill-a-day combination appealing, he notes.

"I already have patients coming in the door asking for the once-a-day pill and whether they can have it yet," Cohen says.

To create the once-a-day combination required Bristol-Myers Squibb and Gilead to form one of the first collaborations of its type in HIV therapy. They formed a joint venture on Dec. 20, 2004, to develop and commercialize the single tablet regimen in the United States.

The proposed new combination pill will contain 600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate.