Bristol-Myers Squibb Company, Gilead Sciences, Inc. and Merck & Co., Inc. announced that they are in discussions on the development of a once-daily, fixed-dose combination of three anti-HIV drugs and are also considering certain co-packaging options for the individual products.
The three companies welcome the comments by US Secretary of Health and Human Services Tommy Thompson on the need for increased treatment options for people with HIV/AIDS in the developing world.
This collaboration - a multi-company effort to create a fixed-dose product with three patented HIV/AIDS medicines - would be the first partnership of its kind in the field of HIV. The parties agree on the importance of the task - to support the need for simplified treatment regimens, particularly in resource-constrained settings.
Fixed-dose combinations contain multiple medicines co-formulated in a single tablet, potentially simplifying combination therapy for HIV treaters and patients. This potential three-drug, fixed-dose combination would include two Gilead drugs, Viread (tenofovir disoproxil fumarate) and Emtriva (emtricitabine). In March, Gilead filed regulatory applications in the United States and Europe for approval of a single-tablet fixed-dose combination of these two drugs. The third drug in the proposed combination, efavirenz, is marketed in the United States, Canada and certain European countries by Bristol-Myers Squibb as Sustiva (efavirenz) and elsewhere by Merck under the brand name Stocrin (efavirenz).
The companies plan to seek regulatory review and approval of the three-drug fixed-dose combination. The companies also are exploring a co-packaged version that would include the three products as an interim step until a fixed-dose combination product could be made available.
"We are pleased to be part of this pioneering initiative with Gilead and Merck and commend the Administration for their efforts to help bring new and better ways to fight the global HIV/AIDS pandemic," said Peter R. Dolan, chairman and chief executive officer of Bristol-Myers Squibb. "Given the complexities of this disease, and the unique challenges in delivering care and treatment in resource limited settings, we recognize the need to work together and combine our expertise to find innovative solutions. At Bristol-Myers Squibb, HIV/AIDS continues to be a major area of focus for our research, and we are committed to making our medicines available at no-profit in those countries hardest hit by this epidemic. In addition, in Africa, we are working with local communities through our $115 million Secure the Future programme to help strengthen their ability to fight this disease."
"While we have made progress in the fight against HIV with new therapies that offer significant advances, further efforts are needed to deliver the benefits of these advancements to those patients most in need," commented John C. Martin, PhD, president and chief executive officer, Gilead Sciences. "Gilead has initiated a programme to provide our antiretrovirals at no profit to developing world countries, and we have been evaluating options for partnerships that will allow us to expand these efforts. We're very pleased with the support we have received from the U.S. government, and we look forward to working with partners from industry, governments and NGOs to increase treatment and treatment options for those affected by HIV and AIDS."
"We welcome the Administration's support for the expedited development of new combinations of HIV medications for use in the President's Emergency Plan for AIDS Relief (PEPFAR) and look forward to working with the FDA on this critical issue," said Raymond V. Gilmartin, chairman, president and chief executive officer of Merck & Co., Inc. "Merck has worked closely for some time with representatives of the WHO, UNAIDS, the Global Fund and the Administration to explore ways to accelerate the development of fixed-dose combinations. We are delighted to be part of this new initiative. The proposed triple combination is expected to be an important new tool offering once-a-day treatment in the fight against the AIDS epidemic."
Efavirenz is available only by prescription and is used in combination with other medicines to treat people who are infected with HIV. Efavirenz does not cure HIV or help prevent passing HIV to others. Efavirenz should not be taken with Hismanal (astemizole), Propulsid (cisapride), Versed (midazolam), Halcion (triazolam), or ergot derivatives. Doctors should be informed about any medications or herbal products (particularly St. John's wort) that their patients are taking. Many patients have dizziness, trouble sleeping, drowsiness, trouble concentrating, and/or unusual dreams. These feelings tend to go away after taking the medication for a few weeks.
A small number of patients have reported severe depression, strange thoughts, or angry behavior. There have been a few reports of suicide but it is not known if efavirenz was the cause. Women should not become pregnant or breastfeed while taking efavirenz. Rash is another common side effect. Rashes usually go 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. Changes in body fat have been seen in some patients taking HIV medicines. The cause and long-term effects are not known at this time. Efavirenz should be taken on an empty stomach, preferably at bedtime. Taking efavirenz with food increases the amount of medicine in the body, which may increase the frequency of side effects. Taking efavirenz at bedtime may make some side effects less bothersome.
In the United States, Emtriva is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. In the European Union, Emtriva is indicated in combination with other antiretroviral agents for the treatment of HIV in adults and children.
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-naïve 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 one 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. In patients co-infected with HIV and chronic hepatitis B, exacerbations of hepatitis B have been reported in patients after discontinuation of Emtriva.
In the United States, 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-naïve 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.