Bristol-Myers Squibb, Gilead Sciences and Merck & Co. Submit Marketing Authorisation Application for ATRIPLA(TM) (efavirenz 600 mg/ emtricitabine 200 mg/ tenofovir disoproxil fumarate 300 mg) to European Medicines Agency

PRINCETON, N.J. & FOSTER CITY, Calif. & WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Oct. 9, 2006--Bristol-Myers Squibb Company (NYSE:BMY), Gilead Sciences, Inc. (Nasdaq:GILD) and Merck & Co., Inc. (NYSE:MRK) today announced the submission of a Marketing Authorisation Application (MAA) for ATRIPLA(TM) (efavirenz 600 mg/ emtricitabine 200 mg/ tenofovir disoproxil fumarate 300 mg) in the European Union to the European Medicines Agency (EMEA). The MAA will be reviewed by the Committee for Medicinal Products for Human Use (CHMP), subject to validation by the EMEA.

The MAA for ATRIPLA in the European Union was filed jointly by the three companies through a newly established three-way joint venture based in Ireland, Bristol-Myers Squibb Gilead Sciences And Merck Sharp & Dohme Limited. Review of the MAA will be conducted by the EMEA under the centralized licensing procedure, which, when finalized, provides one marketing authorization in all member states of the European Union. Discussions among the three companies regarding agreements for manufacturing, commercialization and distribution of ATRIPLA in the European Union are ongoing.

ATRIPLA is a once-daily single tablet regimen approved in the United States for the treatment of HIV-1 infection in adults for use either as stand-alone therapy or in combination with other antiretroviral agents. The product contains 600 mg of efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI), 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, both nucleoside reverse transcriptase inhibitors (NRTIs). Efavirenz is marketed by Bristol-Myers Squibb under the tradename SUSTIVA(R) in the United States, Canada and six European countries (France, Republic of Ireland, Germany, Italy, Spain and the United Kingdom). In other territories, including all other countries of the European Union, efavirenz is commercialized by Merck & Co., Inc., (also known as MSD outside of the United States and Canada) and is marketed in most of these countries under the tradename Stocrin(R). Emtricitabine and tenofovir disoproxil fumarate are commercialized by Gilead Sciences under the tradenames Emtriva(R) and Viread(R), respectively. The compounds are commonly prescribed together as a once-daily, fixed-dose tablet, marketed under the tradename Truvada(R) for use as part of combination therapy.

ATRIPLA was approved by the U.S. Food and Drug Administration (FDA) on July 12, 2006. In the United States, the product is commercialized by Bristol-Myers Squibb and Gilead Sciences through a joint venture. The FDA also granted approval of an alternate tradedress of ATRIPLA for developing countries, where ATRIPLA will be made available as a white-colored tablet to distinguish it from the salmon-colored version currently available in the United States. Gilead and Merck established a separate agreement in August 2006 for distribution of the product in developing countries.

"Bristol-Myers Squibb is committed to delivering effective HIV therapies to patients worldwide and is pleased to work with Gilead and Merck to realize this goal with ATRIPLA," said Lamberto Andreotti, president, Worldwide Pharmaceuticals, Bristol-Myers Squibb. "With the filing of ATRIPLA in Europe, we are one step closer to making available another effective treatment option for European adult patients living with HIV/AIDS."

"As the first and only once-daily single tablet regimen, ATRIPLA may help to simplify therapy for many HIV-infected adults. Gilead is pleased to have established this partnership with Bristol-Myers Squibb and Merck, and we look forward to working with colleagues at both companies to make this product available to people living with HIV in Europe as quickly as possible," said Kevin Young, Executive Vice President, Commercial Operations, Gilead Sciences.

"ATRIPLA has the potential to offer an important new tool to patients and physicians in Europe for treating HIV infection in adults," said Stefan J. Oschmann, President, Europe, Middle East, Africa, Canada, Merck & Co., Inc. "This new single tablet regimen exemplifies our commitment to putting patients first. We look forward to collaborating with BMS, Gilead and national health authorities to deliver ATRIPLA to those who need it as soon as possible."

Important Safety Information About ATRIPLA, Truvada, Viread and Emtriva

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, Truvada, 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 Emtriva or Viread (components of ATRIPLA and Truvada). Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue ATRIPLA, Truvada, Emtriva or Viread and are co-infected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Antiretroviral therapies do not cure HIV infection or AIDS and have not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination.

Additional Important Information About ATRIPLA in the United States

In the United States, 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.

Coadministration of ATRIPLA with astemizole, cisapride, midazolam, triazolam, ergot derivatives, or voriconazole is contraindicated. Concomitant use of ATRIPLA with 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, ATRIPLA should not be coadministered with SUSTIVA, EMTRIVA, VIREAD, or TRUVADA. Due to similarities between emtricitabine and lamivudine, ATRIPLA should not be coadministered with drugs containing lamivudine, including Combivir(R), Epivir(R), Epivir-HBV(R), Epzicom(TM), or Trizivir(R).

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 receiving 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 (CNS) 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 two days of therapy and generally resolve after the first two to four weeks of therapy; they were severe in 2.0% of patients and 2.1% of patients discontinued therapy. After four weeks of therapy, the prevalence of CNS 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 less than 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. Renal impairment occurred 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 (e.g., 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 known medical history of seizures. Redistribution/accumulation of body fat has 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.

Coadministration with ATRIPLA and atazanavir is not recommended due to concerns regarding decreased atazanavir concentrations. Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. Patients on atazanavir or 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 with 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, the most frequently reported grades two to four adverse events through 48 weeks in patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate were dizziness (8%), nausea (8%), diarrhea (7%), fatigue (7%), headache (5%), rash (5%), sinusitis (4%), depression (4%), insomnia (4%), and abnormal dreams (4%).

The dose of ATRIPLA is one tablet (containing 600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate) once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms. ATRIPLA is not recommended for use in patients younger than 18 years of age.

Important Information About Efavirenz

Efavirenz in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection. This indication is based on two clinical trials of at least one year duration that demonstrated prolonged suppression of HIV RNA.

Coadministration with astemizole, cisapride, midazolam, triazolam, ergot derivatives, or voriconazole is contraindicated. Concomitant use of efavirenz and St. John's wort (Hypericum perforatum) or St. John's wort-containing products is not recommended. This list of medications is not complete.

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 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 Days 1-2 of therapy and generally resolve after the first 2-4 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 serious psychiatric symptoms.

Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman. Women should not become pregnant or breastfeed while taking efavirenz. Barrier contraception must always be used in combination with other methods of contraception (e.g. oral or other hormonal contraceptives). If the patient becomes pregnant while taking efavirenz, 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. Efavirenz should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Rash is more common and often more severe in pediatric patients.

Liver enzymes should be monitored in patients with known or suspected hepatitis B or C, in patients treated with other medications associated with liver toxicity, and when efavirenz is administered with ritonavir. Use efavirenz with caution in patients with a history of seizures. Convulsions have been observed in patients receiving efavirenz, generally in the presence of known medical history of seizures. Redistribution and/or accumulation of body fat have been seen in patients receiving antiretroviral therapy. A causal relationship has not been established. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including efavirenz.

It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime. The increased concentrations following administration of efavirenz with food may lead to an increase in frequency of adverse events. Dosing at bedtime may improve the tolerability of nervous system symptoms.

Additional Important Information About Truvada

Truvada is a fixed-dose combination product that combines 200 mg of Emtriva(R) (emtricitabine) and 300 mg of Viread(R) (tenofovir disoproxil fumarate) in one tablet, taken once a day. In the United States and the European Union, Truvada is indicated in combination with other antiretroviral agents (such as non-nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults. Truvada should not be coadministered with Emtriva, Viread or lamivudine-containing products and it is not recommended that Truvada be used as a component of a triple nucleoside regimen. In treatment-experienced patients, the use of Truvada should be guided by laboratory testing and treatment history.

Clinical Study 934 supports the use of Truvada tablets for the treatment of HIV-1 infection. Additional data in support of the use of Truvada are derived from Study 903, in which Viread and lamivudine were used in combination in treatment-naive adults, and clinical Study 303, in which Emtriva and lamivudine demonstrated comparable efficacy, safety and resistance patterns as part of multidrug regimens.

No drug interaction studies have been conducted using Truvada. Drug interactions have been observed when didanosine, atazanavir, or lopinavir/ritonavir is co-administered with Viread, a component of Truvada, and dose adjustments may be necessary. Data are not available to recommend a dose adjustment of didanosine for patients weighing less than 60 kg. In the European Union, the co-administration of tenofovir disoproxil fumarate and didanosine is not recommended unless judged strictly necessary. Patients on atazanavir or lopinavir/ritonavir plus Truvada should be monitored for Truvada-associated adverse events that may require discontinuation. When co-administered with Truvada, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg. Atazanavir without ritonavir should not be co-administered with Truvada.

Four-hundred and forty-seven HIV-1 infected patients have received combination therapy with Emtriva and Viread with either a non-nucleoside reverse transcriptase inhibitor (Study 934) or protease inhibitor for 48 weeks in clinical studies. Adverse events observed in Study 934 were generally consistent with those seen in other studies in treatment-experienced or treatment-naive patients receiving Viread and/or Emtriva. Adverse events observed in more than 5% of patients in the Viread/Emtriva group in Study 934 include diarrhea, nausea, fatigue, headache, dizziness and rash.

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported among patients taking Viread, a component of Truvada (emtricitabine and tenofovir disoproxil fumarate). 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 risk fracture are unknown. Redistribution and/or accumulation of body fat have been observed in patients receiving combination antiretroviral therapy. The cause and long term health effect of these conditions are unknown. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy including Truvada, Viread and Emtriva.

Skin discoloration, manifested by hyperpigmentation on the palms and/or soles, has been reported with the use of Emtriva, a component of Truvada. Skin discoloration was generally mild and asymptomatic and its mechanism and clinical significance are unknown.

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.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global pharmaceutical and related healthcare products company. Visit Bristol-Myers Squibb on the World Wide Web at www.bms.com.

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.

About Merck

Merck & Co. Inc., which operates as Merck Sharp & Dohme (MSD) in countries outside of the United States, is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but also help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

    Forward-Looking Statements

    Bristol-Myers Squibb Forward-Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding product development. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the combination product will receive regulatory approval in the European Union or other geographies, or, if approved, will be commercially successful. Nor is there any guaranty that discussions among the three companies regarding agreements for manufacturing, commercialization and distribution of ATRIPLA in the European Union will be successfully concluded or implemented. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2005 and in our Quarterly Reports on Form 10-Q. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Gilead Forward-Looking Statement

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 ATRIPLA may not be approved in the European Union or other markets and the risk that physicians and regulatory agencies may not see advantages of ATRIPLA over other antiretrovirals and may therefore be reluctant to prescribe the product. 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.

Merck Forward-Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.

Full U.S. prescribing information for ATRIPLA is available at www.atripla.com.

Full U.S. prescribing information for SUSTIVA is available at www.bms.com.

Full U.S. prescribing information for Truvada, Viread and Emtriva is available at www.gilead.com.

EU Summary of Product Characteristics for Truvada, Viread, Emtriva, SUSTIVA and Stocrin are available at http://www.emea.eu.int/humandocs/Humans/EPAR/a-zepar.htm.

ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC.

SUSTIVA is a registered trademark of Bristol-Myers Squibb Pharma Company.

Stocrin is a registered trademark of Merck & Co., Inc.

Truvada, Viread and Emtriva are registered trademarks of Gilead Sciences, Inc.

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Merck & Co., Inc.
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SOURCE: Gilead Sciences, Inc.