ATLANTA -- AmBiLoad Study Evaluated Optimum Use of AmBisome for Patients With Life-Threatening Infections
Gilead Sciences, Inc. (Nasdaq:GILD) today announced results from its clinical trial known as AmBiLoad, which compared a 3 mg/kg/day treatment course of AmBisome(R) (amphotericin B) liposome for injection versus a 10 mg/kg/day loading regimen for the initial two weeks of treatment in immunocompromised patients with invasive aspergillosis and other life-threatening fungal infections. In this study the overall rate of response for the two dosing regimens at end of treatment were associated with similar efficacy and survival (50 percent in the standard dosing group versus 46 percent in the high loading-dose group). The 3 mg/kg/day dose was better tolerated in this study. Results of the AmBiLoad clinical trial were presented today by Oliver A. Cornely, MD, Clinic of Internal Medicine, University of Cologne, Cologne, Germany (Poster #3222) at the American Society of Hematology 47th Annual Meeting in Atlanta, Georgia.
Product labeling for AmBisome varies in each of the countries in which it is marketed. AmBisome is indicated in most countries for the treatment of confirmed invasive fungal infections such as aspergillosis, which primarily affects patients with impaired immune function and can be fatal. The currently approved doses of AmBisome for the treatment of confirmed invasive fungal infections vary from 1 to 5 mg/kg/day. Preclinical data have suggested that increasing doses of AmBisome may be associated with improved antifungal efficacy, and limited studies in human subjects suggested that doses of 10 mg/kg/day could be administered without a significant increase in adverse events.
"This study provided important insights into the optimum dose and dosing regimen of AmBisome for established invasive fungal infections -- data that have been lacking thus far," said Dr. Cornely, a principal investigator. "The results from this study clearly confirm the efficacy of the standard dosing regimen, which was associated with a favorable response in half of patients and a 72 percent survival rate 12 weeks after the end of treatment. These findings are on par with response and survival rates reported in similar studies of other licensed antifungal agents. This is especially impressive, since patients in AmBiLoad had a high burden of risk factors for profoundly impaired immune function."
About the AmBiLoad Study
The multicenter, randomized, controlled study included 201 immunocompromised patients at 46 sites in Europe and Australia. All patients had probable or proven invasive aspergillosis or other fungal infections, as confirmed by an independent data review board. Patients were randomized to receive either the standard dose of 3 mg/kg/day of AmBisome for the entire treatment period (n=107) or 10 mg/kg/day for the first 14 days of treatment, followed by 3 mg/kg/day until the end of treatment (n=94). Study drug was blinded for the first 14 days of treatment. More than 70 percent of patients in each group had neutropenia at study entry (low levels of important infection-fighting white blood cells) and 93 percent of patients in each group had some form of blood-related cancer.
Objectives of the study included overall response rate at the end of treatment (EOT), survival through 12 weeks and safety and tolerability.
The overall rate of favorable response at EOT was 50 percent in the standard dosing group versus 46 percent in the high loading-dose group. Survival rates at day 14 were 94 percent in the standard dosing group and 91 percent in the 10 mg/kg/day group. At 12 weeks, survival among patients who received 3 mg/kg/day was 72 percent versus 59 percent for those who received the high loading dose for the first 14 days. These differences were not statistically significant.
The most commonly reported adverse events in both treatment groups were hypokalemia (abnormally low potassium levels in the blood), elevated creatinine levels, nausea and elevated liver function values. Statistically significant differences between treatment groups were found in the incidence of nephrotoxicity (elevated creatinine levels) and hypokalemia, which were higher in the 10 mg/kg/day treatment group (31 percent versus 14 percent for nephrotoxicity, p less than 0.01; and 30 percent versus 16 percent for hypokalemia, p less than 0.015). Discontinuations due to adverse events were statistically greater in the 10 mg/kg/day group (36 of 111) versus the 3 mg/kg/day group (23 of 115; p=0.035). Drug discontinuations in both groups were primarily due to hypokalemia, elevated creatinine levels and/or liver function test values. No unusual or previously unreported safety signals were seen in either treatment group.
About Invasive Aspergillosis
Invasive aspergillosis is a life-threatening infection caused by the fungus Aspergillus. Aspergillosis and other invasive fungal infections are a major health risk for patients with low white blood cell counts (neutropenia) due to chemotherapy or underlying disease, as well as for patients receiving stem cell or solid organ transplantations. Ubiquitous fungal organisms such as Aspergillus frequently infect the lungs of immunocompromised patients and can spread throughout the body. Prompt diagnosis and initiation of antifungal therapy are imperative to patient survival.
"Aspergillosis is increasingly common and there is a great need for well-designed, prospective studies to determine the most effective treatment strategies for these potentially deadly infections," said Dr. Cornely. "AmBiload further defines the definitive effectiveness of AmBisome in severely immunocompromised patients."
AmBisome is a liposomal formulation of amphotericin B that is administered by intravenous injection. Amphotericin B, the active ingredient, is incorporated in a single bilayer liposomal delivery system. The approved indications and product labeling vary in each country in which AmBisome is marketed. In the United States, AmBisome is approved for empirical therapy for presumed fungal infection in febrile, neutropenic patients; the treatment of cryptococcal meningitis in HIV infected patients; the treatment of Aspergillus species, Candida species and/or Cryptococcus species infections refractory (non-responsive) to conventional amphotericin B, or in patients where renal impairment or unacceptable toxicity precludes the use of conventional amphotericin B; and the treatment of visceral leishmaniasis. The recommended initial dose for empirical therapy of presumed fungal infections in febrile neutropenia patients varies from 1 to 3 mg/kg/day.
AmBisome has a demonstrated superior safety profile compared to conventional amphotericin B for the empirical treatment of febrile, neutropenic patients. In clinical trials, nephrotoxicity and infusion-related reactions were observed. Side effects associated with the use of AmBisome include, but are not limited to, chills, diarrhea, nausea and vomiting.
Gilead and Astellas Pharma US co-promote AmBisome in the United States for the treatment of life-threatening systemic fungal infections. Astellas has sole marketing rights to AmBisome in Canada. Sumitomo Pharmaceuticals maintains marketing rights to AmBisome in Japan. Gilead retains exclusive marketing rights to AmBisome in the rest of the world.
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.
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. 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, 2004 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.
AmBisome is a registered trademark of Gilead Sciences, Inc.
For more information on Gilead, please call the Gilead Public Affairs Department at 1-800-GILEAD-5 (1-800-445-3235) or visit www.gilead.com.
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