AASLD2014:Myrcludex 2a期临床试验

newchinabok

莫非赛定，异噻氟定，nvr1221,oncore算一个，形成核衣壳抑制剂板块了

StephenW

咬牙硬挺 发表于 2014-10-10 07:04
没说疗效吗

有, hbvdna 下降 (6/8, 75%).这些都是初步结果, 证明药物有效果.

StephenW

lgs1 发表于 2014-10-10 07:30
期待进一步解释

抗原基本不变??

Myrcludex是乙肝病毒进入抑制剂, 只能防止再感染, 不能直接治愈.

newchinabok

把myrcludex动物试验数据对比一下现在数据看看

StephenW

回复 newchinabok 的帖子

J Hepatol. 2013 May;58(5):861-7. doi: 10.1016/j.jhep.2012.12.008. Epub  2012 Dec 13.
The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus.Volz T1, Allweiss L, Ben MBarek M, Warlich M, Lohse AW, Pollok JM, Alexandrov A, Urban S, Petersen J, Lütgehetmann M, Dandri M.
Author information  

AbstractBACKGROUND & AIMS: Currently approved antivirals rarely cure hepatitis B virus (HBV) infection. Therefore additional therapeutic strategies interfering with other viral replication steps are needed. Using synthetic lipopeptides derived from the HBV envelope protein, we previously demonstrated prevention of de novo HBV infection in vivo. We aimed at investigating the ability of the lipopeptide Myrcludex-B to block HBV spreading post-infection.
METHODS: uPA/SCID mice reconstituted with human hepatocytes were infected with HBV. Daily subcutaneous Myrcludex-B administration was initiated either 3 days, 3 weeks or 8 weeks post HBV inoculation. Viral loads were quantitated in serum and liver, and visualized by immunohistochemistry.
RESULTS: Myrcludex-B efficiently prevented viral spreading from the initially infected human hepatocytes, as demonstrated by the lack of increase in viremia, antigen levels and amount of HBcAg-positive human hepatocytes determined 6 weeks after treatment. Myrcludex-B efficiently blocked HBV dissemination also when treatment was started in the ramp-up phase of infection, in mice displaying moderate levels of circulating virions (median 3 × 10(6)HBV DNA copies/ml). Notably, after 6 weeks of treatment, not only the amount of HBcAg-positive hepatocytes, but also intrahepatic cccDNA loads, remained comparable to values found in mice sacrificed 3 weeks post-infection. In none of the experimental settings, drug administration affected human hepatocyte half-life or altered virion productivity.
CONCLUSIONS: Myrcludex-B efficiently not only prevented HBV spreading from infected human hepatocytes in vivo, but also hindered amplification of the cccDNA pool in initially infected hepatocytes. Administration of an entry inhibitor, possibly used in combination with current HBV drugs, may improve patients' treatment outcome.

lgs1

StephenW 发表于 2014-10-10 13:19
Myrcludex是乙肝病毒进入抑制剂, 只能防止再感染, 不能直接治愈.

这个药即使有效，也要靠联合治疗的比如说恩替之类

保护新生的肝细胞，等老的肝细胞全部死掉，就OK了

这是最理想的结果对吧？？前提是有强效

据说肝细胞平均寿命是15个月

newchinabok

myrcludex动物试验
THE ENTRY INHIBITOR MYRCLUDEX-B EFFICIENTLY BLOCKS VIRAL SPREADING IN VIVO IN HUMAN LIVER CHIMERIC uPA/ SCID MICE PREVIOUSLY INFECTED WITH HEPATITIS B VIRUS
Antiviral treatments based on interferon-a or polymerase inhibitors are generally notcurative and additional therapeutic strategies interfering with other HBV replicationsteps are needed. We previously demonstrated prevention of de novo HBV infectionby pre-treating uPA/SCID mice with Myrcludex-B, a lipopeptide derived from the HBVpreS1 domain (Nat. Biotech.2008). Aim of this study was to investigate the abilityof Myrcludex-B to block HBV spreading post-infection. Experimental design: humanchimeric uPA/SCID mice were injected with HBV-infectious serum (5×10E7 HBV DNAcopies/mouse). Treatment with Myrcludex-B (2mg/Kg/day; s.c. injection) was initiatedeither 3 days (group A, n=8) or 3 weeks (group B, n=7) post infection (p.i.). After 6 weeksof treatment, mice were analyzed serologically (HBV-DNA, HBsAg), intrahepaticallyby qRT-PCR (rcDNA, cccDNA) and by immunohistochemistry (HBcAg). Results: Myrcludex-B administration initiated 3-days p.i. efficiently prevented viral spreadingfrom the few initially infected human hepatocytes (HBcAg-positive cells). Six weekspost-treatment viremia and HBsAg levels remained low (<10E5 HBV-DNA/ml and<10 IU/ml, respectively), while in untreated mice median viremia increased to 3×10E7and the majority of human hepatocytes stained HBcAg-positive. Myrcludex-B blockedefficiently HBV spreading also when treatment was started 3-weeks p.i., in micedisplaying already median 3×10E6 HBV-DNA/ml. Even in this experimental setting,viremia and HBsAg levels were not significantly increased after 6 weeks of treatment(9 weeks p.i.) and median cccDNA loads remained 50-fold lower as controls andcomparable to values found at week 3 p.i. (0.02 copies/cell). Conclusions: Applicationof Myrcludex-B post HBV-infection showed strong capacities to block viral spreadingin vivo, suggesting that HBV preferentially disseminates via secreted virions and theuse of Myrcludex-B in combination with current HBV-drugs may improve patients’outcome.

HBV - Myrcludex-B - entry inhibitor - uPA/SCID

newchinabok

myrcludex动物试验
的进入抑制剂MYRCLUDEX-B高效积木病毒性蔓延体内人肝嵌合的uPA/ SCID小鼠以前感染过乙肝病毒
基于干扰素-a或聚合酶抑制剂的抗病毒治疗，一般notcurative和额外的治疗策略干扰，需要其他乙肝replicationsteps。我们以前表明预防新发乙肝infectionby预处理的uPA/ SCID小鼠与Myrcludex-B，从HBVpreS1域（NAT。Biotech.2008）衍生的脂肽。本研究的目的是调查的abilityof Myrcludex-B阻断乙肝病毒传播感染后。实验设计：humanchimeric的uPA/ SCID小鼠注射HBV感染的血清（5×10E7 HBV DNAcopies/小鼠）。治疗Myrcludex-B（2毫克/千克/天;皮下注射）为initiatedeither3天（A组，n=8）〜3周（B组，n=7）感染后（PI）。 6后weeksof治疗，小鼠血清学分析（HBV-DNA，乙肝表面抗原），intrahepaticallyby定量RT-PCR（rcDNA抑制，cccDNA的），并通过免疫组织化学（核心抗原）。结果：Myrcludex-B总局发起的3天PI有效地防止病毒spreadingfrom的几个最初感染的人肝细胞（HBcAg的阳性细胞）。六weekspost治疗病毒血症和HBsAg水平仍然很低（<10E5 HBV-DNA/ ml和<10 IU/ ml时，分别），而在未经处理的小鼠中位数病毒血症增加至3×10E7and大多数染色的HBcAg阳性的人肝细胞。 Myrcludex-B blockedefficiently乙肝病毒也在蔓延，当治疗开始3周丕，在micedisplaying已经平均3×10E6 HBV-DNA/毫升。即使在该实验设置，病毒血症和HBsAg的水平没有显著治疗6周（9周圆周率）和平均cccDNA的负载增加后仍50倍下作为对照andcomparable到的值在周3圆周率发现（0.02个拷贝/细胞）。结论：Applicationof Myrcludex-B后的HBV感染表现出较强的能力，以阻断病毒spreadingin体内，这表明乙肝病毒优先通过分泌病毒颗粒和theuse Myrcludex-B的组合传播与目前的乙肝药物可改善patients'outcome。

乙肝 - Myrcludex-B - 进入抑制剂 - 的uPA/ SCID

newchinabok

HBV-DNA，乙肝表面抗原。rcDNA抑制，cccDNA  免疫组织化学  （核心抗原 ） 为评估指标

再比较人体试验看看