Zlecone: BARACLUDE(R) (entecavir) Approved by the European Commission for the Treatment of Chronic Hepatitis B in Adult Patients With Evidence of Decompensated Liver Disease

PARIS, March 1, 2011 /PRNewswire-FirstCall/ - Bristol-Myers Squibb (NYSE:BMY) announced today that BARACLUDE(R) (entecavir) has been approved by the European Commission on February 28th 2011 to treat chronic hepatitis B (CHB) in adult patients with evidence of decompensated liver disease.

BARACLUDE(R) was already approved in Europe in June 2006 for use in adult patients with CHB with compensated liver disease and evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.

This approval grants BARACLUDE(R) marketing authorisation in the 27 countries of the European Union. In the U.S., the Food and Drug Administration (FDA) approved the decompensated indication for BARACLUDE(R) in October 2010.

Decompensated liver disease is characterised by failure of the liver to maintain adequate function, usually due to severe scarring, leading to fibrosis and/or cirrhosis caused by chronic liver inflammation.[1] It represents the end stage of hepatitis. Natural history data demonstrate that up to 40% of patients with CHB develop cirrhosis over their lifetimes, at a reported rate of 2-6% per year.[1] Among CHB patients with cirrhosis, 3-5% per year progress to decompensated cirrhosis and 2-5% develop hepatocellular carcinoma (HCC).[2,3] Currently, the median survival rate in decompensated patients is two to three years, with only 28% of patients surviving for more than five years.[1,4] Once liver disease progresses to the decompenstated stage, a liver transplant is often necessary.

"The approval of this additional indication is an important milestone for CHB patients living with decompensated liver disease, a difficult to treat population whose mortality rates are high," said Professor Jorg Petersen. "The data used to support this indication shows that BARACLUDE(R) is efficacious in treating decompensated patients."

This approval is based on a randomised, open-label, multi-centre study (ETV-048) that compared the efficacy & safety of

BARACLUDE(R) (1.0 mg once daily) with adefovir (10.0 mg once daily) administered in patients with HBeAg positive or negative CHB who had evidence of liver decompensation.

Data demonstrated that BARACLUDE(R) showed greater viral suppression compared to adefovir at 24 and 48 weeks following treatment initiation. At 48 weeks, 57% (57/100) of patients treated with BARACLUDE(R) achieved an undetectable viral load (less than or equal to 300 copies/ml) compared to 20% (18/91) of patients on adefovir.

ETV-048 Study Results

The 048 study evaluated 191 patients who were either HBeAG-positive or HBeAG-negative. Patients were either treatment-naive or had been previously treated excluding pre-treatment with BARACLUDE(R), adefovir or tenofovir.

Patients were randomised to receive BARACLUDE(R) (1.0 mg once daily) or adefovir (10.0 mg once daily) and were analysed through 48 weeks.

Baseline demographics were similar for both groups. Importantly, at baseline, patients had a mean CPT (child-pugh score) of 8.81 in the BARACLUDE(R) arm and 8.35 in the adefovir arm, and the mean MELD (Model for End stage Liver Disease) score was 17.1 and 15.3, respectively. Both of these parameters measure the severity of hepatic decompensation.

The mean age of the study population was 52 years and the majority of the subjects were male (74%) and either Asian (54%) or Caucasian (33%).[5]

In the primary efficacy endpoint of mean change from baseline in serum HBV DNA at Week 24, BARACLUDE(r) was superior to adefovir (-4.48 versus -3.40; p

Secondary efficacy endpoints included mean change from baseline in serum HBV DNA at Week 48 (-4.66 in the BARACLUDE(R) arm and -3.90 in the adefovir arm). In addition a greater proportion of patients on BARACLUDE(R) achieved an undetectable viral load compared to patients on adefovir at 48 weeks: 57%(57/100) versus 20% (18/91), respectively. Also patients on the BARACLUDE(R) arm decreased their MELD score from baseline by -2.6% versus -1.7% in the

adefovir arm at Week 48, even though baseline MELD score had been higher with 17.1 for BARACLUDE(R) than 15.3 for adefovir. Further the normalization of

ALT (Alanine Aminotransferase enzyme) was achieved to a higher proportion in the BARACLUDE(R)-treated patients (less than or equal to 1 x Upper Limit of

Normal) at Week 48 [63% (49/78)] compared with adefovir-treated patients [46% (33/71)].

The time to onset of HCC or death was comparable in the two treatment groups; on-study cumulative death rates were 23% (23/102) and 33% (29/89) for patients treated with BARACLUDE(R) and adefovir, respectively; and on-study cumulative rates of HCC were 12% (12/102) and 20% (18/89) for BARACLUDE(R) and adefovir, respectively.

BARACLUDE(R) was generally well tolerated and safety results were comparable between the treatment groups and consistent with those previously reported for a population with decompensated liver disease. Serious adverse events occurred in 69% of the BARACLUDE(R) patients and 66% of the adefovirpatientsand discontinuations due to adverse events occurred in 7% of the Baraclude patients and 6 % of the adefovir patients.[5]

Important Information About BARACLUDE(R)

Discovered at Bristol-Myers Squibb, BARACLUDE(R) is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with:

- Compensated liver disease and evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.

- Decompensated liver disease.

A higher rate of serious hepatic adverse events (regardless of causality) has been observed in patients with decompensated liver disease, in particular in those with Child-Turcotte-Pugh (CTP) class C disease, compared with rates in patients with compensated liver function. In addition, patients with decompensated liver disease may be at higher risk for lactic acidosis and specific renal adverse events such as hepatorenal syndrome. Clinical and laboratory parameters should be closely monitored in this patient population.

* For full prescribing information for BARACLUDE(R), please consult the Summary of Product Characteristics.

About Chronic Hepatitis B (CHB)

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.[6]

About Decompensated Liver Disease

Decompensated liver disease is characterised by failure of the liver to maintain adequate function, often due to severe scarring leading to fibrosis and/or cirrhosis caused by chronic liver inflammation.[1] Symptoms of liver decompensation can include but are not limited to: jaundice (yellowing of the skin or eyes), ascite (swollen abdomen from abnormal accumulation of fluid), oesophageal varices (distorted blood vessels that may cause potentially fatal bleeding), and hepatic encephalopathy (neuropsychiatric abnormality resulting in personality changes, intellectual impairment and reduced levels of consciousness).[1]

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.

BARACLUDE(R) (entecavir) is a registered trademark of Bristol-Myers Squibb Company.

References

1. 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.

2. Chu C-M and Liaw Y-F. Hepatitis B virus-related cirrhosis: Natural history and treatment. Seminars in Liver Disease 2006;26(2):142-152.

3. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: Incidence and risk factors. Gastroenterology 2004;127(5 Suppl 1):S35-S50.

4. 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.

5. Y. Liaw, et al. Efficacy and Safety of Entecavir versus Adefovir in Chronic Hepatitis B Patients with Evidence of Hepatic Decompensation. Abstract and Poster 442. AASLD 2009.

6. World Helath Organization Web site. Fact sheet N- 204.

http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed 3 December 2010.

Source: Bristol-Myers Squibb

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