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发表于 2002-4-23 10:42
作者 主题: Adefovir Dipivoxil Improves Liver Histology
中尉排长 发表于 2002-04-20.12:07:08
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Gilead Sciences today (4/19/02) announced 48-week data from a Phase III clinical trial (study 438) of its novel, once-daily, oral antiviral agent adefovir dipivoxil 10 mg that is being developed for the treatment of patients with chronic hepatitis B.
Study results show that 48 weeks of treatment with adefovir dipivoxil was associated with improved liver histology and reduced serum hepatitis B virus (HBV) DNA concentration (a marker of viral replication) in patients infected with the precore mutant strain of the virus.
In addition, serum HBV DNA concentration was reduced to below the limit of detection (<400 copies/mL as measured by Roche Amplicor PCR) in more than half of patients. Precore mutant HBV is a strain of the virus in which a mutation in the viral genome destroys the virus' ability to produce its hallmark "e" antigen. It is more common in Asian and Mediterranean countries, and can be associated with more severe liver disease.
These data were outlined in an oral presentation (Abstract 648) given by Stephanos Hadziyannis, MD, Department of Internal Medicine, Hipprokration General Hospital, Athens, Greece at the 37 th Annual Meeting of the European Association for the Study of the Liver (EASL) in Madrid, Spain.
This presentation is among the more than 20 abstracts at EASL describing the anti-HBV, safety and resistance profile of adefovir dipivoxil in a variety of chronic hepatitis B patient populations. Preliminary data from Study 438 previously were announced in September 2001.
Adefovir dipivoxil belongs to a class of drugs called nucleotide analogues that are designed to work by blocking HBV DNA polymerase, an enzyme involved in the replication of the virus in the body. Gilead recently filed a New Drug Application (NDA) for adefovir dipivoxil with the U.S. Food and Drug Administration (FDA) and a Marketing Authorisation Application (MAA) with the European Medicines Evaluation Agency (EMEA).
Gilead has requested a priority, or six month, review in the United States, and anticipates receiving an opinion from the Committee for Propriety Medicinal Products (CPMP) in Europe in the first half of 2003.
"The results presented today demonstrate that treatment with adefovir dipivoxil may potentially alter the course of chronic hepatitis B infections by positively impacting several important clinical markers - liver histology, serum HBV DNA and ALT levels," said Dr. Hadziyannis. " atients infected with precore mutant chronic hepatitis B often experience poor clinical outcomes and may exhibit more advanced liver disease. Based on its activity, safety and resistance profile, adefovir dipivoxil offers new hope for potential successful treatment of
patients with chronic hepatitis B who are infected with the precore mutant form of the virus."
Long-term Data from Phase II Studies
The resistance profile and prolonged antiviral response of adefovir dipivoxil will be further characterized in a poster presentation (Abstract 590) given by Jenny Heathcote, MD, Toronto Western Hospital. The presentation will highlight long-term resistance, efficacy and safety data from the extension phase of Gilead's Study 412. In this Phase II study, 39 patients with chronic hepatitis B who had previously been treated with adefovir dipivoxil 30 mg for greater than or equal to 40 weeks received adefovir dipivoxil 10 mg. Of these patients, 11 had the precore mutant strain of HBV.
In patients treated with adefovir dipivoxil 10 mg beyond 48 weeks, adefovir dipivoxil was associated with a significant median reduction in serum HBV DNA of 3.40 log10 copies/mL (p<0.0001) that remained durable through up to nearly two years (3.36 log10 copies/mL at 100 weeks, p<0.0001). Furthermore, by week 100, HBV DNA was undetectable (<400 copies/mL) in 70 percent of patients.
Median reductions in ALT levels improved from week 48 to week 100 (36 IU/L to 48 IU/L), at which time these levels normalized in 63 percent of patients. In addition, over the course of the study, 21 percent of patients achieved seroconversion, in which the hepatitis B "e" antigen (used to denote HBV replication) disappears and antibodies specific for this antigen appear. Finally, genotypic and phenotypic analyses revealed no adefovir-associated resistance mutations in patients who received 72 to 136 weeks of treatment with adefovir dipivoxil.
"In patients with chronic hepatitis B and evidence of liver inflammation, the long-term suppression of the hepatitis B virus is essential to prevent liver damage and help maintain health," commented Dr. Heathcote. "These data are an important indicator of the potential durability of response to adefovir dipivoxil."
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Early Access Program Initiated
In March 2002, Gilead announced the initiation of an early access program in the United States to provide adefovir dipivoxil to chronic hepatitis B patients with lamivudine-resistant HBV. A similar program opened in France in July 2001 and has enrolled 300 patients to date, and additional programs in Canada, Australia and in other countries in Europe will open in the coming months as appropriate regulatory approvals are obtained.
04/19/02
Source
www.gilead.com
References
S Hadzijannis and others. GS-98-438 A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY OF ADEFOVIR DIPIVOXIL (ADV) FOR PRESUMED PRECORE MUTANT CHRONIC HEPATITIS B: 48 WEEK RESULTS. Abstract 648. 37th Annual Meeting of the European Association for the Study of the Liver (EASL). April 18-22, 2002. Madrid, Spain.
E Heathcote. SUSTAINED ANTIVIRAL RESPONSE AND LACK OF VIRAL RESISTANCE WITH LONG TERM ADEFOVIR DIPIVOXIL (ADV) THERAPY IN CHRONIC HBV INFECTION. Abstract 590. 37th Annual Meeting of the European Association for the Study of the Liver (EASL). April 18-22, 2002. Madrid, Spain.
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Gilead公司今天(4/19/02)宣布了阿第福韦48周的三期临床数据（研究号（438）。阿第福韦是该公司研发的新的抗HBV
药物，每日一次，口服10mg. 研究结果表明，对前C区变异的患者，48周的阿第福韦治疗可以改善肝组织，减少HBVDNA血清浓度（病毒复制的指标）。
并且，有超过一半的患者，血清HBVDNA浓度减到了可测量限度以下（<400 copies/mL，PCR）。前C区变异是HBV
病毒变化，病毒基因破坏了病毒产生e抗原的能力。这在亚洲和地中海国家更常见，同严重的肝病有关联。
该数据由Stephanos Hadziyannis（医学博士，雅典Hipprokration General医院内科）在马德里的37届欧洲肝病研究
年会(EASL)上口头摘要发布（摘要648）
该声明是EASL上20个摘要中的一个，描述了阿第福韦在不同HBV患者中的抗病毒效果，安全性，耐药性。
实验438的初步数据在2001年9月已公布。
阿第福韦属于核苷类似物药族，都通过抑制HBVDNA聚合酶（一种病毒复制时用到的酶）起作用。Gilead
最近向FDA提出了阿第福韦新药申请（NDA）和欧洲药物评估局提出上市申请（MAA）
Gilead曾请求6个月的特许权，正在美国评估，希望在2003年上半年获得欧洲药品适用委员会CPMP批准。
Dr. Hadziyannis 说，“今天公布的结果证明，用阿第福韦治疗，可以潜在的改变慢性HBV感染的几个重要症状：肝
组织，血清HBVDAN和ALT水平。”“前C区变异的患者经常经历坏的临床结果，会发生更多的严重肝病。基于阿
第福韦的活性，安全性，低抗药性，阿第福韦为前C区变异的患者提供了全新的成功希望。
Long-term Data from Phase II Studies
二期临床的长程数据
阿第福韦的耐药性和长期抗病毒反应会在摘要590上发布。（Jenny Heathcote，医学博士，oronto Western
Hospital）该报告将强调长期的耐药性，效果和安全性，从Gilead的实验412开始。在二期临床中，39名慢
性HBV患者经阿第福韦治疗10mg ~30mg40周。在这些患者中，11名有前C区变异。
用阿第福韦10mg治疗48周的患者，阿第福韦明显同HBVDNA的中值减少有关（3.40 log10 copies/mL），效果持续
多达两年(3.36 log10 copies/mL at 100 weeks)。另外，70%的患者在100周后HBVDNA测不到。
ALT水平的中值减少从48周到100周都有改善(36 IU/L to 48 IU/L)，在 |
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