替诺福韦延胡索酸双异丙酰氧基甲酯（Tenofovir DF）
替诺福韦DF是替诺福韦的酯质前体，是一种与阿德福韦酯相关的AMP（单磷酸腺苷）类似物。其肾毒性明显低于阿德福韦酯，已被批准用于HIV治疗，剂量300 mg/日。替诺福韦降低HBV DNA的效果比拉米夫定、阿德福韦更为迅速强力。替诺福韦对拉米夫定耐药的rtM204V/I突变株有效，对少见的原发耐阿德福韦rtI233V变异株有效。两项Ⅲ期临床研究中，替诺福韦治疗48周均未显示耐药。然而，在合并HIV感染的慢性乙型肝炎患者中，发现rtA194T的拉米夫定耐药相关突变。
两项随机对照双盲的Ⅲ期临床研究，分别以替诺福韦300 mg/日和阿德福韦10 mg/日，治疗初治乙型肝炎患者（无HIV合并感染）。在HBeAg阳性患者（176例替诺福韦，90例阿德福韦）中，治疗48周时替诺福韦组获得完全应答率67%（阿德福韦组12%），HBV DNA水平＜400 拷贝/ml者比率76%（阿德福韦组13%）。完全应答的定义是HBV DNA水平＜400 拷贝/ml和肝脏组织学改善（Knodel炎症坏死得分至少下降2分，纤维化无加重），替诺福韦组69%患者ALT复常（阿德福韦组54%），HBeAg血清转换率两组分别为20.9%和17.5%（无统计学意义），HBsAg阴转率分别为3.2%和0%。在HBeAg阴性患者（250例替诺福韦，125例阿德福韦）中，治疗48周时替诺福韦组获得完全应答率71%（阿德福韦49%），HBV DNA水平＜400 拷贝/ml者比率93%（阿德福韦63%）。替诺福韦组250例患者中，41例曾有拉米夫定治疗史，HBV DNA受抑制程度同初治患者相同，说明替诺福韦对初治患者和拉米夫定耐药患者均有较好疗效。
包括101例患者的一项回顾性研究也表明，替诺福韦对有拉米夫定治疗史的患者有较好疗效。其中部分患者在拉米夫定耐药后又接受了阿德福韦治疗，再经替诺福韦治疗48周，HBV
DNA水平下降4.1 log 拷贝/ml，91%患者HBV DNA水平＜400 拷贝/ml。
克拉夫定
克拉夫定（L-FMAU）具有抗EBV活性，同时具有较强的抗乙型肝炎病毒作用。在旱獭肝炎病毒感染模型中，克拉夫定使肝外病毒RNA和ccc DNA显著下降。
两项初步Ⅲ期临床试验对克拉夫定（30 mg）的疗效进行了分析。一项是HBeAg阳性患者（182例克来夫定，61例安慰剂）：治疗24周时，克拉夫定组HBV DNA水平下降5.10 log 拷贝/ml，而安慰剂组下降0.27 log 拷贝/ml。另一项是HBeAg阴性患者（63例克拉夫定，23例安慰剂：治疗24周时，克拉夫定组HBV DNA水平下降4.25 log 拷贝/ml，而安慰剂组下降0.48 log 拷贝/ml。在撤除治疗后，48周时检测HBV DNA水平，HBeAg阳性组较治前下降2.02 log，HBeAg阴性组下降3.1 log。
克拉夫定这一独特的停药后持续抗病毒作用的机制尚不清楚，推测与克拉夫定抑制ccc DNA有关。该作用只维持数月，6个月后HBV DNA水平会逐渐回到治疗前基线水平。克拉夫定间断给药，当HBV DNA水平回到基线时再次治疗的方案，似乎并不合理。任何间断给药抑制病毒的方案都有可能增加耐药发生风险，并有可能抵消长期治疗永久抑制HBV DNA的益处。
体外试验结果表明，克拉夫定和拉米夫定存在交叉耐药，包括YMDD突变。尽管治疗12周时未见耐药发生，30 mg剂量24周已见个别患者出现rtA181T变异。
LB80380
LB80380是一种与阿德福韦酯结构相似的口服核苷前体，其肾毒性仅为阿德福韦酯的1/30。一项LB80380剂量递增Ⅰ/Ⅱ期试验显示，60 mg/日剂量可使HBV DNA被最大程度抑制。与其他无环磷酸盐一样，LB80380对拉米夫定耐药HBV有效。一项剂量递增Ⅱ期药物试验中，有明确拉米夫定耐药突变的患者接受LB80380（ANA380）治疗12周，结果30、60、90、150、240 mg/日剂量组HBV DNA分别下降2.8、3.2、3.9、3.9、4.1 log10 拷贝/ml，进一步的Ⅱ期药物试验还在进行。
相关链接
慢性乙型肝炎抗病毒治疗的有效药物可分为三类：非天然L构型脱氧胞苷类似物拉米夫定（LMV），及相关的L核苷，包括恩曲他滨、替比夫定和克来夫定；无环磷酸盐，包括阿德福韦酯（ADV），及与ADV结构类似的替诺福韦（TDF），后者目前可用于治疗HIV感染的患者；近年研发的，含有环戊烷糖部分的脱氧鸟苷类似物恩替卡韦（ETV），是迄今临床使用的抗HBV药物中效果最强的。
通 用 名：Clevudine (L-FMAU)
研发进展：III期临床
研发公司: 韩国Bukwang公司
作用机理：抑制HBV DNA聚合酶
适 应 症：乙型病毒性肝炎
简介：
Clevudine (L-FMAU)是嘧啶核苷酸类似物，韩国Bukwang公司正在将其作为抗HBV药开发。Clevudine通过磷酸化形成三磷酸盐，从而抑制HBV DNA聚合酶。目前在进行III期临床研究。
在体外试验中，clevudine与 emtricitabine, lamivudine, DAPD, adefovir dipivoxil 和 penciclovir具有协同作用。给成年美洲旱獭，静脉注射25mg/kg clevudine，半衰期（t1/2β）为7.2小时，总清除率（CL）为0.23lhr/kg，稳定态分布体积（Vd）为1.0 l/kg。单剂量经口给药25mg/kg，生物利用度为25.5%。对4个慢性携带WHV的旱獭，给予10mg/kg/day的clevudine共12周，与对照组相比，病毒复制被快速、显著地抑制；治疗后2周，血清WHV DNA下降1000倍，再之后则不能测出。通过药物治疗的旱獭，血浆WHV DNA的起始t1/2是17hr；在治疗末，与治疗前和对照组相比，肝WHV DNA复制量下降10倍。未发现任何毒性。10mg/kg/day 治疗后36周，仍未测到病毒。大鼠经口给药的生物利用度为59-64%。
在12名志愿者中进行I期剂量爬坡试验，口服clevudine的剂量为 150-1200mg。在剂量600-1200mg,耐受性良好。口服剂量300mg时，Cmax、AUC和t1/2分别是1.12μg/ml, 5.4μg?hr/ml和11.6hr。
在对乙肝病人的II期临床试验中，对clevudine + emtricitabine联合用药的病人，有74%未测出HBV DNA，而单用Emtricitabine则为65%。在对32名慢性HBV感染病人进行的剂量爬坡试验中，这些病人在6个月研究中没有经过干扰素（IFN）的治疗，给予clevudine 10-200mg/day共4周，随后停药并随访直至28周，结果HBV DNA水平降低。在Clevudine治疗4周期间，降低最明显(降低2.5-3.0 log copies/ml)；可是28周后，HBV DNA水平仍处于基值水平以下。治疗期间无任何严重的不良反应，治疗后发现4例不良反应，但认为与治疗无关。Clevudine的t1/2为40h，以原型从肾脏排出。
正准备在中国进行III期临床试验，为期48周，遴选200名以上病人参加。他们将接受clevudine 30mg/d 24周，随后10mg/d 24周的治疗。在韩国进行的2个独立的24周III期临床试验结果表明，在HBeAg(+)和HBeAg(-)病人中，clevudine可减少病毒量到测不出的水平，降低的幅度分别为59 and 92%。
研发进展：III期临床
研发公司: 韩国Bukwang公司
作用机理：抑制HBV DNA聚合酶
适 应 症：乙型病毒性肝炎
简介：
Clevudine (L-FMAU)是嘧啶核苷酸类似物，韩国Bukwang公司正在将其作为抗HBV药开发。Clevudine通过磷酸化形成三磷酸盐，从而抑制HBV DNA聚合酶。目前在进行III期临床研究。
在体外试验中，clevudine与 emtricitabine, lamivudine, DAPD, adefovir dipivoxil 和 penciclovir具有协同作用。给成年美洲旱獭，静脉注射25mg/kg clevudine，半衰期（t1/2β）为7.2小时，总清除率（CL）为0.23lhr/kg，稳定态分布体积（Vd）为1.0 l/kg。单剂量经口给药25mg/kg，生物利用度为25.5%。对4个慢性携带WHV的旱獭，给予10mg/kg/day的clevudine共12周，与对照组相比，病毒复制被快速、显著地抑制；治疗后2周，血清WHV DNA下降1000倍，再之后则不能测出。通过药物治疗的旱獭，血浆WHV DNA的起始t1/2是17hr；在治疗末，与治疗前和对照组相比，肝WHV DNA复制量下降10倍。未发现任何毒性。10mg/kg/day 治疗后36周，仍未测到病毒。大鼠经口给药的生物利用度为59-64%。
在12名志愿者中进行I期剂量爬坡试验，口服clevudine的剂量为 150-1200mg。在剂量600-1200mg,耐受性良好。口服剂量300mg时，Cmax、AUC和t1/2分别是1.12μg/ml, 5.4μg?hr/ml和11.6hr。
在对乙肝病人的II期临床试验中，对clevudine + emtricitabine联合用药的病人，有74%未测出HBV DNA，而单用Emtricitabine则为65%。在对32名慢性HBV感染病人进行的剂量爬坡试验中，这些病人在6个月研究中没有经过干扰素（IFN）的治疗，给予clevudine 10-200mg/day共4周，随后停药并随访直至28周，结果HBV DNA水平降低。在Clevudine治疗4周期间，降低最明显(降低2.5-3.0 log copies/ml)；可是28周后，HBV DNA水平仍处于基值水平以下。治疗期间无任何严重的不良反应，治疗后发现4例不良反应，但认为与治疗无关。Clevudine的t1/2为40h，以原型从肾脏排出。
正准备在中国进行III期临床试验，为期48周，遴选200名以上病人参加。他们将接受clevudine 30mg/d 24周，随后10mg/d 24周的治疗。在韩国进行的2个独立的24周III期临床试验结果表明，在HBeAg(+)和HBeAg(-)病人中，clevudine可减少病毒量到测不出的水平，降低的幅度分别为59 and 92%。
韩国公司核苷类LB80380 (ANA380)获II期临床
Anadys Pharmaceuticals, Inc. (ANDS) And LG Life Sciences, Ltd. Enter into Joint Development And License Agreement For LB80380 (ANA380), A Phase II Hepatitis B Compound
Alliance Further Enhances Anadys' Commitment to Chronic Viral Hepatitis
SAN DIEGO & SEOUL, South Korea--(BUSINESS WIRE)--April 19, 2004-- Anadys Pharmaceuticals, Inc. (Nasdaq:ANDS - News) and LG Life Sciences (KOSPI:68870) of Seoul, Korea announced today that they have entered into an agreement to develop for potential commercialization LB80380 (ANA380), a Phase II nucleotide analog for the treatment of chronic hepatitis B virus infection. Based on pre-clinical and clinical study results to date, LG Life Sciences and Anadys are pursuing the development of LB80380 (ANA380) as a potential front-line therapy for the treatment of chronic HBV infection.
Under the terms of the agreement, Anadys has acquired an exclusive license from LG Life Sciences for the clinical development and commercialization of LB80380 (ANA380) for the treatment of chronic HBV infection in North America, Europe, Japan and the rest of the world other than China, Korea, India and countries in Southeast Asia. The agreement further provides that the parties will work jointly and will share costs for the clinical development of LB80380 (ANA380) on a global basis. Specific financial terms were not disclosed.
"LB80380 (ANA380) significantly enhances Anadys' franchise in anti-infective medicines, and we are pleased to have the opportunity to work with LG Life Sciences on the development of this compound," said Kleanthis G. Xanthopoulos, Ph.D., Anadys' President and CEO.
"LG Life Sciences is very pleased to work closely with Anadys to pursue a global joint development plan. The Anadys management team has a significant track record developing and commercializing anti-infectives. We look forward to a long and productive relationship with Anadys," said Heung-Joon Yang, Ph.D., President and CEO of LG Life Sciences.
About LB80380 (ANA380)
LB80380 (ANA380) is a nucleotide analog currently in Phase II clinical trials for the treatment of chronic HBV infection. The compound has exhibited activity in vitro against both HBV typically found in untreated patients and also HBV variants that demonstrate resistance to treatment with the nucleotide analog lamivudine, which is a currently commercialized therapy for HBV. Preclinical studies have demonstrated significant activity against HBV, low potential for drug interactions and good tolerability in a range of preclinical toxicology studies. Based on clinical trials to date, LB80380 (ANA380) appears to offer the potential for once daily dosing. Data from a 28 day, once daily clinical trial, which enrolled 28 patients, demonstrated that oral administration of LB80380 (ANA380) reduced HBV viral load by up to four log10 units, or 99.99%.
About hepatitis B
Hepatitis B virus, or HBV, infection is a growing global health problem that can cause both acute and chronic viral infections. Approximately 350 million people are chronically infected and have become carriers of HBV. About 15% to 40% of these patients will develop serious consequences of infection during their lifetime, including loss of liver function, cirrhosis, and liver cancer. According to the World Health Organization, approximately 1 million people die each year from chronic HBV or related conditions.
Anadys Pharmaceuticals, Inc. is a biopharmaceutical company committed to advancing patient care by discovering, developing and commercializing novel and powerful small molecule, anti-infective medicines for the treatment of hepatitis C virus, hepatitis B virus and bacterial infections.
LG Life Sciences, Ltd. (LGLS), an LG affiliate, is a R&D based biopharmaceutical company based in Seoul, Korea that discovers, develops and commercializes new medicines in anti-infectives, cancer, diabetes and other chronic diseases. LGLS had approximately $150 million in sales last year.
Statements in this press release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to references to Anadys' business relationship with LGLS, activities expected to occur in connection with that relationship, the nature of LB80380 (ANA380) in HBV infected patients and expectations regarding further clinical trials of and commercial opportunities for LB80380 (ANA380). Such forward-looking statements involve known and unknown risks, uncertainties and other factors which may cause the actual results of LGLS and/or Anadys Pharmaceuticals to be materially different from historical results or from any results expressed or implied by such forward-looking statements. These factors include risks related to the implementation of the business relationship between Anadys and LGLS, the uncertainty of results to be obtained in future clinical trials, the use of unproven technologies and delays in the completion of clinical testing. These and other factors that may cause actual results to differ are more fully discussed in the "Risk Factors" section of Anadys' Registration Statement on Form S-1 on file with the SEC. Anadys and LGLS are providing this information as of this date and do not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.
Contact:
Anadys Pharmaceuticals, Inc. Michael Kamdar, 858-530-3600 cc@anadyspharma.com or
LG Life Sciences In-Chull Kim, Ph.D., +82-2-3773-7009 ickim@lgls.co.kr or
LG Life Sciences, Ltd. Jay J.H. Kwon, +82-2-3773-3358 jhkwonb@lgls.co.kr or
Atkins + Associates for Anadys Pharmaceuticals Trista Morrison, 858-527-3490 tmorrison@irpr.com
Source: Anadys Pharmaceuticals, Inc.