American Foundation for AIDS Research, October 2003
Kristen Kresge

Less than two weeks after the US Food and Drug Administration (FDA) approved a protease inhibitor for the treatment of HIV, another drug won marketing approval. Emtriva, also known as emtricitabine or FTC, was approved July 2 and joins the nucleoside class of existing HIV drugs.

FTC represents another step toward simpler, more forgiving HIV drug regimens. Like atazanavir (or Reyataz), which was approved last month, it is a once daily therapy available as a single 200 mg capsule.

FTC, initially discovered at Emory University, was under development by Triangle Pharmaceuticals until Gilead Sciences purchased the company earlier this year. With FTC’s approval—and tenofovir’s debut in 2001—Gilead has become a major player in the anti-HIV drug market in the last two years.

Two phase III studies led to FTC’s approval. In treatment-naïve volunteers, FTC was compared with d4T in combination with a background regimen of efavirenz and ddI. Because of the toxicity of the ddI/d4T combination, investigators unblinded the study after 24 weeks and offered everyone FTC. Not surprisingly, the study found that an FTC-containing regimen was slightly more potent. At 48 weeks, 78% of those receiving FTC were below 50 copies/mL, while only 59% reached the same level with d4T.

FTC’s structure is akin to 3TC (lamivudine or Epivir), and another phase III trial found the potency and safety of the two drugs to be strikingly similar. In the yearlong FTC-303 study, volunteers on a stable three-drug regimen containing 3TC were randomized to switch to FTC or continue 3TC. Of the 294 patients who switched, 67% (197/294) had viral loads below 50 copies/mL, compared with 72% (105/146) of those who stayed on 3TC.

Similarities extend beyond structure. FTC’s toxicity profile appears to mirror that of 3TC, although experience with FTC is much more limited; its full safety profile will be defined in the marketplace over the next several years. Like 3TC, dosing of FTC must be adjusted for people with kidney problems, who may eliminate the drug more slowly. FTC also has activity against hepatitis B virus, so clinicians should carefully consider giving it to HIV/HBV co-infected patients.

Unfortunately, FTC’s similarity to 3TC also translates into a similar resistance profile. The major mutation that causes 3TC resistance—M184V—also causes FTC resistance. For this reason, anyone who has failed 3TC therapy would experience less benefit from FTC. This limits FTC’s potency in treatment-experienced people, where previous exposure to 3TC is common. But some studies have shown that continuing 3TC even after resistance has developed is advantageous. Although you may get a smaller reduction in viral load, these drugs are still pulling weight, according to Dr. Michael Saag, Director of the HIV Clinic at the University of Alabama at Birmingham.

And despite FTC’s comparability to 3TC, some clinicians caution against calling it a “me too” drug—implying that it offers no particular benefits over an existing drug. “Each new drug approved adds something to our ability to take care of our patients over the longer run,” said Dr. Donald Abrams, of San Francisco General Hospital.

In this case, FTC adds to the growing number of once-daily drugs. (3TC was approved last year as a once-a-day tablet.) FTC’s other distinguishing trait is its stability once in the body. After one FTC dose, drug concentration remains high for up to 38 hours, compared with 13 hours for 3TC. “Missing one [FTC] dose is probably not a major danger,” said Saag. “It’s a little bit more forgiving than 3TC. And with all things being equal, you may lean toward a drug with a longer half life.” But Saag warned that you don’t want patients missing a dose of any HIV medication.

In community meetings, Gilead representatives acknowledged that FTC’s potency and resistance profile did not warrant a higher price tag than established drugs, a trend in new drug pricing. So Gilead is not expecting big profits from FTC alone. Priced at just over $250 for a one-month’s supply, FTC comes at the same price as 3TC.

But Gilead hopes to collect blockbuster profits by co-formulating FTC and its best-selling nucleotide inhibitor, tenofovir. This single once-a-day pill could compete with the popular drug Combivir (AZT and 3TC), which is taken twice daily. GlaxoSmithKline manufactures Combivir and sells it for under $600 for a 30-day supply. Tenofovir alone sells for about $455 a month.

Gilead expects to launch this co-formulated drug in early 2005 and is meeting with the FDA to decide on the equivalence studies needed for approval. The company has already developed a single pill containing both drugs and is confident that manufacturing will not delay availability or impact the pricing of the FTC/tenofovir combination.

A Gilead sponsored study (934) comparing FTC, tenofovir and efavirenz with Combivir and efavirenz begins enrolling this summer. Abbott is also conducting a study comparing Kaletra—taken once or twice daily—with FTC and tenofovir. The study’s interim 24-week results are expected this fall. Until then, FTC is a simpler, but not extraordinarily unique, option in the anti-HIV armamentarium. “It’s a longer acting version of 3TC,” said Saag. “I’d use it the exact same way.”

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