Decompensated cirrhosis: BARACLUDE® (entecavir) demonstrated high potent viral suppression #aasld

Bristol-Myers Squibb (NYSE: BMY) today announced 48-week data from a new study (ETV-048) of chronic hepatitis B patients with decompensated cirrhosis, in which BARACLUDE^® (entecavir) demonstrated more potent viral suppression compared to adefovir.  Adefovir is an antiviral that is indicated for chronic hepatitis B patients, including those with decompensated liver disease. The 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 % 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% 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 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 patients with decompensated cirrhosis an effective treatment option.” 

Study Results

      In this comparative Phase IIIb study of 195 patients, BARACLUDE^® (entecavir) demonstrated superior antiviral activity compared to adefovir at 24 and 48 weeks. A statistically significant difference was also 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% (49/100) of patients being treated with BARACLUDE achieved an undetectable viral load,  compared with 16% (15/91) of patients who received adefovir; at 48 weeks, 57% (57/100) of patients on BARACLUDE achieved an undetectable viral load, compared with 20% (18/91) of patients on adefovir (p< 0.0001). Among patients with baseline abnormal ALT, a higher proportion of BARACLUDE-treated patients than adefovir-treated patients achieved ALT normalization at weeks 24 and 48.

      Additionally, of the 100 patients treated with BARACLUDE, 61% had an improvement or no worsening of the Child-Pugh Score (which assesses severity of hepatic decompensation), with 35% of patients having achieved a ≥ 2-point reduction in Child-Pugh score. Findings at weeks 24 and 48 were comparable with patients receiving adefovir.  Patients treated with BARACLUDEalso experienced an improvement of the Model for End-Stage Liver Disease (MELD) Score (another score 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.

      BARACLUDE was generally well-tolerated and safety results were comparable between treatment groups. Grade 3-4 adverse events were comparable across the two groups. Cumulative rates for deaths for BARACLUDE was 23%; and adefovir 33%.  
 

About Study ETV-048 

      Study ETV-048 is a 96-week 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 (190 treated) were HBeAg-positive or HBeAg-negative, and nucleos(t)ide-naïve or lamivudine pre-treated. 

      Patients were randomized to receive BARACLUDE^® (entecavir) 1 mg or adefovir 10 mg daily and were treated for up to 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. 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).

      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. ^3,4 
 

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.
5. Asian Liver Center Web site. FAQ About Hepatitis B. http://liver.stanford.edu/Education/faq.html. Accessed August 14, 2008.
6. Liaw Y-F, et al. Long-term Entecavir Therapy Results in Reversal of Fibrosis/Cirrhosis and Continued Histologic Improvement in Patients with HBeAg(+) and (-) Chronic Hepatitis B: Results from Studies ETV-022, -027 and -901. Abstract at AASLD, San Francisco, 2008.