By Lisa Seachrist
Gilead Sciences Inc. said a long-term Phase II study of tenofovir disproxil fumarate showed the drug decreased the viral load in heavily pretreated HIV-infected patients without causing renal toxicity.
The Foster City, Calif.-based company tested three doses of tenofovir against placebo and chose to conduct a 48-week rather than 24-week trial in order to evaluate the potential for tenofovir to cause renal toxicity. The results of the study will serve as supporting data for the two Phase III pivotal trials the company is undertaking.
"We are very pleased with the Phase II results," said Gilead spokeswoman Sheryl Meredith. "This will allow us to go into Phase III with some strong data."
Tenofovir is a member of a new class of drugs called nucleotide analogues that stymie the virus' reverse transcriptase enzyme. It is a second-generation nucleotide analogue developed by Gilead. In November, the company's first-generation nucleotide analogue, adefovir dipivoxil, was granted the dubious distinction of being the first antiviral drug directed against HIV to fail to get a panel recommendation for approval. (See BioWorld Today, Nov. 2, 1999, p.1.)
The primary issue for the panel was the nephrotoxicity associated with the use of the drug. In addition, the panel pointed out the vast majority of HIV-infected patients were likely to use these drugs chronically for many years and, as a result, sponsors needed to show some long-term data. Gilead dropped development of adefovir in favor of tenofovir for the treatment of HIV infection, but continues to develop the drug in a lower dosage form as a treatment for hepatitis B.
This Phase II study is a strong indication the company made the right choice. The study was a 48-week double-blind, dose-ranging study of 189 treatment-experienced patients. All of the patients had to be on a stable antiretroviral regimen for at least eight weeks prior to entering the study. Patients received one of three tenofovir doses (300 milligrams, 150 milligrams or 75 milligrams) or placebo once a day in addition to their existing treatment regimen.
Patients had on average received 4.6 years of antiretroviral therapy, and most had at least one mutation in the viruses isolated from their bloodstreams conferring resistance to the three commonly prescribed classes of drugs to treat HIV.
The company found anti-HIV activity in all three tenofovir arms of the study, but the 300 milligram dose resulted in the greatest reduction in the concentration of virus circulating in the bloodstream after 48 weeks. Patients on that dosage experienced a reduction of 0.68 log10 copies per milliliter. A reduction of 0.25 log10 copies per milliliter often shows clinical benefit for patients.
"This reduction was both statistically significant and meaningful," Meredith said.
The drug didn't show the nephrotoxicity associated with adefovir. The company also found the drug didn't cause any unusual resistance profiles. Meredith said two participants in the study developed a mutation of the virus infecting them. The mutation is one found with the use of two of the other therapies commonly used to treat HIV infection. Because the genotyping portion of the study remains blinded, the company doesn't know whether the resistance mutation occurred in the treatment or placebo arms.
"We did this vanguard 48-week study to make sure tenofovir is as clean as they come," Meredith said.
The company has initiated a Phase III study of tenofovir in treatment-experienced patients. The company will start an additional trial in patients who never have been treated with antiretroviral therapy.
Elise Wang, an analyst with PaineWebber in New York, called the results "encouraging" in a note, but also pointed out the drug was unlikely to come to market before 2002.
Tim Wilson, an analyst with S.G. Cowen & Co. in Boston, noted the need for a drug like tenofovir in a research report. He pointed out that "any new drug with a low side effect profile, simple compliance, a unique resistance profile and that can induce even greater viral load drop over background treatment is a powerful weapon in the fight against HIV. Data to date clearly show tenofovir to be such a drug."
Gilead's stock (NASDAQ:GILD) closed Monday at $50.875, down $4.437.