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Bristol-Myers Squibb Company (BMY) Use Of Investigational Agent Entecavir Demonstrated Statistically Significant Improvement In Liver Histology And Viral Suppression Compared To Lamivudine In Chronically Infected Hepatitis B E-Antigen (HBeAg) Positive Patients


10/19/2005 5:12:00 PM

BOSTON, Oct. 29 /PRNewswire/ -- Data to be presented at the 55th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) demonstrated that treatment with the Bristol-Myers Squibb Company investigational chronic hepatitis B antiviral agent entecavir was associated with significantly greater improvements in liver histology (primary study endpoint), and reductions of hepatitis B virus (HBV) DNA levels as well as normalization of alanine aminotransferase (ALT) levels (secondary study endpoint) compared to lamivudine in nucleoside-naïve, chronic hepatitis B e-antigen (HBeAg) positive patients in a multinational, double-blind, Phase III clinical trial (Study AI463-022). Hepatitis B e-antigen (HBeAg) positive hepatitis B virus is a wild type strain of HBV and is responsible for deterioration of liver function, cirrhosis and liver cancer in 25 to 40 percent of patients who are chronically infected.(1)

The study evaluated 709 nucleoside-naive HBeAg positive chronic hepatitis B patients randomized to receive 0.5 mg of entecavir once daily (n=354) or lamivudine 100 mg once daily (n=355) for at least 52 weeks. At Week 48, histologic improvement was observed in 72 percent of patients taking entecavir compared to 62 percent of patients receiving lamivudine using the Knodell necroinflammatory score analysis. The 48-week results were statistically significant (p=0.0085); however, there was no significant difference between the two treatment arms in the secondary endpoint measure of liver histology using the Ishak Fibrosis Score analysis.

Patients taking entecavir experienced a significant mean reduction in HBV DNA (-6.98 log10 copies/mL) from baseline (a secondary endpoint of the study, measured by a common assay-polymerase chain reaction or PCR) compared to lamivudine (-5.46 log10 copies/mL) (p-value less than 0.0001). Additionally, through 48 weeks of treatment, 69 percent (n=354) of people in the entecavir arm had HBV DNA less than 400 copies/mL (a secondary endpoint of the study) compared to 38 percent (n=355) of people in the lamivudine arm (p-value less than 0.0001).

Normalization of ALT levels (a secondary endpoint of the study) was observed more frequently in patients receiving entecavir (78 percent) compared to patients receiving lamivudine (70 percent) (p=0.014). Elevated ALT levels can be a sign of liver inflammation and liver disease progression. There were no significant differences between entecavir and lamivudine among patients with loss of HBeAg (22 percent, 20 percent) or seroconversion (21 percent, 18 percent), both secondary endpoints.

Safety was comparable between the treatment groups, with similar incidence of serious adverse events (7 percent for both treatment groups) and total adverse events (85 percent with entecavir, 83 percent with lamivudine). The most frequent adverse events (occurring at a rate of greater than or equal to 10 percent) in this study included: headache (23 percent for entecavir vs. 21 percent for lamivudine), upper respiratory infection (20 percent, 17 percent), cough (15 percent, 12 percent), nasopharyngitis (14 percent, 14 percent), upper abdominal pain (10 percent, 10 percent), fatigue (10 percent, 10 percent), and fever (10 percent, 9 percent).

Fewer discontinuations due to adverse events were observed in the entecavir group when compared to lamivudine (less than 1 percent vs. 3 percent), and fewer ALT level elevations were observed with entecavir compared to lamivudine both on-treatment (12 vs. 20 patients) and off-treatment (2 vs. 8 patients).

"Preventing the progression of liver disease is the primary objective when treating chronic hepatitis B patients," said Dr. Robert Gish, an AI463-022 study investigator and medical director of the California Pacific Medical Center's liver transplant program in San Francisco. "Phase III data for entecavir have demonstrated that hepatitis B e-antigen positive patients receiving entecavir experienced statistically significant improvements in liver histology and viral suppression compared to lamivudine."

Entecavir, currently in Phase III clinical development, and discovered at Bristol-Myers Squibb, is an investigational oral nucleoside analogue discovered at Bristol-Myers Squibb which is a selective inhibitor of the hepatitis B virus. Bristol-Myers Squibb recently submitted a new drug application (NDA) for entecavir to the U.S. Food and Drug Administration (FDA) and a marketing authorization application (MAA) for entecavir with the European Medicines Evaluation Agency (EMEA). The applications include data from Phase III clinical trials investigating the use of entecavir in more than 1,600 patients on five continents.

More than two billion people worldwide have been infected with hepatitis B virus and approximately 350-400 million of these people are chronically infected.(2) Those infected are at high risk of death from cirrhosis of the liver and liver cancer.(2) Primary liver cancer, or hepatocellular carcinoma (HCC), is among the top three causes of cancer deaths in many Asian countries.(3) According to the World Health Organization, more than half a million people worldwide die each year from primary liver cancer, and up to 80 percent of liver cancers are due to hepatitis B.(3)

Bristol-Myers Squibb is a global pharmaceutical and related health care products company whose mission is to extend and enhance human life.

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. There can be no guarantee that entecavir 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, 2003 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.

References: (1) Kao, JH, Chen, DS. The Natural History of Hepatitis B Virus Infection. In HBV Human Virus Guide, edited by S. Locarnini, C.L. Lai. International Medical Press, London, 2002. (2) World Health Organization. "Hepatitis B Fact Sheet". Available at http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed Sept. 28, 2004 (3) Hepatitis B Foundation. "Liver Cancer". Available at http://www.hepb.org/PrinterFriendly.aspx?PageID=256&Locale=en-US. Accessed Sept. 30, 2004.

Bristol-Myers Squibb does not endorse and is not responsible for the content of any of the listed resources.

Bristol-Myers Squibb Company

CONTACT: David M. Rosen of Bristol-Myers Squibb, Phone: +1-609-252-5675,Pager: 1-866-308-4484, or Email: david.m.rosen@bms.com



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