Study: New drug doesn’t display cross-resistance

Fewer side effects, easier dosage

Agenerase, the first of a new generation of protease inhibitors to make it to the finish line, holds promise for clinicians looking for a powerful drug to use in salvage therapy, as well as for use with treatment-naive patients, according to a researcher who has studied the drug for a year.

"Because we have so many resistant species of virus in the community, we’re always looking for new drugs that may have a chance of getting around those resistance patterns," says Jeff Goodgame, MD, principal investigator of clinical trials for Agenerase. Goodgame is associated with the Central Florida Research Initiative in Altamonte Springs, FL.

Agenerase (amprenavir), manufactured by Glaxo Wellcome in Research Triangle Park, NC, is the first protease inhibitor to be approved by the Rockville, MD-based U.S. Food and Drug Administration in more than two years.

So far, researchers have published data based on 24-week clinical trials, although 48 weeks of trials have been completed. Those data will be published in September, Goodgame says. "We’re seeing a high range of effectiveness with the 48-week data," he says.

The 24-week studies show that amprenavir brought viral loads down to 400 copies/mL in therapy-naive patients, as well as in non-nucleoside reverse transcriptase inhibitor-experienced and nucleoside analog reverse transcriptase inhibitor-experienced patients when the drug was administered in triple combination therapy.

"Used in a combination with various drugs, it’s very synergistic," Goodgame says. Amprenavir appears to do well with AZT and abacavir, for example.

However, Goodgame says, the drug’s most promising aspect is that patients who take it do not exhibit the mutation pattern found in patients on other protease inhibitor therapies. This means clinicians could use amprenavir as a salvage therapy and probably not see a cross-resistance pattern develop.

The key mutation associated with resistance to amprenavir is 50V, which has not been observed in patients who’ve taken other protease inhibitor therapies.

The drug’s second big benefit is that it doesn’t elevate glucose levels or lipids/triglycerides as much as other protease inhibitors do. This means patients may not develop lipodystrophy as readily. While some clinicians may be skeptical that this pattern will continue beyond the study’s 24-week period, Goodgame says researchers saw the same trend at 48 weeks, as well.

"Amprenavir is more convenient than other regimens, and you can allow patients to take it twice a day with or without food," Goodgame says. The recommended dosage is eight 150 mg capsules twice daily.

Clinicians should caution patients that if they eat a high-fat diet, there will be some reduction in the drug’s levels. The majority of adverse events were nausea, diarrhea, vomiting, rash, and perioral paresthesia. In 1% of patients, there were severe and life-threatening skin reactions, including Stevens-Johnson syndrome. The drug also may be associated with acute hemolytic anemia, diabetes mellitus, and hyperglycemia, as are other protease inhibitors.

"With all the protease inhibitors, the side effects become the primary issue," Goodgame says. "But after one month, this drug becomes very tolerable, with a little nausea and very little diarrhea, and if a patient develops a rash it’s usually limited."

Researchers studied the drug’s safety in more than 1,400 patients. They found that the drug could cause life-threatening reactions in interaction with some drugs, so clinicians should review the full prescribing information.

Glaxo Wellcome’s wholesale price for Agenerase is $16.50 per day or $6,132 yearly.