Pressing forward with development of the antiretroviral tenofovir disoproxil fumarate (DF), Gilead Sciences Inc. has started a second Phase III study of the drug in patients infected with HIV who have never received antiretroviral therapy.
The study will test whether tenofovir DF, as a part of a simplified treatment regimen, can suppress viral replication while offering the convenience of a once-daily dosing regimen. The trial will take place at sites in the U.S., Europe and South America, and, in combination with a study in patients already receiving antiretroviral therapy, will serve as the basis for a new drug application.
"There is a possibility looking at the enrollment patterns that we are looking at an NDA sometime in early 2002," said Sheryl Meredith, a spokeswoman for the Foster City, Calif.-based company. "We're working all the time to accelerate that time line."
The Phase III randomized study will last 48 weeks. It is a double-blind, multi-center study comparing a treatment regimen including 300 milligrams of tenofovir DF, efavirenz and lamivudine (3TC) to a treatment regiment of stavudine (d4T), efavirenz and lamivudine. Gilead will enroll 600 HIV-1 infected patients who haven't been treated previously with antiretroviral therapy and who have HIV-1 RNA levels in their bloodstream greater than 5,000 copies per milliliter.
Patients will be randomized into one of the two groups and will be evaluated at the end of 24 and 48 weeks. The study will look at the ability of both regimens to achieve HIV RNA levels less than or equal to 50 copies per milliliter and will seek to establish safety and tolerability.
In December, Gilead announced it had begun enrollment to see whether adding tenofovir DF to an existing regimen could extend the effectiveness of the regimen. That trial, also designed to include 600 patients, recently completed the enrollment phase. (See BioWorld Today, Dec. 2, 1999, p. 1.)
"Getting trials enrolled is the rate-limiting step," Meredith said. "We are very pleased with the enrollment we've had."
Tenofovir DF is a member of a new class of drugs called nucleotide analogues that hinder the virus's reverse transcriptase enzyme. It is a second-generation nucleotide analogue developed by Gilead. The company's first-generation product, adefovir dipivoxil, has the dubious distinction of being the first anti-HIV agent to be denied an FDA advisory panel endorsement. (See BioWorld Today, Nov. 2, 1999, p. 1.)
The panel's primary concern with adefovir was a potential to develop serious renal toxicity. A Phase II study of tenofovir DF released in April demonstrated renal toxicity was an unlikely side effect of treatment with the second-generation drug. The company is continuing to develop adefovir in a lower dose for the treatment of hepatitis B. Two late-stage Phase III clinical trials are ongoing and nearing an NDA filing. (See BioWorld Today, April 18, 2000, p. 1.)
"For tenofovir, the NDA submission will include the Phase II study, an open-label, 48-week safety study, the Phase III study in treatment-experienced patients and some or all of the Phase III study in treatment-naove patients," Meredith said.
The company is looking for a partner for adefovir, but has decided to take tenofovir to the market on its own.
Gilead's stock (NASDAQ:GILD) closed Monday at $59.50, down $7.00.