Bristol-Myers Squibb And Gilead Sciences Submit New Drug Application To U.S. FDA For A Once-Daily Single Tablet Regimen Of Sustiva® (efavirenz) And Truvada® (emtricitabine and tenofovir disoproxil fumarate) For HIV Treatment
Princeton, N.J. and Foster City, Calif. (April 27, 2006) -- Bristol-Myers Squibb Company (NYSE: BMY) and Gilead Sciences, Inc. (Nasdaq: GILD) today announced the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of a product that combines the anti-HIV medications Sustiva® (efavirenz), manufactured by Bristol-Myers Squibb, and Truvada® (emtricitabine and tenofovir disoproxil fumarate), manufactured by Gilead Sciences, in a once-daily single tablet regimen. Truvada itself is a fixed-dose product that contains two of Gilead’s anti-HIV medications, Viread® (tenofovir disoproxil fumarate) and Emtriva® (emtricitabine), in a single once-daily tablet. If approved by the FDA, the new single tablet regimen would be the first and only product that contains a complete Highly Active Antiretroviral Therapy (HAART) regimen in a single once-daily tablet, intended for the treatment of HIV-1 infection in adults as a complete regimen or in combination with other antiretrovirals.
The collaboration between Bristol-Myers Squibb and Gilead is the first of its kind in the field of HIV therapy. On December 20, 2004 the companies established a U.S. joint venture to develop and commercialize the single tablet regimen in the United States. The work necessary to file the NDA for the single tablet regimen, including bioequivalence studies and the initiation of stability studies, has since been completed.
“The partnership between Bristol-Myers Squibb and Gilead was founded on the companies’ shared commitment to addressing the needs of people living with HIV,” commented John C. Martin, PhD, President and Chief Executive Officer, Gilead Sciences. “Significant progress in science and medicine has been achieved since the advent of the first combination regimens 10 years ago, but more work is needed and we view this partnership to create the first-ever once-daily single tablet regimen for HIV as an important step toward further simplifying dosing of HIV therapy for physicians and patients.”
“Bristol-Myers Squibb is pleased to partner with a company that, like us, values scientific and commercial innovation to help patients,” said Anthony C. Hooper, President, U.S. Pharmaceuticals, Bristol-Myers Squibb. “The collaboration between the companies is an important milestone for patients living with HIV. Working together, Bristol-Myers Squibb and Gilead Sciences are ushering in a new era of collaboration driven by the need to deliver HIV therapies to patients in need.”
The proposed once-daily single tablet regimen contains 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate. All three active ingredients work by blocking reverse transcriptase, an enzyme necessary for HIV replication. It is important for patients to be aware that these medications do not cure HIV infection or prevent passing HIV to others.
Subject to marketing approval of the once-daily single tablet regimen, Bristol Myers-Squibb and Gilead will share responsibility for commercializing the product in the United States. Both companies will provide funding and field-based sales representatives in support of promotional efforts for the combination product. Bristol-Myers Squibb and Gilead will receive revenues from future net sales at percentages relative to the contribution represented by their individual products that comprise the once-daily single tablet regimen. Sustiva, Truvada, Viread and Emtriva will continue to be sold by the respective companies as individual products.
Guidelines issued by the U.S. Department of Health and Human Services (DHHS) list the combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate as one of the preferred non-nucleoside reverse transcriptase inhibitor (NNRTI)-based treatment regimens for use in appropriate patients who have never taken anti-HIV medicines before. Efavirenz should not be used during the first trimester of pregnancy due to the potential harm to the fetus. Pregnancy should be avoided in women receiving efavirenz.
2006 marks the 25th anniversary of the start of the AIDS epidemic. The first cases of HIV/AIDS were reported by the U.S. Centers for Disease Control and Prevention (CDC) in the June 5, 1981 issue of the Morbidity and Mortality Weekly Report (MMWR). Today, the CDC estimates that more than one million Americans are infected with HIV, the virus that causes AIDS. Of these, approximately 25 percent are unaware of their infection. Although HIV treatment options have expanded rapidly in recent years, the CDC estimates that 216,000 Americans who are HIV infected and eligible for antiretroviral treatment are currently not receiving it.
Important Information About SUSTIVA® (efavirenz)
SUSTIVA is a prescription medicine used in combination with other medicines to treat people who are infected with the human immunodeficiency virus type 1 (HIV-1). SUSTIVA does not cure HIV or help prevent passing HIV to others. SUSTIVA should not be taken with Hismanal® (astemizole), Propulsid® (cisapride), Versed® (midazolam), Halcion® (triazolam), ergot medicines (for example, Wigraine® and Cafergot®), or Vfend® (voriconazole). This list of medicines is not complete. Patients should discuss all prescription and non-prescription medicines, vitamin and herbal supplements, or other health preparations (particularly St. John’s wort) they are taking or plan to take with their healthcare provider.
Patients taking SUSTIVA (efavirenz) should tell their doctor right away if they have any side effects or conditions including: severe depression, strange thoughts, or angry behavior, which have been reported in a small number of patients. A few reports of suicide have been made, but it is not known if SUSTIVA was the cause. Dizziness, trouble sleeping, drowsiness, trouble concentrating, and/or unusual dreams are common. These feelings tend to go away after taking SUSTIVA for a few weeks.
Women should not become pregnant or breastfeed while taking SUSTIVA. Serious birth defects have been seen in children of women treated with SUSTIVA during pregnancy. Women must use a reliable form of barrier contraception, such as a condom, even if they also use other methods of birth control. Patients should tell their doctor if they have a history of mental illness or are using drugs or alcohol. Rash is a common side effect that usually goes away without any change in treatment. Rash may be a serious problem in some children. If a child develops a rash, their doctor should be contacted right away. Patients with liver disease, a history of seizures, or taking medicine for seizures, may require the healthcare provider to check the liver or check drug levels in the blood.
Changes in body fat have been seen in some patients taking HIV medicines, however, the cause and long-term effects of these changes are not known at this time. Other common side effects include: tiredness, upset stomach, vomiting and diarrhea. SUSTIVA should be taken on an empty stomach, preferably at bedtime, which may make some side effects less bothersome. SUSTIVA and other anti-HIV medicines should be taken exactly as instructed by healthcare providers.
SUSTIVA is marketed in the United States, Canada and certain European countries by Bristol-Myers Squibb. Elsewhere in the world, efavirenz is marketed by Merck & Co., Inc., under the brand name Stocrin®.
Important Safety Information for Truvada® (emtricitabine and tenofovir disoproxil fumarate), Viread® (tenofovir disoproxil fumarate) and Emtriva® (emtricitabine)
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. 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 Viread or Emtriva. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue Truvada, Viread or Emtriva and are co-infected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
Changes in body fat have been observed in patients taking Truvada, Viread and Emtriva and other anti-HIV medicines. 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.
Truvada, Viread, and Emtriva do not cure HIV and do not prevent infection or passing HIV to others.
About Truvada® (emtricitabine and tenofovir disoproxil fumarate)
Truvada is a fixed-dose combination product that combines Emtriva (200 mg of emtricitabine) and Viread (300 mg of tenofovir disoproxil fumarate) in one tablet, taken once a day, as part of combination therapy. In the United States, 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 (emtricitabine and tenofovir disoproxil fumarate) 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-naïve 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 are 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. Patients on atazanavir and 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.
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.
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-naïve patients receiving Viread and/or Emtriva. Adverse events observed in more than five percent of patients in the Viread/Emtriva group in Study 934 include diarrhea, nausea, fatigue, headache, dizziness and rash.
For additional safety information about Viread or Emtriva in combination with other antiretroviral agents, please see “About Viread” and “About Emtriva” below.
About Viread® (tenofovir disoproxil fumarate)
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.
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. 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.
About Emtriva® (emtricitabine)
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-naïve 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. 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 Bristol-Myers Squibb
Bristol-Myers Squibb is a global pharmaceutical and related healthcare products company whose mission is to extend and enhance human life. For more than a decade, Bristol-Myers Squibb Company has been a global leader in the science of infectious diseases and has invested consistently in innovative research leading to the development of important treatments for people with HIV/AIDS.
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
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, or, if approved, will be commercially successful. 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 willingness of regulatory authorities to grant regulatory approval for the combination product based on data from studies conducted to support the NDA. 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.
Sustiva is a registered trademark of Bristol-Myers Squibb Pharma Company.
Truvada, Viread and Emtriva are registered trademarks of Gilead Sciences, Inc.
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