December 15, 2006
96-Week Data From Gilead's Study 934 Comparing Viread(R) and Emtriva(R) to Combivir(R) Both in Combination With Sustiva(R) Published in Journal of Acquired Immune Deficiency Syndrome
FOSTER CITY, Calif.--(BUSINESS WIRE)--Dec. 15, 2006--Gilead Sciences, Inc. (Nasdaq:GILD) today announced the publication of 96-week data from an ongoing clinical trial, Study 934, in the Journal of Acquired Immune Deficiency Syndrome (JAIDS). This study compares a once-daily regimen of Viread(R) (tenofovir disoproxil fumarate), Emtriva(R) (emtricitabine) and Sustiva(R) (efavirenz) to a twice-daily regimen of Combivir(R) (lamivudine/zidovudine) with Sustiva once daily. The study article, "Tenofovir Disoproxil Fumarate, Emtricitabine, and Efavirenz Versus Fixed-Dose Zidovudine/Lamivudine and Efavirenz in Antiretroviral-Naive Patients," appears in the December 15 issue of JAIDS (Vol. 43; issue 5).
"The efficacy, safety and resistance profile of Viread/Emtriva/Sustiva in this study underscores the importance of this treatment option for antiretroviral therapy-naive patients," said lead author Anton Pozniak, MD, of the Chelsea and Westminster Hospital, London. "Sustiva, Emtriva and Viread were administered as individual agents in this trial, but a fixed-dose combination of these drugs is now available, offering more convenient dosing."
Viread and Emtriva are available as once-daily Truvada(R) (emtricitabine and tenofovir disoproxil fumarate), the most commonly prescribed backbone for HIV combination therapy. Viread, Emtriva and Sustiva are available in the United States as ATRIPLA(TM) (efavirenz 600 mg/ emtricitabine 200 mg/ tenofovir disoproxil fumarate 300 mg), the only once-daily single tablet regimen for the treatment of HIV-1 infection in adults. ATRIPLA was developed through a U.S. joint venture between Bristol-Myers Squibb and Gilead Sciences. Together with Merck & Co., Inc., the companies recently submitted a Marketing Authorisation Application (MAA) for the product to the European Medicines Agency (EMEA).
Ninety-six week data from this study were originally presented at the XVI International AIDS Conference in Toronto, Canada in August, 2006. Data from this analysis have not been reviewed by the U.S. Food & Drug Administration.
Study 934 is a Phase III, open-label, non-inferiority study that enrolled 517 HIV-infected patients in the United States and Europe. The study's primary endpoint was at 48 weeks and the study is continuing through 144 weeks. The prespecified primary efficacy population included 487 patients. Twenty-four patients (12 from each arm) who completed week 48 of the study with HIV RNA less than 400 copies/mL did not consent to participate after week 48 and were excluded from the analysis. Participants were randomized to receive Viread 300 mg, Emtriva 200 mg and Sustiva 600 mg, all dosed once daily, or Combivir twice daily and Sustiva 600 mg once daily. At study entry, patients were treatment-naive and had HIV RNA (viral load) greater than 10,000 copies/mL.
After 96 weeks of treatment (n=463), 75 percent of Viread/Emtriva/Sustiva patients compared to 62 percent of Combivir/Sustiva patients achieved and maintained viral load less than 400 copies/mL using the Time to Loss of Virologic Response algorithm (TLOVR) (p=0.004; 95% CI, +4% to +21%). Sixty-seven percent of patients in the Viread/Emtriva/Sustiva arm compared to 61 percent of patients in the Combivir/Sustiva arm achieved and maintained viral load less than 50 copies/mL using TLOVR (p=0.16; 95% CI, -2% to +15%). Patients receiving Viread/Emtriva/Sustiva experienced a significantly greater increase from baseline in CD4 cell counts at week 96 compared to those receiving Combivir/Sustiva (270 vs. 237 cells/mm(3); p=0.036).
There was a significant difference between the two study arms in terms of virologic rebound at 96 weeks (defined as having a confirmed viral load of greater than 400 copies/mL after achieving confirmed viral load of less than 400 copies/mL). Five percent of patients in the Combivir/Sustiva group experienced rebound compared to less than 1 percent of Viread/Emtriva/Sustiva patients (p=0.007).
Through 96 weeks, 43 patients in the study met criteria for resistance testing. The K65R mutation, which can be selected by Viread, did not arise in any patient. There was a significant difference between study arms in the development of the M184V mutation, which was observed in 2 patients in the Viread/Emtriva/Sustiva group compared with 9 patients in the Combivir/Sustiva group (p=0.036).
After 96 weeks of treatment, discontinuation of study medications due to adverse events was significantly higher among Combivir/Sustiva patients compared to the Viread/Emtriva/Sustiva arm (11 vs. 5 percent, respectively; p=0.008). The most common cause of discontinuation related to study drug in at least 2 percent of patients in either arm include anemia (6 percent in the Combivir/Sustiva group vs. 0 percent in the Viread/Emtriva/Sustiva group), fatigue (2 percent in the Combivir/Sustiva group vs. 0 percent in the Viread/Emtriva/Sustiva group), nausea (2 percent in the Combivir/Sustiva group vs. less than 1 percent in the Viread/Emtriva/Sustiva group), and rash (less than 1 percent in the Combivir/Sustiva group vs. 2 percent in the Viread/Emtriva/Sustiva group).
Patients receiving Viread/Emtriva/Sustiva had a significantly greater median increase in weight from baseline compared to patients receiving Combivir/Sustiva (2.7 kg vs. 0.5 kg, respectively; p less than 0.001). Patients receiving Viread/Emtriva/Sustiva had significantly greater median limb fat at week 96 compared to patients receiving Combivir/Sustiva (7.7 kg, n=144 vs. 5.5 kg, n=136, respectively; p less than 0.001). In addition, in a subset of patients with 48- and 96-week data, significant differences in median limb fat were observed (decrease of 0.7 kg in the Combivir/Sustiva arm; n=44; p=0.001; increase of 0.3 kg in the Viread/Emtriva/Sustiva arm; n=49; p=0.01).
Renal adverse events were uncommon at 96 weeks, which is consistent with study data at 48 weeks and results from other randomized clinical trials involving Viread in treatment-naive and treatment-experienced patients. Renal safety was similar and renal function remained stable in the two arms of the study. No patient discontinued study medication due to renal events.
Important Product Safety Information
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.
ATRIPLA, Viread and Emtriva are not indicated for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of these drugs have not been established in patients co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued Viread or Emtriva (components of ATRIPLA). Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue ATRIPLA, Viread or Emtriva and are co-infected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
It is important for patients to be aware that anti-HIV medicines including ATRIPLA, Viread and Emtriva do not cure HIV infection or AIDS, nor have they been shown to reduce the risk of transmission of HIV to others.
Additional Important Information About ATRIPLA
ATRIPLA is indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.
ATRIPLA is contraindicated for use with astemizole, cisapride, midazolam, triazolam, ergot derivatives, or voriconazole. Concomitant use of ATRIPLA and St. John's wort (Hypericum perforatum) or St. John's wort-containing products is not recommended. Since ATRIPLA contains efavirenz, emtricitabine and tenofovir disoproxil fumarate, it should not be coadministered with Sustiva, Emtriva, Viread, or Truvada (emtricitabine/tenofovir disoproxil fumarate). Due to similarities between emtricitabine and lamivudine, ATRIPLA should not be coadministered with drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir(R) (lamivudine), Epivir-HBV(R), Epzicom(TM)(abacavir/lamivudine), or Trizivir(R) (abacavir/lamivudine/zidovudine).
Serious psychiatric adverse experiences, including severe depression (2.4%), suicidal ideation (0.7%), nonfatal suicide attempts (0.5%), aggressive behavior (0.4%), paranoid reactions (0.4%) and manic reactions (0.2%) have been reported in patients treated with efavirenz. In addition to efavirenz, factors identified in a clinical study that were associated with an increase in psychiatric symptoms included a history of injection drug use, psychiatric history and use of psychiatric medication. There have been occasional reports of suicide, delusions and psychosis-like behavior, but it could not be determined if efavirenz was the cause. Patients with serious psychiatric adverse experiences should be evaluated immediately to determine whether the risks of continued therapy outweigh the benefits. Fifty-three percent of patients reported central nervous system symptoms including dizziness (28.1%), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%) and hallucinations (1.2%) when taking efavirenz compared to 25% of patients receiving control regimens. These symptoms usually begin during the first or second day of therapy and generally resolve after the first two to four weeks of therapy. After four weeks of therapy, the prevalence of central nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing efavirenz. Nervous system symptoms are not predictive of the less frequent psychiatric symptoms.
ATRIPLA should not be given to patients with creatinine clearance below 50 mL/min. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of tenofovir disoproxil fumarate, most often in patients with underlying systemic or renal disease, or in patients taking concomitant nephrotoxic agents. Some cases have occurred in patients with no identified risk factors. ATRIPLA should be avoided with concurrent or recent use of a nephrotoxic agent.
ATRIPLA may cause fetal harm when administered during the first trimester to a pregnant woman. Women should not become pregnant or breastfeed while taking ATRIPLA. Barrier contraception must always be used in combination with other methods of contraception such as oral or other hormonal contraceptives. If the patient becomes pregnant while taking ATRIPLA, she should be apprised of the potential harm to the fetus.
Mild to moderate rash is a common side effect of efavirenz. In controlled clinical trials, 26% of patients treated with efavirenz experienced new-onset skin rash compared with 17% of patients treated in control groups. Skin discoloration, associated with emtricitabine, may also occur. ATRIPLA should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Liver enzymes should be monitored in patients with known or suspected hepatitis B or C and when ATRIPLA is administered with ritonavir or other medications associated with liver toxicity. Decreases in bone mineral density (BMD) have been seen with tenofovir disoproxil fumarate. Use ATRIPLA with caution in patients with a history of seizures. Convulsions have been observed in patients receiving efavirenz, generally in the presence of a known medical history of seizures. Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of ATRIPLA.
Saquinavir should not be used as the only protease inhibitor in combination with ATRIPLA. Coadministration of ATRIPLA and atazanavir is not recommended due to concerns regarding decreased atazanavir concentrations. Patients on lopinavir/ritonavir plus ATRIPLA should be monitored for tenofovir-associated adverse events. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse events. Coadministration of ATRIPLA and didanosine should be undertaken with caution. Patients receiving this combination should be monitored closely for didanosine-associated adverse events. See full prescribing information for complete list of drug-drug interactions.
In Study 934, adverse events observed in greater than or equal to 5% of patients in the Viread/Emtriva/Sustiva group include dizziness, nausea, diarrhea, fatigue, headache, and rash.
The dose of ATRIPLA is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms.
In the United States, Viread is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Viread should not be used in combination with Truvada. Truvada should not be used in combination with its component drugs, Viread or Emtriva.
Drug interactions have been observed when didanosine, atazanavir or lopinavir/ritonavir is co-administered with Viread and dose adjustments may be necessary. Data are not available to recommend a dose adjustment of didanosine for patients weighing less than 60 kg. Patients on atazanavir and lopinavir/ritonavir plus Viread should be monitored for Viread-associated adverse events, which may require discontinuation. When co-administered with Viread, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg. Atazanavir without ritonavir should not be co-administered with Viread.
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported among patients taking Viread. 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. Decreases in bone mineral density (BMD) at the lumbar spine and hip have been seen with the use of Viread. The effects of Viread-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy including Viread.
The most common adverse events among patients receiving Viread with other antiretroviral agents in clinical trials were mild to moderate gastrointestinal events and dizziness. Moderate to severe adverse events occurring in more than 5 percent of patients receiving Viread included rash (rash, pruritis, maculopapular rash, urticaria, vesiculobullous rash and pustular rash), headache, pain, diarrhea, depression, back pain, fever, nausea, abdominal pain, asthenia and anxiety (Study 903). Less than 1 percent of patients discontinued participation because of gastrointestinal events (Study 907).
The parent compound of Viread was discovered through a collaborative research effort between Dr. Antonin Holy, Institute for Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic (IOCB) in Prague and Dr. Erik DeClercq, Rega Institute for Medical Research, Katholic University in Leuven, Belgium.
In the United States, Emtriva is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in patients over three months of age. This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts from controlled studies of 48 weeks duration in antiretroviral-naive patients and antiretroviral-treatment-experienced patients who were virologically suppressed on an HIV treatment regimen. In antiretroviral-treatment-experienced patients, the use of Emtriva may be considered for adults with HIV strains that are expected to be susceptible to Emtriva as assessed by genotypic or phenotypic testing.
Adverse events that occurred in more than 5 percent of patients receiving Emtriva with other antiretroviral agents in clinical trials include abdominal pain, asthenia (weakness), headache, diarrhea, nausea, vomiting, dizziness and rash (rash, pruritis, maculopapular rash, urticaria, vesiculobullous rash, pustular rash and allergic reaction). Approximately 1 percent of patients discontinued participation because of 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 on the palms and/or soles, was generally mild and asymptomatic. The mechanism and clinical significance are unknown.
Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy including Emtriva. For pediatric patients over three months of age, the adverse event profile observed during clinical trials was similar to that of adult patients, with the exception of anemia and a higher frequency of hyperpigmentation.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Australia. Visit Gilead on the World Wide Web at www.gilead.com.
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 physicians may not see advantages of ATRIPLA, Viread and Emtriva over other antiretrovirals and may therefore be reluctant to prescribe these products. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in the Gilead Annual Report on Form 10-K for the year ended December 31, 2005, filed 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.
Full prescribing information for ATRIPLA is available at www.atripla.com. Full prescribing information for Viread, Emtriva and Truvada is available at www.gileadHIV.com.
ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. Viread, Emtriva and Truvada are registered trademarks of Gilead Sciences, Inc.
CONTACT: Gilead Sciences, Inc.
Susan Hubbard, 650-522-5715 (Investors)
James Loduca, 650-522-5908 (Media)
SOURCE: Gilead Sciences, Inc.