July 11, 2004
Pivotal Studies of Gilead's Viread and Emtriva Published in Special International Aids Conference Issue of Journal of the American Medical AssociationData from Separate Clinical Studies Compare Safety and Efficacy of Viread and Emtriva to Stavudine
BANGKOK, Thailand, Jul 11, 2004 (BUSINESS WIRE) -- Gilead Sciences, Inc. (Nasdaq:GILD) today announced the publication of results from two separate studies evaluating the efficacy and safety of Viread(R) (tenofovir disoproxil fumarate) and Emtriva(R) (emtricitabine), respectively, compared with stavudine (d4T), in combination with other antiretroviral agents. Viread is a nucleotide reverse transcriptase inhibitor (NtRTI) and Emtriva and stavudine are nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infection. Gilead has filed a New Drug Application for a fixed-dose combination of Viread and Emtriva, to be taken in combination with other antiretroviral agents, and anticipates a decision from the U.S. Food and Drug Administration (FDA) by September 12, 2004.
As reported in the Journal of the American Medical Association, Studies 903 and 301A were designed to compare Viread and Emtriva, respectively, both of which are dosed as one pill taken once daily in combination regimens, with stavudine, which is dosed twice daily and was a top prescribed NRTI in the United States at the time the studies were initiated. These data appear in the July 14, 2004 edition of the publication, a special issue that is being published to coincide with the 15th International AIDS Conference, taking place in Bangkok, Thailand. Data from Study 903 will also be presented at the conference.
"We are pleased that the editorial staff of JAMA has included the results of these pivotal studies of Viread and Emtriva in this special issue focused on important developments in HIV/AIDS treatment," said John C. Martin, PhD, President and CEO of Gilead Sciences. "As a company committed to providing therapeutic advancements, Gilead continually works to improve upon available treatment options to help address the unmet medical needs of patients and their physicians. We believe that the combination of Viread and Emtriva, which Gilead is developing as a single-tablet once-daily fixed-dose combination, will help to further simplify effective treatment regimens."
Study 903 is the first three-year, international, randomized, double-blind clinical trial comparing antiretroviral agents. Results of the study were reported in "Efficacy and Safety of Tenofovir DF vs. Stavudine in Combination Therapy in Antiretroviral-Naive Patients: A 3 year Randomized Trial." The study evaluated 600 patients with a viral load of at least 5,000 copies/mL. Patients were randomized (1:1) to receive either once-daily Viread or twice-daily stavudine, with corresponding placebo, plus lamivudine (3TC), an NRTI, and efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI).
The data show that after three years (144 weeks) of treatment, Viread and stavudine had comparable success in suppressing HIV. The rate of virologic failure during the three years of treatment was similar in both arms of the study (16 percent; p=0.91). Clinical adverse events occurred with similar frequency in both arms of the study. Certain adverse events that have been attributed to mitochondrial toxicity were observed more frequently among patients receiving stavudine. Investigator-defined lipodystrophy was seen in 19 percent of stavudine patients compared to 3 percent of Viread patients (p less than 0.001). Peripheral neuropathy was observed in 10 percent of stavudine patients and 3 percent of Viread patients (p less than 0.001), while investigator-defined lactic acidosis occurred in three patients, all of whom were taking stavudine.
"These data indicate that we no longer have to choose between efficacy on the one hand, and convenience, tolerability and safety on the other," said Joel Gallant, MD, MPH of Johns Hopkins University School of Medicine, the study's principal investigator and lead author of the paper. "In fact, it's now true that some of our most effective regimens are also the easiest regimens for patients to take."
Study 301A was the first controlled and adequately-powered clinical study to evaluate a completely once-daily regimen for the treatment of HIV infection. Results of the study were reported in a paper titled "Efficacy and Safety of Emtricitabine vs. Stavudine in Combination Therapy in Antiretroviral-Naive Patients." The study evaluated 571 treatment-naive patients who at screening had a viral load of at least 5,000 copies/mL. Patients were randomized (1:1) to receive once-daily Emtriva or twice-daily stavudine, in combination with once-daily efavirenz and didanosine (ddI), which is another NRTI.
Based on an interim analysis when the last patient randomized completed 24 weeks of double-blind treatment (median follow-up time of 42 weeks), the independent Data and Safety Monitoring Board (DSMB) recommended that all patients be offered the regimen containing Emtriva, due to its superiority in primary and secondary endpoints for efficacy and safety. The results presented in the paper characterize all double-blind data through the time the last patient randomized completed week 48, with a median follow up of 60 weeks.
At the median follow up time of 60 weeks, the probability of persistent virologic response with plasma HIV-1 RNA levels less than or equal to 50 copies/mL was significantly higher in the Emtriva group (n=286) compared with the stavudine group (n=285) (76 percent vs. 54 percent; p less than 0.001), based on Kaplan-Meier estimates. The probability of persistent virologic response with plasma HIV-1 RNA levels less than or equal to 400 copies/mL was 79 percent in the Emtriva group and 63 percent in the stavudine group (p less than 0.001). The probability of virologic failure was 4 percent in the Emtriva group and 12 percent in the stavudine group (p less than 0.001).
The probability of developing a treatment-limiting adverse event resulting in the discontinuation of treatment through week 60 was statistically greater in the stavudine group (15 percent) compared to the Emtriva group (7 percent) (p=0.005). This difference became significant after 24 weeks. Skin discoloration, manifested by hyperpigmentation on the palms and/or soles, was observed in 10 Emtriva patients and one stavudine patient and was generally mild and asymptomatic, though the mechanism and clinical significance is unknown.
"Well tolerated and convenient medications are rapidly becoming the foundation of initial treatment regimens for HIV," said lead author Michael Saag, MD, Professor of Medicine and Director of the HIV Clinic at the University of Alabama at Birmingham. "The results from this study suggest that drug regimens featuring potency, simplicity and tolerability are key to successful HIV therapy."
Viread is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. Assessment of adverse reactions, as described in the U.S. package insert, is based on one study of treatment-experienced patients and one study of treatment-naive patients. In Study 907, a total of 550 treatment-experienced patients received treatment with Viread 300 mg (n=368) or placebo (n=182) for 24 weeks followed by extended treatment with the drug. In Study 903, a total of 600 patients received treatment with Viread (n=299) or stavudine (n=301) in combination with lamivudine and efavirenz for 48 weeks. The most common adverse events in these patients were dizziness and mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting and flatulence.
In clinical practice, a number of adverse events, including renal impairment, nausea, rash and asthenia (weakness) have been reported. Renal impairment occurred most often in patients with underlying systemic or renal disease or in patients taking concomitant nephrotoxic agents, though some cases have appeared in patients without identified risk factors. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals. In patients co-infected with HIV and the hepatitis B virus, exacerbations of hepatitis B have been reported in patients after discontinuation of Viread. Decreases in bone mineral density (BMD) at the lumbar spine and hip have been seen with the use of Viread. The clinical significance of changes in BMD and biochemical markers is unknown and follow-up is continuing to assess long-term impact.
Emtriva is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. Assessment of adverse events, as described in the U.S. package insert, is based on pooled data from two Phase III studies in which 571 treatment-naive and 440 treatment-experienced patients received Emtriva (n=580) or a comparator drug (n=431) for 48 weeks. The most common adverse events that occurred in patients receiving Emtriva were headache, diarrhea, nausea and rash, which were generally of mild to moderate severity. Approximately 1 percent of patients discontinued participation in the clinical studies due to these events. All adverse events were reported with similar frequency in Emtriva and control treatment groups with the exception of skin discoloration, which was reported with higher frequency in the Emtriva treated group. Skin discoloration, manifested by hyperpigmentation (excess pigmentation) on the palms and/or soles, was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals. Emtriva is not indicated for the treatment of chronic hepatitis B. Exacerbations of hepatitis B have been reported in patients infected with chronic hepatitis B after discontinuation of Emtriva.
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes therapeutics to advance the care of patients suffering from life-threatening diseases worldwide. The company has six marketed products and focuses its research and clinical programs on anti-infectives. Headquartered in Foster City, CA, Gilead has operations in North America, Europe and Australia.
This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors including the risk that in a clinical setting or through longer treatment periods Gilead may not continue to observe the data observed in these studies for Viread and Emtriva and that regulatory authorities in the United States may ultimately determine that the application for the fixed dose co-formulation of Viread and Emtriva does not support approval. These risks and uncertainties could cause actual results to differ materially from those referred to in the forward-looking statements. Risks are described in detail in the Gilead Annual Report on Form 10-K for the year ended December 31, 2003 and in Gilead's Quarterly Reports on Form 10-Q, all of which are on file with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead and Gilead assumes no obligation to update any such forward-looking statements.
Viread and Emtriva are registered trademarks of Gilead Sciences, Inc.
For complete prescribing information, please visit www.viread.com or www.emtriva.com.
For more information on Gilead Sciences, please visit the company's web site at www.gilead.com or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
SOURCE: Gilead Sciences, Inc.
Gilead Sciences, Inc. Susan Hubbard, 650-522-5715 (Investors) Jenna Conley, 650-245-1886 (Media - Bangkok) James Loduca, 650-522-5908 (Media - U.S.)
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