PRINCETON, N.J., March 8 /PRNewswire-FirstCall/ -- BARACLUDE(TM) (entecavir) demonstrated greater benefit in treating nucleoside-naive chronic hepatitis B patients compared to lamivudine, the most commonly used antiviral therapy for treatment of chronic hepatitis B worldwide, according to two studies published in The New England Journal of Medicine. BARACLUDE, discovered and developed by Bristol-Myers Squibb Company , is a prescription medicine indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
The multinational, Phase III clinical trials found that BARACLUDE treatment resulted in significantly greater improvements in liver histology and reductions of HBV DNA to undetectable levels (defined as less than 300 copies/mL) compared to treatment with lamivudine in both nucleoside-naive hepatitis B e-antigen (HBeAg) positive and HBeAg negative chronic hepatitis B patients at 48 weeks. In both studies, no evidence of virologic rebounds due to resistance to BARACLUDE was detected, and safety was comparable between the two treatments.
“Hepatitis B is a highly infectious disease and remains a serious global public health issue, with approximately 400 million people chronically infected worldwide despite the availability of a vaccine,” said Ting-Tsung Chang, M.D., a Phase III study investigator and professor of medicine at National Cheng Kung University Medical College in Tainan, Taiwan. “Currently, only a small percentage of diagnosed chronic hepatitis B patients worldwide are treated with prescription therapy. It is important for physicians and patients to understand the benefits of taking an active approach to managing chronic hepatitis B when prescription therapy is appropriate.”
“These BARACLUDE studies were the first large Phase III clinical trials to investigate the activity of one chronic hepatitis B treatment versus another,” said C. L. Lai, professor of Medicine and Hepatology; Chief, Division of Gastroenterology and Hepatology, Department of Medicine, the University of Hong Kong, Hong Kong SAR, China. “More than 1,600 patients worldwide participated in the Phase III program for BARACLUDE, making it one of the most robust clinical trial programs for a chronic hepatitis B treatment to date.”
BARACLUDE Compared to Lamivudine for Treatment of Nucleoside-Naive, HBeAg- Positive Chronic Hepatitis B Patients at 48 Weeks
A multinational, double-blind, Phase III clinical trial evaluated 715 nucleoside-naive, HBeAg-positive chronic hepatitis B patients who were randomized to receive 0.5 mg of BARACLUDE once daily (n=357) or lamivudine 100 mg once daily (n=358) for at least 52 weeks.
Histologic examination of the liver remains the definitive method of assessing disease progression. At 48 weeks, histologic improvement was observed in 72 percent of BARACLUDE patients compared to 62 percent of lamivudine patients (p=0.009) using the primary efficacy endpoint of a reduction in Knodell necroinflammatory score by at least two points with no worsening of fibrosis. Treatment with both BARACLUDE and lamivudine resulted in reductions in fibrosis as measured by the Ishak fibrosis score (39 percent and 35 percent of patients, respectively; p=0.41). Normalization of ALT levels was observed in more patients receiving BARACLUDE (68 percent) compared to patients receiving lamivudine (60 percent) (p=0.02).
According to the study, 67 percent of patients taking BARACLUDE through 48 weeks experienced viral load reductions to undetectable levels (less than 300 copies/mL) compared to 36 percent of lamivudine patients (p<0.001) as measured by the polymerase chain reaction (PCR) assay. Additionally, BARACLUDE patients experienced a 6.9 log10 copies/mL mean reduction in HBV DNA from baseline, which was significantly greater than lamivudine patients who experienced a 5.4 log10 copies/mL reduction (p<0.001).
There was no significant difference between BARACLUDE and lamivudine among patients experiencing HBeAg loss (22 and 20 percent respectively; p=0.45) or seroconversion (21 and 18 percent respectively; p=0.33).
By 48 weeks, there was no evidence of viral mutations leading to resistance to BARACLUDE among the 339 patients evaluated.
Safety was comparable between the two groups, with similar frequency of on-treatment adverse events. The most frequent adverse events included headache, upper respiratory tract infection, nasopharyngitis, cough, pyrexia, upper abdominal pain, fatigue and diarrhea, which were generally of mild to moderate severity. The frequencies of serious adverse events were also comparable in the two treatment groups (8 percent versus 8 percent). Fewer discontinuations due to adverse events occurred in the BARACLUDE treatment group compared to the lamivudine group (one patient versus nine patients, respectively). On-treatment ALT flares, defined as elevations in aminotransferase levels to more than twice the reference level and to more than 10 times the upper limit of normal, were observed less frequently on treatment among patients treated with BARACLUDE (3 percent) compared to lamivudine (6 percent). Four of the nine patients in the lamivudine group and the single patient in the BARACLUDE group with on-treatment ALT flares discontinued treatment. Post-treatment ALT flares occurred in 2 of the 134 patients (1 percent) in the BARACLUDE group and 9 of 129 patients (7 percent) in the lamivudine group who underwent post-treatment follow-up.
BARACLUDE Compared to Lamivudine for Treatment of Nucleoside-Naive, HBeAg- Negative Chronic Hepatitis B Patients at 48 Weeks
The clinical profile of HBeAg-negative chronic hepatitis B differs from that of HBeAg-positive disease in that patients are typically older, serum HBV DNA levels are usually lower, and liver disease may fluctuate. Patients with HBeAg-negative chronic hepatitis B may also have more advanced liver disease, and the likelihood of spontaneous remission is very low.
As part of a multinational, double-blind, Phase III clinical trial, 648 nucleoside-naive patients with HBeAg-negative chronic hepatitis B were randomized to receive BARACLUDE 0.5 mg once daily (n=331) or lamivudine 100 mg once daily (n=317) for at least 52 weeks.
After 48 weeks of treatment, 70 percent of patients treated with BARACLUDE demonstrated histologic improvement compared to 61 percent of patients treated with lamivudine (p=0.01) using the primary efficacy endpoint defined as a reduction in Knodell necroinflammatory score by at least two points with no worsening of fibrosis. Both BARACLUDE and lamivudine therapies resulted in reductions in fibrosis, as measured by Ishak fibrosis scores, in 36 percent and 38 percent of patients, respectively (p=0.65). Significantly more patients treated with BARACLUDE than lamivudine achieved ALT normalization at 48 weeks (78 percent versus 71 percent; p=0.04).
90 percent of patients taking BARACLUDE experienced reductions in HBV DNA to undetectable levels through 48 weeks compared to 72 percent of patients taking lamivudine (p=0.001). Additionally, BARACLUDE patients experienced a significant 5.0 log10 copies/mL mean reduction in HBV DNA from baseline, compared to a 4.5 log10 copies/mL reduction for lamivudine patients (p<0.001). There was no evidence of viral mutations leading to resistance to BARACLUDE seen in patients experiencing virologic rebound or in 211 evaluated patients after 48 weeks of treatment.
Safety was comparable between the two treatment groups, with similar frequency of on-treatment adverse events. The most frequent adverse events on-treatment were headache, upper respiratory tract infection, upper abdominal pain, influenza, nasopharyngitis, dyspepsia, fatigue, back pain, arthralgia, diarrhea, insomnia, cough, nausea and myalgia, which were generally of mild to moderate severity. Frequencies of serious adverse events were also comparable between the two treatment groups, with fewer discontinuations due to adverse events occurring in the BARACLUDE group (six) compared to the lamivudine group (nine). ALT flares during treatment, defined as elevations to more than twice the reference level and to more than 10 times the upper limit of normal, were observed in three patients (<1 percent) in the BARACLUDE group and five patients (2 percent) in the lamivudine group. No patient discontinued therapy because of an ALT flare. Of the 297 patients in the entecavir group and 263 patients in the lamivudine group who entered post-treatment follow-up, post- treatment ALT flares occurred in 23 (8 percent) and 29 (11 percent), respectively.
About BARACLUDE
BARACLUDE is a nucleoside analog, approved for marketing in the United States by the U.S. Food and Drug Administration (FDA) on March 29, 2005. In addition to the United States, BARACLUDE has been approved in Argentina, Brazil, China, Indonesia, Macau, Mexico, the Philippines and Singapore. Bristol-Myers Squibb has submitted marketing applications for entecavir in other regions and countries around the world, including the European Union, Australia, Canada, Hong Kong, Israel, Japan, Korea, Malaysia, Peru, Taiwan, Thailand, Turkey, Uruguay and Russia.
In the United States, Bristol-Myers Squibb offers a Patient Assistance Program (PAP) designed to provide access to BARACLUDE(TM) (entecavir) for patients who meet certain financial criteria and who are not eligible for Medicare or Medicaid and lack other prescription coverage or whose plans’ formularies do not cover BARACLUDE. Additional information on the PAP is available by calling 800-272-4878.
Important Information About BARACLUDE(TM) (entecavir) Tablets
BARACLUDE is a prescription medicine used for chronic infection with hepatitis B virus (HBV) in adults where the virus is multiplying and damaging the liver. BARACLUDE does not cure HBV or stop the spread of HBV to others. People should not take BARACLUDE if they are allergic to it or any of its ingredients. BARACLUDE has not been studied in children and is not recommended for anyone less than 16 years of age.
People taking BARACLUDE should tell their healthcare provider right away if they feel very weak or tired, have unusual muscle pain, have trouble breathing, have stomach pain with nausea and vomiting, feel cold -- especially in their arms and legs, feel dizzy or lightheaded, or have a fast or irregular heartbeat, as they may be signs of a serious condition called lactic acidosis (buildup of an acid in the blood). Lactic acidosis is a medical emergency and must be treated in the hospital. Some people who have taken medicines like BARACLUDE have developed serious liver problems called hepatotoxicity. This may occur with liver enlargement (hepatomegaly) and fat in the liver (steatosis). People should call their healthcare provider right away if they get any of the following signs of liver problems: yellowing (jaundice) of the skin or the white part of the eyes, darkening of the urine, lightening in the color of bowel movements (stools), not feeling like eating food for several days or longer, feeling sick to the stomach (nausea), or having lower stomach pain. Lactic acidosis and hepatotoxicity have happened in some people taking medicines like BARACLUDE.
In some people, hepatitis B symptoms may get worse or become very serious when they stop taking BARACLUDE. People should not stop BARACLUDE without talking to their healthcare provider. Healthcare providers will need to follow their patients and do blood tests to check the liver when BARACLUDE is stopped. People should tell their healthcare provider if they have or develop kidney problems because their healthcare provider may want to do tests to see if a lower dose is needed.Because BARACLUDE is removed from the body through the kidneys, a lower dose may be required. Healthcare providers may want to perform tests to determine whether a patient needs a lower dose.
It is not known if BARACLUDE is safe to use during pregnancy. It is not known if BARACLUDE helps to prevent a pregnant mother from passing HBV to her baby. A pregnant woman and her healthcare provider will need to decide if BARACLUDE is right for her. A woman should not breastfeed if she is taking BARACLUDE.
People should discuss with their healthcare provider all prescription and non-prescription medicines, vitamins, herbal supplements, and other health preparations they are taking or plan to take. BARACLUDE may interact with medicines that leave the body through the kidneys. The most common side effects of BARACLUDE in clinical studies were headache, tiredness, dizziness, and nausea. This list of side effects is not complete at this time because BARACLUDE is still under study. People should report any new or continuing symptom to their healthcare provider. BARACLUDE should be taken once daily on an empty stomach (at least two hours after a meal and two hours before the next meal). To learn more about BARACLUDE (entecavir) and for Full Prescribing Information, including boxed WARNINGS, please visit www.bms.com.
Bristol-Myers Squibb is a global pharmaceutical and related health care products company whose mission is to extend and enhance human life. Visit Bristol-Myers Squibb on the World Wide Web at www.bms.com.
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 BARACLUDE 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, 2004 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.
BARACLUDE(TM) is a trademark of Bristol-Myers Squibb Company.
Full prescribing information for BARACLUDE is available at www.bms.com.
Bristol-Myers Squibb Company
CONTACT: Kathy Baum, +1-609-252-4227, or Ken Dominski, +1-609-252-5251,both of Bristol-Myers Squibb
Web site: http://www.bms.com/
