BARACLUDE® (entecavir) Demonstrated Greater Antiviral Efficacy Compared to Adefovir in New Study of Chronic Hepatitis B Patients with Evidence of Decompensated Cirrhosis

Bristol-Myers Squibb (NYSE: BMY) today announced 48-week data from an ongoing study (ETV-048) of chronic hepatitis B patients with decompensated cirrhosis, in which BARACLUDE demonstrated greater viral suppression compared to adefovir. The new BARACLUDE data were presented today at the 60th Annual Meeting of the American Association for the Study of Liver Diseases.

Decompensated cirrhosis is characterized by severe scarring of the liver caused by chronic liver inflammation, including inflammation associated with chronic hepatitis B infection. It is estimated that 15 to 25 percent of chronic hepatitis B patients die from complications of liver disease.¹ Currently, the median survival rate in decompensated patients is two to three years, with only 28 percent of patients surviving for more than five years.^2,3 The treatment of chronic hepatitis B patients with decompensated cirrhosis remains an area of unmet medical need, and these patients often require liver transplant.

"This study represents an important first step in addressing an unmet medical need, as this is one of the first comparative studies to evaluate the safety and efficacy of antiviral therapy in this difficult-to-treat patient population,” said Professor Hugo Cheinquer, ETV-048 study investigator and associate professor of gastroenterology and hepatology, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil. "Chronic hepatitis B is a lifelong disease and these data suggest that treatment with BARACLUDE may offer chronic hepatitis B patients with decompensated cirrhosis a treatment option.”

Study Results through Week 48

The primary study endpoint of ETV-048 was the mean change from baseline HBV DNA at Week 24, analyzed by linear regression and adjusted for baseline HBV DNA and lamivudine resistance status. The study successfully met its primary objective; at Week 24, BARACLUDE achieved a greater reduction in viral load than adefovir: -4.48 (0.200) versus -3.40 (0.251) log copies/mL, respectively (p < 0.0001).

A statistically significant difference was observed in the proportion of patients achieving undetectable viral load [HBV DNA <300 copies/mL as measured by polymerase chain reaction (PCR)] and ALT normalization. At 24 weeks, 49 percent (49/100) of patients treated with BARACLUDE^® (entecavir) achieved an undetectable viral load, compared with 16 percent (15/91) of patients who received adefovir; at 48 weeks, 57 percent (57/100) of patients on BARACLUDE achieved an undetectable viral load, compared with 20 percent (18/91) of patients on adefovir (p< 0.0001). Also, among patients with baseline abnormal ALT, a higher proportion of BARACLUDE-treated patients achieved ALT normalization at Weeks 24 and 48 [59 percent (46/78) and 63 percent (49/78) respectively, compared with 39 percent (28/71) and 46 percent (33/71) of adefovir-treated patients].

Additionally, of the 100 patients treated with BARACLUDE, 66 percent had an improvement or no worsening of the Child-Pugh Score (which assesses severity of hepatic decompensation), with 32 percent of patients having achieved a = 2-point reduction in Child-Pugh score at Week 24; these rates were 61 percent and 35 percent, respectively, at Week 48. Findings at Weeks 24 and 48 were comparable for patients receiving adefovir; 71 percent saw an improvement or no worsening of the Child-Pugh Score and 24 percent achieved a = 2-point reduction in Child-Pugh score at Week 24; these rates were 67 percent and 27 percent, respectively, at Week 48. Patients treated with BARACLUDE also experienced an improvement of the Model for End-Stage Liver Disease (MELD) Score (another scoring system that assesses severity of hepatic decompensation). The change from baseline for patients treated with BARACLUDE was a decrease of 2.6 points compared with 1.7 points for patients treated with adefovir at Week 48.

The overall safety profile was comparable across the two treatments. As might be expected in this patient population, the overall incidence of adverse events was high with 89 percent (91/102) for the BARACLUDE arm and 97 percent (86/89) for the adefovir arm. Serious adverse events occurred in 69 percent (70/102) and 66 percent (59/89) of BARACLUDE- and adefovir-treated patients, respectively. Rates for death and hepatocellular carcinoma (HCC) were comparable. Overall, 23 percent (23/102) of BARACLUDE-treated patients died compared with 33 (29/89) percent of adefovir-treated patients. HCC occurred in 12 percent (12/102) of the BARACLUDE^® (entecavir) arm compared with 20 (18/89) percent of the adefovir arm. Renal function was monitored for all patients. Increases in serum creatinine levels of =0.5 mg/dL from baseline were observed in 17 percent (17/102) of BARACLUDE-treated and 24 percent (21/89) of adefovir-treated patients.

About Study ETV-048

Study ETV-048 is a randomized, open-label, comparative Phase IIIb study of BARACLUDE compared to adefovir in treatment-naïve and lamivudine-experienced patients with chronic hepatitis B infection and decompensated cirrhosis (Child-Pugh score = 7). The 195 adult patients (191 treated) were HBeAg-positive or HBeAg-negative, and nucleos(t)ide-naïve or lamivudine pre-treated.

Patients were randomized to receive BARACLUDE 1 mg or adefovir 10 mg daily and were treated for a minimum of 96 weeks. Baseline patient populations were comparable in the two treatment arms. Patients had a mean MELD score of 17 and 15, respectively, in the BARACLUDE and adefovir treatment groups. Approximately one third of patients were previously exposed and resistant to lamivudine.

The primary study endpoint was the mean change from baseline HBV DNA at Week 24, analyzed by linear regression and adjusted for baseline HBV DNA and lamivudine resistance status.

Secondary study endpoints specific to measuring improvement in cirrhosis included the MELD Score, an exam which scores patients on the severity of chronic liver disease, and the Child-Pugh Score (greater than or equal to a two-point decrease), which were evaluated at baseline, Week 24 and Week 48.

About Chronic Hepatitis B

Chronic hepatitis B is a serious global health issue. Worldwide, more than 2 billion people have been in contact with the hepatitis B virus and approximately 350 million people are chronically infected. ⁴

INDICATION and IMPORTANT SAFETY INFORMATION about BARACLUDE^® (entecavir) Tablets:

INDICATION:

BARACLUDE is 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.

This indication is based on histologic, virologic, biochemical, and serologic responses in nucleoside-naïve and lamivudine-resistant adult patients with HBeAg-positive or HBeAg-negative chronic HBV infection with compensated liver disease. Limited data are available in adult patients with HIV/HBV co-infection who have received prior lamivudine therapy. BARACLUDE has not been evaluated in patients with decompensated liver disease.

IMPORTANT SAFETY INFORMATION:

• Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including BARACLUDE. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
• Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if BARACLUDE is used to treat chronic HBV infection in patients with HIV infection that is not being treated. Therapy with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART). Before initiating BARACLUDE therapy, HIV antibody testing should be offered to all patients. BARACLUDE has not been studied as a treatment for HIV infection and is not recommended for this use.
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals.
• There are no adequate and well-controlled studies of BARACLUDE^® (entecavir) in pregnant women. BARACLUDE should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits. There are no studies on the effect of BARACLUDE on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV. Risks and benefits should be considered when deciding whether to discontinue breastfeeding or discontinue BARACLUDE in nursing women.
• Safety and effectiveness of BARACLUDE in pediatric patients below the age of 16 years have not been established.
• Dosage adjustment of BARACLUDE is recommended for patients with a creatinine clearance <50 mL/min, including those on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).
• The safety and efficacy of BARACLUDE in liver transplant recipients are unknown. Renal function must be carefully monitored both before and during treatment with BARACLUDE in a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus.
• Since entecavir is primarily eliminated by the kidneys, coadministration of BARACLUDE with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug.
• Patients should be advised that treatment with BARACLUDE has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.
• The most common adverse events of moderate to severe intensity among patients treated with BARACLUDE^® (entecavir) in clinical trials included: headache (4%), fatigue (3%), diarrhea (1%), and dyspepsia (1%).

The recommended dose of BARACLUDE is 0.5 mg once daily in nucleoside-naïve adults, and 1 mg once daily in lamivudine-refractory adults. BARACLUDE should be administered on an empty stomach (at least 2 hours after a meal and at least 2 hours before the next meal). The optimal duration of treatment with BARACLUDE for patients with chronic HBV infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.

Please see Full Prescribing Information, including boxed WARNINGS. For more information, please visit www.BARACLUDE.com.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company committed to discovering, developing and delivering innovative medicines that help patients prevail over serious diseases. For more information, please visit www.bms.com.

BARACLUDE^® (entecavir) is a registered trademark of Bristol-Myers Squibb.

References

1. NHS Choices. Complications of hepatitis B. Available at http://www.nhs.uk/Conditions/Hepatitis-B/Pages/Complications.aspx. Accessed 15 September 2009

2. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J. Hepatol. 2006; 44: 217–31. 7 Ginés P, Quintero E, Arroyo V et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology 1987; 7: 122–8.

3. Fattovich G, Pantalena M, Zagni I et al. Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients. Am. J. Gastroenterol. 2002; 97: 2886–95.

4. World Health Organization Web site. Fact sheet N°204. http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed August 28, 2009.