PMPA For Resistance & Salvage Looks Promising for Safety & Antiviral Activity
GILEAD SCIENCES ANNOUNCES PRELIMINARY RESULTS FROM PHASE III STUDY OF INVESTIGATIONAL ANTI-HIV AGENT TENOFOVIR DF (PMPA)
Data from this study (907) confirms data previously seen with 48 week results from study 902. To read the results of study 902 here is a link: http://www.natap.org/2000/oct/summer2000_newsletter/new_drugs_101800.htm
Foster City, CA, February 20, 2001 - Gilead Sciences, Inc. (Nasdaq: GILD) today announced that 24-week data from Study 907 were unblinded and show that treatment of HIV-infected patients with once-daily tenofovir disoproxil fumarate 300 mg (tenofovir DF) is associated with a statistically significant HIV RNA decrease in mean DAVG24 of -0.61 log10 copies/mL compared to -0.03 log10 copies/mL in the placebo group (p<0.0001). These preliminary results, which meet the study's primary efficacy endpoint, are froman ongoing 48-week pivotal Phase III clinical trial designed to investigate the safety and efficacy of tenofovir DF when used to intensify a stable background antiretroviral regimen in 552 treatment-experienced patients. Gilead expects to present these data in detail at scientific conferences later this year.
Study 907 Design
The 48-week study enrolled 552 treatment-experienced patients who had HIV RNA levels of 400-10,000 copies/mL and were receiving stable antiretroviral therapy for at least eight weeks prior to entering the study. Patients were randomized (2:1) to receive tenofovir DF (one pill dosed once daily) or placebo in addition to their existing antiretroviral therapy. After 24 weeks of blinded, placebo-controlled dosing, patients assigned to tenofovir DF or placebo were allowed to receive tenofovir DF for the remainder of the 48-week study period. This multi-center study included sites in Australia, Europe and North America.
At baseline, patients had a mean HIV RNA level of 3.36 log10 copies/mL and a mean CD4 cell count of 427 cells/mm 3 . Prior to enrollment, patients had received antiretroviral therapy for a mean duration of 5.4 years. Approximately half of all study participants (n=253) were randomly assigned to a virology sub-study of this clinical trial. Baseline genotypic analysis of HIV isolates from these patients revealed that 94 percent of patients had evidence of nucleoside reverse transcriptase inhibitor resistance mutations, 58 percent had protease inhibitor resistance mutations and 48 percent had non-nucleoside reverse transcriptase inhibitorresistance mutations. The level of viral resistance seen in this cohort is consistent with the extensive prior treatment experience of this patient population.
In addition to DAVG24 , a measurement of the average post-baseline change in HIV RNA over 24 weeks, other secondary analyses were performed to measure antiviral activity in Study 907. The mean absolute change in HIV RNA at 24 weeks compared to baseline was -0.59 log10 copies/mL for the tenofovir DF group compared with a -0.01 log10 change in the placebo group (p<0.0001). Additionally, 45 percent (155/346) of patients treated with tenofovir DF achieved HIV RNA reductions below 400 copies/mL at 24weeks compared to 13 percent (23/172) in the placebo group (p<0.0001), as determined by the Roche Amplicor ® Monitor T Ultrasensitive Test. Reduction in HIV RNA to less than 50 copies/mL was achieved by 22 percent (76/346) of patients in the tenofovir DF group compared to one percent (2/172) in the placebo group (p<0.0001). The DAVG24 for CD4 cells was an increase of 12.6 cells/mm 3 in the tenofovir DF group compared with a decrease of 10.6 cells/mm 3 in the placebo group (p=0.0008).
It appears from data so far in studies that the problems with nephrotoxicity seen with adefovir have not been seen with PMPA. Through the 24-week, placebo-controlled portion of the trial, the incidence of grade 3 and 4 laboratory abnormalities and clinical adverse events was similar between the placebo and tenofovir DF arms. Additionally, drug discontinuation at 24 weeks was six percent in both the placebo and tenofovir DF arms of the study. Following the 24-week phase of the study, 170 patients who received placebo rolled over to receive treatment with tenofovir DF.
Tenofovir DF in Treatment-Naïve
To evaluate the potential role of tenofovir DF in treatment-naïve patients, Gilead initiated a Phase III clinical trial (Study 903) in June 2000. This trial is designed to compare the safety and tolerability of two treatment regimens, tenofovir DF, efavirenz and lamivudine (3TC) versus stavudine (d4T), efavirenz and lamivudine. This randomized, double-blind, multi-center, active-controlled trial was fully enrolled in January 2001 with 601 treatment-naïve patients.
Early Access Program Initiated
In January, Gilead announced the initiation of a limited expanded access program to provide tenofovir DF to people with advanced HIV infection in the United States and five countries in the European Union. Regulatory review has been concluded and programs are open for registration in the United States and France. Early access programs will be initiated in Germany, Italy, Spain and the United Kingdom as regulatory approvals are obtained.For more information regarding the tenofovir DF early access program or to request registration materials, physicians in the United States may call 1-800-GILEAD-5 and those within Europe may call 33-1-44-90-34-46.