| Investigational Hepatitis B Agent Entecavir Demonstrated Statistically Significant Improvement Over Lamivudine In Chronically Infected Hepatitis B Patients
BOSTON, MASSACHUSETTS (October 29, 2004) -- According to data to be presented at the 55th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), the Bristol-Myers Squibb Company (NYSE: BMY) investigational chronic hepatitis B compound entecavir demonstrated significantly greater improvements in both liver histology and reductions of hepatitis B virus (HBV) DNA levels compared to lamivudine in two studies investigating both nucleoside-naïve, e-antigen-negative (HBeAg-) chronic hepatitis B patients (Study AI463-027) and e-antigen-positive (HBeAg+) chronic hepatitis B patients who had developed resistance to lamivudine (Study AI463-026) -- both multinational, double-blind, Phase III clinical trials.
Study AI463-027
Study AI463-027 evaluated 638 nucleoside-naïve patients with HBeAg negative chronic hepatitis B, who received entecavir 0.5 mg once daily (n=325) or lamivudine 100 mg once daily (n=313) for at least 52 weeks. HBeAg negative chronic hepatitis B is characterized by a progressive course of severe liver damage with a poor long-term prognosis and frequent progression to cirrhosis and liver cancer. After 48 weeks of treatment, 70 percent of patients treated with entecavir demonstrated histologic improvements compared to 61 percent of patients treated with lamivudine using the Knodell necroinflammatory score analysis (primary endpoint of the study, 'non-completer=failure' [NC=F] statistical analysis). The 48-week results were statistically significant (p=0.014); 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, NC=F statistical analysis.
Patients taking entecavir experienced a significant mean reduction in HBV DNA (-5.20 log10 copies/mL) from baseline (a secondary endpoint of the study, measured by a common assay -- polymerase chain reaction or PCR) compared to lamivudine (-4.66 log10 copies/mL) (p-value less than or equal to 0.0001). Additionally, at Week 48, undetectable HBV DNA (less than 400 copies/mL; a secondary endpoint of the study) was achieved in 91 percent (n=325) of people in the entecavir arm compared to 73 percent (n=313) of people in the lamivudine arm (p-value less than 0.0001). There was no significant difference in the proportion of patients with alanine aminotransferase (ALT) level normalization (a secondary endpoint of the study). Elevated ALT levels can indicate liver inflammation and liver disease progression.
Safety was comparable between the treatment groups, with similar incidence of serious adverse events (6 percent with entecavir, 8 percent with lamivudine) and total adverse events (75 percent with entecavir, 79 percent with lamivudine). The most frequent adverse events (greater than or equal to 10 percent of patients on treatment) in this study included headache (15 percent for entecavir vs. 17 percent for lamivudine) and upper respiratory infection (13 percent and 14 percent, respectively).
Discontinuations due to adverse events were observed in 2 percent of patients in the entecavir group compared to 3 percent in the lamivudine group. ALT level elevations were observed in 3 percent of patients on treatment receiving entecavir compared to 5 percent on treatment receiving lamivudine and in 14 percent versus 22 percent of patients off treatment, respectively.
"In this study, a higher proportion of hepatitis B e-antigen negative patients receiving entecavir experienced improvements in liver histology and viral suppression compared to lamivudine," said Dr. Daniel Shouval, a lead AI463-027 investigator and director of the Hadassah University Hospital's liver unit in Jerusalem, Israel.
Study AI463-026
Study AI463-026 evaluated 286 patients with lamivudine-refractory e-antigen positive chronic hepatitis B (HBeAg+) who were either switched to receive entecavir 1.0 mg once daily (n=141) or continued to receive lamivudine 100 mg once daily (n=145) for 48 weeks. As part of the study, lamivudine-refractory patients were defined as patients who had persistently detectable HBV DNA levels (as measured by branched chain DNA assay) for 36 weeks or longer while receiving lamivudine therapy; patients who experienced breakthrough viremia while receiving lamivudine; patients who experienced a recurrence of HBV viremia after lamivudine discontinuation that persisted when lamivudine was resumed; or patients with documented lamivudine resistance and HBV viremia while receiving lamivudine.
After 48 weeks of treatment in the study, patients who switched to entecavir showed significantly higher improvements in liver histology and viral load suppression compared to patients who continued taking lamivudine. Histologic improvement (co-primary study endpoint) was observed in 55 percent of patients taking entecavir compared to 28 percent of patients receiving lamivudine using the Knodell necroinflammatory score analysis (p-value less than 0.0001). In addition, 34 percent of patients treated with entecavir showed an improvement in their Ishak fibrosis score (secondary study endpoint) compared to 16 percent of patients taking lamivudine (p=0.0019). At Week 48, significantly more patients taking entecavir (55 percent) reached the study's composite endpoint, as defined by undetectable serum HBV DNA (measured by branched chain DNA assay) and normalization of serum ALT (less than 1.25 times the upper limit of normal [ULN]), compared to patients who continued taking lamivudine (4 percent) (p-value less than 0.0001).
Patients treated with entecavir experienced a significant mean reduction in HBV DNA (-5.14 log10 copies/mL) from baseline (a secondary endpoint of the study, measured by a common assay -- polymerase chain reaction or PCR) compared to patients who continued treatment with lamivudine (-0.48 log10 copies/mL) (p-value less than 0.0001). Additionally, through 48 weeks of treatment, 21 percent of people in the entecavir arm had HBV DNA less than 400 copies/mL compared to 1 percent of people in the lamivudine arm (p-value less than 0.0001). Liver function test improvement (ALT normalization) at Week 48 occurred more frequently in patients taking entecavir (75 percent) versus lamivudine (23 percent) (p-value less than 0.0001).
Significantly more patients treated with entecavir (n=141), when compared to lamivudine (n=145), achieved loss of HBeAg (10 percent vs. 3 percent; p=0.028) and complete virologic response (9 percent vs. 1 percent; p=0.0008); however, seroconversion (8 percent vs. 3 percent; p=0.06) did not reach statistical significance. Complete virologic response was defined as HBV DNA less than 0.7 MEq/mL by branched chain DNA and loss of HBeAg.
Safety was comparable between the treatment groups, with similar incidence of serious adverse events (10 percent with entecavir, 8 percent with lamivudine) and total adverse events (85 percent with entecavir, 81 percent with lamivudine). The most frequent adverse events (greater than or equal to 10 percent of patients on treatment) in this study included: upper respiratory infection (18 percent for entecavir vs. 11 percent for lamivudine), headache (17 percent, 17 percent), fatigue (13 percent, 11 percent), cough (12 percent, 10 percent), upper abdominal pain (9 percent, 13 percent), nausea (8 percent, 10 percent) and nasopharyngitis (9 percent, 10 percent).
Discontinuations due to adverse events were observed in 1 percent of patients in the entecavir group compared to 7 percent in the lamivudine group. Sixteen lamivudine-refractory patients continuing on lamivudine experienced ALT flares compared to one patient taking entecavir.
Entecavir, currently in Phase III clinical development, 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 three extensive Phase III clinical trials investigating more than 1,600 patients on five continents.
More than 2 billion people worldwide have been infected with the hepatitis B virus; approximately 350-400 million of these people are chronically infected.1 Those infected are at high risk of death from cirrhosis of the liver and liver cancer.1 Primary liver cancer, or hepatocellular carcinoma (HCC), is among the top three causes of cancer deaths in many Asian countries.2 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.2
Bristol-Myers Squibb is a global pharmaceutical and related health care products company whose mission is to extend and enhance human life.
For more information, contacts: David M. Rosen, Bristol-Myers Squibb, 609-252-5675, 866-308-4484 (Pager), [email protected]
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 World Health Organization. "Hepatitis B Fact Sheet." Available at http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed Sept. 28, 2004.
2 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.
Article Date: 10/29/2004
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发表于 2004-11-3 00:16
