entecavir Approved for the Treatment of Decompensated Liver Disease

StephenW

http://www.digitaljournal.com/pr/233780
BARACLUDE(R) (entecavir) Approved by the European Commission for the Treatment of Chronic Hepatitis B in Adult Patients With Evidence of Decompensated Liver Disease

PR Newswire

PARIS, March 1, 2011

    PARIS, March 1, 2011 /PRNewswire-FirstCall/ -- Bristol-Myers Squibb(NYSE:BMY) announced today that BARACLUDE(R) (entecavir) has been approved bythe 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 adultpatients with CHB with compensated liver disease and evidence of active viralreplication, 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 27countries of the European Union. In the U.S., the Food and DrugAdministration (FDA) approved the decompensated indication for BARACLUDE(r)in October 2010.
    Decompensated liver disease is characterised by failure of the liver tomaintain adequate function, usually due to severe scarring, leading tofibrosis and/or cirrhosis caused by chronic liver inflammation.[1] Itrepresents the end stage of hepatitis. Natural history data demonstrate thatup to 40% of patients with CHB develop cirrhosis over their lifetimes, at areported rate of 2-6% per year.[1] Among CHB patients with cirrhosis, 3-5%per year progress to decompensated cirrhosis and 2-5% develop hepatocellularcarcinoma (HCC).[2,3] Currently, the median survival rate in decompensatedpatients is two to three years, with only 28% of patients surviving for morethan five years.[1,4] Once liver disease progresses to the decompenstatedstage, a liver transplant is often necessary.
    "The approval of this additional indication is an important milestone forCHB patients living with decompensated liver disease, a difficult to treatpopulation whose mortality rates are high," said Professor Jorg Petersen."The data used to support this indication shows that BARACLUDE(r) isefficacious 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 oncedaily) with adefovir (10.0 mg once daily) administered in patients with HBeAgpositive or negative CHB who had evidence of liver decompensation.
    Data demonstrated that BARACLUDE(r) showed greater viral suppressioncompared to adefovir at 24 and 48 weeks following treatment initiation. At 48weeks, 57% (57/100) of patients treated with BARACLUDE(r) achieved anundetectable 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 orHBeAG-negative. Patients were either treatment-naive or had been previouslytreated excluding pre-treatment with BARACLUDE(r), adefovir or tenofovir.
    Patients were randomised to receive BARACLUDE(r) (1.0 mg once daily) oradefovir (10.0 mg once daily) and were analysed through 48 weeks.
    Baseline demographics were similar for both groups. Importantly, atbaseline, patients had a mean CPT (child-pugh score) of 8.81 in theBARACLUDE(r) arm and 8.35 in the adefovir arm, and the mean MELD (Model forEnd stage Liver Disease) score was 17.1 and 15.3, respectively. Both of theseparameters measure the severity of hepatic decompensation.
    The mean age of the study population was 52 years and the majority of thesubjects were male (74%) and either Asian (54%) or Caucasian (33%).[5]
    In the primary efficacy endpoint of mean change from baseline in serumHBV 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 serumHBV DNA at Week 48 (-4.66 in the BARACLUDE(r) arm and -3.90 in the adefovirarm). In addition a greater proportion of patients on BARACLUDE(r) achievedan 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 theadefovir arm at Week 48, even though baseline MELD score had been higher with17.1 for BARACLUDE(r) than 15.3 for adefovir. Further the normalization ofALT (Alanine Aminotransferase enzyme) was achieved to a higher proportion inthe BARACLUDE(r)-treated patients (less than or equal to 1 x Upper Limit ofNormal) 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 treatmentgroups; on-study cumulative death rates were 23% (23/102) and 33% (29/89) forpatients treated with BARACLUDE(r) and adefovir, respectively; and on-studycumulative 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 werecomparable between the treatment groups and consistent with those previouslyreported for a population with decompensated liver disease. Serious adverseevents occurred in 69% of the BARACLUDE(r) patients and 66% of theadefovirpatientsand discontinuations due to adverse events occurred in 7% ofthe Baraclude patients and 6 % of the adefovir patients.[5]
    Important Information About BARACLUDE(r)
    Discovered at Bristol-Myers Squibb, BARACLUDE(r) is indicated for thetreatment 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 particularin those with Child-Turcotte-Pugh (CTP) class C disease, compared with ratesin patients with compensated liver function. In addition, patients withdecompensated liver disease may be at higher risk for lactic acidosis andspecific renal adverse events such as hepatorenal syndrome. Clinical andlaboratory parameters should be closely monitored in this patient population.
    * For full prescribing information for BARACLUDE(r), please consult theSummary of Product Characteristics.
    About Chronic Hepatitis B (CHB)
    Chronic hepatitis B is a serious global health issue. Worldwide, morethan 2 billion people have been in contact with the hepatitis B virus andapproximately 350 million people are chronically infected.[6]
    About Decompensated Liver Disease
    Decompensated liver disease is characterised by failure of the liver tomaintain adequate function, often due to severe scarring leading to fibrosisand/or cirrhosis caused by chronic liver inflammation.[1] Symptoms of liverdecompensation can include but are not limited to: jaundice (yellowing of theskin or eyes), ascites (swollen abdomen from abnormal accumulation of fluid),oesophageal varices (distorted blood vessels that may cause potentially fatalbleeding), and hepatic encephalopathy ( neuropsychiatric abnormalityresulting in personality changes, intellectual impairment and reduced levelsof consciousness).[1]
    About Bristol-Myers Squibb
    Bristol-Myers Squibb is a global biopharmaceutical company committed todiscovering, developing and delivering innovative medicines that helppatients prevail over serious diseases.
    BARACLUDE(R) (entecavir) is a registered trademark of Bristol-MyersSquibb Company.
    References
    1. D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognosticindicators 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: Naturalhistory and treatment. Seminars in Liver Disease 2006;26(2):142-152.
    3. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellularcarcinoma in cirrhosis: Incidence and risk factors. Gastroenterology2004;127(5 Suppl 1):S35-S50.
    4. Fattovich G, Pantalena M, Zagni I et al. Effect of hepatitis B and Cvirus infections on the natural history of compensated cirrhosis: a cohortstudy of 297 patients. Am. J. Gastroenterol. 2002; 97: 2886-95.
    5. Y. Liaw, et al. Efficacy and Safety of Entecavir versus Adefovir inChronic 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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StephenW

博路定（R）公司（恩替卡韦）核准在治疗成人慢性乙型肝炎由欧洲委员会与失代偿期肝硬化疾病的证据

美通社

巴黎，2011年3月1日

巴黎，2011年3月1日/新华美通/ - 施贵宝公司（NYSE：BMY牛）今天宣布，博路定（R）公司（恩替卡韦）已批准2011年2月28日由欧盟委员会来治疗慢性乙型肝炎（CHB ）与证据失代偿性肝病的成年患者。

博路定（R）已经在欧洲已经批准2006年6月使用成人慢性乙型肝炎患者的代偿性肝脏疾病与病毒复制活跃的证据，持续升高血清谷丙转氨酶（ALT）水平和组织学活动性炎症的证据和/或纤维化。

该批准授予博路定（R）的销售在欧洲联盟27个国家的批准。在美国，美国食品和药物管理局（FDA）批准博路定的代偿指示（r）在2010年10月。

失代偿性肝病的特点是肝衰竭，以维持足够的功能，通常是由于严重的疤痕，导致纤维化和/或肝硬化的慢性肝脏炎症引起的。[1]它代表了肝炎终末期。自然历史数据表明，高达40％的慢性乙型肝炎患者对他们的一生发展肝硬化，在2-6％，每年报告。[1]在慢性乙肝肝硬化患者，每年3-5％，至失代偿期肝硬化的进展率和2-5％左右的肝细胞癌（HCC）。[2,3]目前，在失代偿期患者的平均存活率为两至三年，只有28％的患者超过五年存活。[1,4]一旦肝脏疾病发展到了decompenstated阶段，肝移植通常是必要的。

“这种额外的适应症是用于慢性乙肝失代偿期肝病患者生活的重要里程碑，一个难以治疗人群的死亡率都很高，”约尔格彼得森教授说。 “用于支持此适应症的数据显示，博路定（R）是治疗失代偿期病人的疗效。”

这个批准是基于一项随机，开放标签，多中心研究（教育电视- 048）相比，博路定的疗效及安全（R）公司（1.0毫克每天一次），阿德福韦（10.0 mg，每天一次）患者与管理HBeAg阳性或阴性慢性乙型肝炎肝脏失代偿了谁的证据。

数据显示，博路定（R）的表现出更大的病毒抑制比在24和48周阿德福韦治疗后开始。在48周时，57％（57/100）与博路定治疗的患者（R）的实现了检测不到病毒载量（小于或等于300拷贝/ ml）相比，20％（九十一分之一十八）对阿德福韦的病人。

教育电视- 048研究结果

048研究评估的191例无论谁是e抗原阳性或HBeAg阴性。病患都是治疗初治或治疗不包括先前已与博路定治疗前（R）的阿德福韦或替诺福韦。

患者随机接受博路定（R）公司（1.0毫克每天一次）或阿德福韦（10.0 mg，每天一次），并通过48周进行分析。

基线人口统计学两组相似。重要的是，在开始时，病人的平均中华映管（Child - Pugh评分）的8.81的博路定（R）的臂在阿德福韦手臂和8.35，平均（终末期肝病模型）的MELD评分为17.1和15.3，分别。这两个参数测量肝脏失代偿的严重程度。

这项研究的人口平均年龄为52岁，大多数的受试者为男性（74％），要么亚洲（54％）或白人（33％）。[5]

在从血清中HBV DNA的基线的平均变化的主要功效在24周时，博路定端点（R）的优于阿德福韦（-4.48比-3.40，p“0.0001）。

次要疗效指标包括平均血清HBV DNA从基线的变化在第48周（在手臂-4.66阿德福韦在博路定（R）的胳膊和-3.90）。另外一个更大比例的患者对博路定（R）的病毒载量检测不到取得了比较于阿德福韦患者在48周：57％和20％（57/100）（91分之18），分别为。患者也对博路定（R）的手臂从基线下降的MELD评分由-2.6％与-1.7在48周时阿德福韦手臂％，虽然已基本MELD评分较高17.1比15.3博路定（R）用于阿德福韦。进一步的ALT（丙氨酸氨基转移酶酶）是实现正常化中的一个BARACLUDE治疗的比例较高（R）的治疗的患者（小于或等于1个上部正常范围）在第48周[63％（49/78）]与阿德福韦治疗的患者[46％（33/71）]。

对肝癌的发病或死亡的时间是在两个治疗组相似;上研究的累积死亡率分别为23％（102分之23）和33％与博路定治疗（R）和阿德福韦的患者（89分之29），分别为;肝癌及上研究的累积率分别为12％（一百零二分之一十二）和20％（八十九分之十八）的博路定（R）和阿德福韦，分别为。

博路定（R）的一般耐受性良好和安全结果治疗组之间，与以前为失代偿性肝病人口报道一致比较。严重不良事件发生在69％的博路定（R）的患者和66由于不良反应adefovirpatientsand停药％的博路定7％的病人和6％的患者发生阿德福韦[5]。

博路定的重要信息（注册商标）

在施贵宝，BARACLUDE治疗组发现（R）是适应症为治疗慢性乙型肝炎病毒（HBV）的成人感染：

     - 代偿性肝脏疾病与病毒复制活跃的证据，
      持续升高血清谷丙转氨酶（ALT）水平和
      组织学活动性炎症的证据和/或纤维化。

     - 失代偿期肝病。


一个严重的肝不良反应率较高（不管因果关系）一直在与失代偿期肝病患者的观察，比较与儿童，特科特- Pugh分级（CTP）的C类疾病的人，特别是在患者的肝功能代偿率。此外，失代偿期肝病患者可在更高的乳酸性酸中毒和肝肾等具体肾综合征不良事件的风险。临床和实验室指标应密切监测这些病患。

如需完整的处方信息*博路定（R）的，请咨询产品特性概要。

关于慢性乙型肝炎（CHB）

慢性乙型肝炎是一种严重的全球性健康问题。在世界范围内，超过2亿人一直与乙型肝炎病毒接触，约3.5亿人长期感染。[6]

关于失代偿性肝病

失代偿性肝病的特点是肝衰竭，以维持足够的功能，常因严重的疤痕，导致纤维化和/或慢性肝脏炎症[1]肝脏失代偿症状可能包括但不限于造成肝硬化：。黄疸（泛黄的皮肤或眼睛），腹水（从流体异常堆积腹部肿胀），食管静脉曲张（扭曲血管，可能导致潜在的致命性出血），肝性脑病（神经精神异常，性格改变，智力障碍和水平下降造成意识）[1]。

关于百时美施贵宝

施贵宝公司是一家全球性制药公司，致力于发现，开发和提供，帮助患者战胜了严重的疾病创新药物。

博路定（R）公司（恩替卡韦）是百时美施贵宝公司的注册商标。

参考文献

1。达米科克，加西亚曹克，Pagliaro属自然史和生存预后指标肝硬化：118个研究的系统回顾。 j的肝脏病杂志。 2006年，44：217-31。

2。楚的C - M和廖运楼。乙型肝炎病毒相关的肝硬化：自然史和治疗。 2006年在肝病研讨会，26（2）:142 - 152。

3。 Fattovich克，Stroffolini笔，Zagni我，多纳托楼肝癌肝硬化：发病率和危险因素。胃肠病学杂志2004; 127（5增刊1）：S35 - S50的。

4。 Fattovich克，Pantalena男，Zagni我等人。 B和C型肝炎病毒感染对自然的代偿性肝硬化史：有297名病患的研究。上午。 j的数据中华医学会。 2002; 97：2886-95。

5。廖华，等。恩替卡韦的疗效和安全性与阿德福韦治疗慢性乙型肝炎病人肝脏失代偿的证据。摘要及海报442。 2009年美国肝病学会。

6。世界Helath组织网站。实况报道的N - 204。 http://www.who.int/mediacentre/factsheets/fs204/en/。 2010年12月3日访问。

源施贵宝

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