European Commission approves BMY's BARACLUDE(r) to treat CHB in adult patients with liver disease

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. 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. Among CHB patients with cirrhosis, 3-5% per year progress to decompensated cirrhosis and 2-5% develop hepatocellular carcinoma (HCC). Currently, the median survival rate in decompensated patients is two to three years, with only 28% of patients surviving for more than five years. 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%).

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 < 0.0001).

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.

SOURCE Bristol-Myers Squibb