"Pulmonary arterial hypertension is a progressive, life-threatening disease for which new therapies are clearly needed," said Ronald J. Oudiz, MD, Associate Professor of Medicine, UCLA School of Medicine and Director, Liu Center for Pulmonary Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. "The long-term clinical profile observed in these ambrisentan studies is very encouraging."
About the Studies
In the first presentation (Abstract #2307), Dr. Oudiz presented results from an integrated analysis of an ongoing, long-term extension study (ARIES-E) involving patients from the two 12-week Phase III placebo-controlled studies (ARIES-1 and ARIES-2). A total of 383 patients with idiopathic PAH or PAH associated with connective tissue disease, HIV infection, or anorexigen use who received at least one dose of ambrisentan (2.5, 5 or 10 mg once-daily) in ARIES-1, ARIES-2 or ARIES-E were included in the integrated analysis, which reflect data available as of February 2006 (mean exposure = 39 weeks; maximum exposure = 109 weeks).
Improvements in the non placebo-corrected 6-minute walk distance observed during the first 12 weeks of ambrisentan treatment (+37.7 meters) were sus tained for at least 48 weeks (+36.4 meters). Improvements in WHO functional class and Borg dyspnea index were also maintained with long-term ambrisentan treatment. In addition, the one-year probability of survival was 95 percent for patients receiving ambrisentan.
Ambrisentan adverse events were similar in nature to those reported in the previous 12-week placebo-controlled studies. The most common adverse event was peripheral edema which was generally reported to be mild or moderate and did not lead to discontinuation of ambrisentan.
As of October 2006 (mean exposure = 1.4 years; maximum exposure = 2.8 years), 2.1 percent of patients developed liver enzyme (aminotransferase) elevations greater than three times the upper limit of normal, which was similar to the incidence observed for the placebo groups (2.3 percent) in the 12-week ARIES-1 and ARIES-2 studies. One patient required discontinuation of ambrisentan due to liver enzyme abnormalities.
Long-term results from the AMB-222 study (Abstract #2171) were presented by Michael McGoon, MD, Professor of Medicine, Mayo Clinic, Rochester, Minnesota. This open-label study evaluated 36 patients who had previously discontinued the ERAs bosentan (86 percent), sitaxsentan (6 percent), or both (8 percent) due to the development of liver function abnormalities. In this study, patients with idiopathic PAH or PAH associated with connective tissue disease, congenital heart defects, HIV infection, or anorexigen use received once-daily doses of ambrisentan -- 2.5 mg/day for four weeks, 5 mg/day for 20 weeks, and 2.5, 5 or 10 mg/day thereafter -- for up to 18 months. Twenty-five of the 36 patients enrolled were also receiving concomitant sildenafil and/or prostanoid treatment. The primary endpoint of the study was the incidence of liver function abnormalities during 12 weeks of therapy that resulted in discontinuation of drug.
No patients had liver function abnormalities that required discontinuation of a mbrisentan during the 12-week primary endpoint period. Of the 36 patients evaluated, two patients discontinued due to adverse events not related to liver toxicity. As of October 2006 (mean exposure = 1.1 years, maximum duration 1.4 years), one patient had developed a transient liver function abnormality that was greater than three times the upper limit of normal and this patient continued receiving treatment with ambrisentan. The long-term adverse event profile appeared similar to results from previous ambrisentan clinical studies and included peripheral edema, headache, dyspnea and flushing.
"Endothelin receptor antagonism has well-established clinical benefits in patients with PAH, but liver toxicity, which frequently leads to discontinuation of treatment, has limited the usefulness of these drugs in some patients," said Dr. McGoon. "The results of this study support the potential of ambrisentan in newly diagnosed patients with PAH, as well as patients who have failed other ERA therapies due to liver function abnormalities."
"PAH is a chronic disease and, as such, we recognize the importance of evaluating the long-term efficacy and safety profile of ambrisentan," said Michael J. Gerber, MD, Senior Vice President, Clinical Research at Gilead. "We will continue to work with the clinical investigators and follow patients from each of these studies so we can better understand the benefits and risks of ambrisentan with long-term treatment."
In addition to these long-term ambrisentan data presentations, two posters describing an integrated analysis of 12-week ARIES-1 and ARIES-2 data are also being presented at ATS. The first poster (Abstract #3192) titled "Ambrisentan Therapy for Pulmonary Arterial Hypertension: An Integrated Analysis of the ARIES-1 and ARIES-2 Studies" was presented today by Nazzareno Galie, MD, Professor of Cardiology at the University of Bologna in Bologna, Italy. The second poster (Abstract #2873) titled "Ambrisentan Improves E xercise Capacity and Dyspnea in WHO Functional Class II and Class III Patients with Pulmonary Arterial Hypertension" will be presented on Wednesday, May 23 by Horst Olschewski, MD, Professor of Medicine in the Division of Pulmonology at the Medical University of Graz in Graz, Austria.
Ambrisentan is a non-sulfonamide, propanoic acid-class, endothelin receptor antagonist that is selective for the endothelin type-A (ETA) receptor. Activation of the ETA receptor by endothelin, a small peptide hormone, leads to vasoconstriction (narrowing of blood vessels) and cell proliferation. PAH is associated with elevated endothelin blood levels. Ambrisentan has been granted orphan drug designation for the treatment of PAH in both the United States and European Union.
The U.S. Food and Drug Administration (FDA) recently accepted for filing and granted a Priority Review for Gilead's New Drug Application (NDA) for marketing approval of ambrisentan (5 mg and 10 mg) for the once-daily treatment of PAH. The FDA has established a target review date, under the Prescription Drug User Fee Act (PDUFA), of June 18, 2007.
As an investigational compound, ambrisentan has not yet been determined safe or efficacious in humans.
GlaxoSmithKline holds rights to commercialize ambrisentan for PAH in territories outside of the United States. A Marketing Authorisation Application (MAA) for ambrisentan was filed with the European Medicines Agency (EMEA) earlier this year.
About Pulmonary Arterial Hypertension
PAH is a debilitating disease characterized by constriction of the blood vessels in the lungs leading to high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated. Patients with PAH suffer from shortness of breath as the heart struggles to pump against these high pressures, causing such patients to ultimately die of heart failure. PAH can occur with no kno wn underlying cause, or it can occur secondary to diseases such as connective tissue disease, congenital heart defects, cirrhosis of the liver and HIV infection. PAH afflicts approximately 200,000 patients worldwide.
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. For more information on Gilead Sciences, please visit the company's website at www.gilead.com or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
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 risks related to Gilead's ability to successfully commercialize ambrisentan for PAH. For example, the FDA may not approve ambrisentan for the treatment of PAH in the United States, and marketing approval, if granted, may have significant limitations on its use. In addition, future discussions with the FDA may impact the amount of data needed and timelines for review, which may differ materially from Gilead's current projections. Further, safety and efficacy data from additional clinical studies may not warrant further development of this compound and completing our clinical studies may take longer or cost more than expected. 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 Gilead's Annual Report on Form 10-K for the year ended December 31, 2006 and its Report on Form 10-Q for the fi rst quarter of 2007, 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.
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