肝胆相照论坛

标题: AASLD2014:Myrcludex 2a期临床试验 [打印本页]

作者: StephenW 时间: 2014-10-10 04:09 标题: AASLD2014:Myrcludex 2a期临床试验

本帖最后由 StephenW 于 2014-10-10 04:11 编辑

Final ID: LB-20
A proof-of-concept Phase 2a clinical trial with HBV/HDV entry inhibitor Myrcludex B
S. Urban; 2; P. Bogomolov; 4; N. Voronkova; 4; L. Allweiss; 3; M. Dandri; 3; M. Schwab; 6, 7; F. A. Lempp; 2; M.
Haag; 6; H. Wedemeyer; 5; A. Alexandrov; 1;
1. MYR GmbH, Bad Homburg, Germany.
2. University Hospital Heidelberg, Heidelberg, Germany.
3. University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
4. Moscow Regional Research Clinical Institute, Moscow, Russian Federation.
5. Hannover Medical School, Hannover, Germany.
6. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
7. Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany.
Abstract Body: Introduction: Current therapies for chronic hepatitis B rarely induce cure. Moreover, no effective treatment for the majority of hepatitis D patients is available. Myrcludex B is a first-in-class entry inhibitor inactivating the HBV/HDV receptor NTCP, thereby addressing a replication step possibly required for curative therapy. We here present findings of the first clinical trials of Myrcludex B in chronic hepatitis B and D.
Aim: To evaluate safety and tolerability, as well as antiviral efficacy of Myrcludex B.
Methodology: Cohort A: 40 chronically HBV infected, HBeAg negative patients (all HBV DNA >2000 IU/ml median HBV DNA 4.7 log10 IU/ml; no cirrhosis) were treated for 12 weeks with once daily sc 0.5mg, 1mg, 2mg, 5mg and 10mg Myrcludex B for 12 weeks (8 patients per dose). Treatment was extended to 24 weeks in patients receiving 10mg. Cohort B: 24 patients with hepatitis delta (compensated liver disease; 12.5% cirrhosis) scheduled for 48 weeks
of pegylated interferon alpha (PEG-IFNα) therapy. 8 hepatitis delta patients are receiving pre-treatment with 2mg Myrcludex B alone for 24 weeks (B1); Myrcludex B was added to (PEG-IFNa) for the first 24 weeks to another 8 patients (B2) while 8 patients are treated with PEG-IFNa alone (B3).
Results:
Myrcludex B was very well tolerated, injection side dermatitis occurred in 3 patients (10mg group) of Myrcludex B, regressed on treatment. A psoriasis exacerbation occurred in one HDV patient (B2) leading to discontinuation.
>1log10 HBV DNA decline at week 12 was observed in 6/8 (75%) patients receiving 10mg Myrcludex B while this occurred less often in the remaining dose groups (7/40; 17%). ALT normalized in 22/40 (55%) patients, median ALT values declined from 76 U/l before therapy to 36 U/l at week 12 (p<0.001). No significant changes in HBsAg levels occurred. In hepatitis delta, 6/7 and 7/7 of patients with data available experienced >1log10 HDV RNA decline at week 24 during Myrcludex B monotherapy (B1) or combination therapy (B2) while this response was observed in 7/7 of B3 patients at week 12. HDV RNA became negative in 2 (B1) and 5 (B2) patients at week 24. ALT values declined at week 24 in 6/7 (B1), 4/7 (B2) and 3/7 (B3, week 12) patients. One patient in B1 and one in B2 had negative HDV RNA and normal ALT at week 24. One patient (B2) experienced 1log10 HBsAg decline at week 24. Myrcludex B treatment induced preS-specific antibodies and bile acid elevation at doses >1mg.
Conclusion: Myrcludex B is safe and well tolerated in HBsAg positive patients with or without HDV coinfection. HBV entry inhibition seems to be associated HBV DNA and HDV RNA declines and improvement of biochemical disease activity.

作者: StephenW 时间: 2014-10-10 04:10

最终编号：LB-20
概念验证的2a期临床试验乙肝病毒/ HDV进入抑制剂Myrcludex乙
南城市; 2;第博戈莫洛夫; 4;北Voronkova; 4;属Allweiss; 3; M. Dandri; 3; M.施瓦布; 6,7; F. A. Lempp; 2; M。
哈格; 6; H·魏德迈; 5;答：亚历山德罗夫; 1;
1 MYR有限公司，巴特洪堡，德国。
2，大学医院海德堡，德国海德堡。
3，大学医学中心汉堡Eppendorf公司，德国汉堡。
4，莫斯科地区临床研究学院，莫斯科，俄罗斯联邦。
5，汉诺威医学院，德国汉诺威。
6，玛格丽特博士费 - 博世临床药理研究所，德国斯图加特。
临床药理学的7系，大学医院蒂宾根大学，蒂宾根大学，德国。
摘要正文：前言：目前治疗慢性B型肝炎很少引起治愈。此外，没有有效
治疗为广大丁型肝炎病人的是可用的。 Myrcludex B是第一的一流的进入抑制剂失活
乙肝/ HDV受体NTCP，从而解决可能需要根治疗法复制步骤。我们在这里
Myrcludex B的第一次临床试验在慢性乙型肝炎和D目前的研究结果
目的：为了评估Myrcludex B的安全性和耐受性，以及抗病毒疗效
方法：队列答：40慢性乙肝病毒感染者，HBeAg阴性患者（所有的HBV DNA>2000 IU/ ml的中位数
HBV-DNA4.7日志10国际单位/毫升;无肝硬化），共12周均采用每天一次SC0.5毫克，1毫克，2毫克，5毫克和
10毫克Myrcludex乙，共12周（8例，每剂）。治疗延长至24周，接受患者
10毫克。队列B：24例丁型肝炎（代偿性肝病，12.5％的肝硬化）预定48周
聚乙二醇化干扰素α（PEG-IFNα）治疗。 8丁型肝炎患者正在接受治疗前用2毫克
Myrcludex B独24周（B1）; Myrcludex B加入到（PEG-干扰素a）为在第一个24周〜另一个8
例（B2），而8例与聚乙二醇干扰素a单（B3）的治疗。
结果：
Myrcludex B的耐受性很好，注射侧皮炎发生在Myrcludex乙的3例（10毫克组）
退步治疗。牛皮癣发作发生在一个病人的HDV（B2）导致停药。
>1log10的HBV DNA下降12周，观察6月8日（75％）患者接受10毫克Myrcludex乙，而这
少经常在剩余的剂量组出现（40分之7;17％）。 ALT正常化四十〇分之二十二（55％）的患者，中位ALT
价值76单位/升下降了治疗前36单位/升，在12周（P <0.001）。在HBsAg水平无显著变化
发生。在丁型肝炎，6/7和数据提供经验>1log10 HDV RNA的跌幅在本周7/7患者
期间Myrcludex乙单一疗法（B1）或组合疗法（B2），同时此反应中观察到B3的七分之七24
患者在第12周的HDV RNA2（B1）和图5（B2）的患者在第24周的ALT值成为负，在下降
在7分之6（B1），4/7（B2）和七分之三（B3，第12周）的患者24周。一名患者在B1，一个在B2有负面的HDV RNA
并在第24周一个病人（B2），ALT正常经历1log10 HBsAg的下降，在第24周Myrcludex B处理
前S诱导特异性抗体和胆汁酸升高，剂量>1毫克。
结论：Myrcludex B是安全的，耐受性良好的HBsAg阳性患者有无HDV合并感染。乙肝
条目抑制似乎是相关联的HBV DNA和HDV RNA下降和改善生化疾病的
活动。

作者: 咬牙硬挺 时间: 2014-10-10 07:04

没说疗效吗

作者: newchinabok 时间: 2014-10-10 07:04

基本失败

作者: wunaidewo 时间: 2014-10-10 07:26

什么意思

作者: lgs1 时间: 2014-10-10 07:30

期待进一步解释

抗原基本不变??

作者: 重韧 时间: 2014-10-10 08:52

这个药好像跳出来都好久了，现在才2a，看来未来并不看好啊。这也是在混经费的感觉啊。

作者: lgs1 时间: 2014-10-10 09:12

看来还是要指望美国大公司啊

作者: newchinabok 时间: 2014-10-10 09:25

5年内看arc520,gs9620和核衣壳抑制剂了

作者: 重韧 时间: 2014-10-10 11:45

newchinabok 发表于 2014-10-10 09:25
5年内看arc520,gs9620和核衣壳抑制剂了

核衣壳抑制剂应该是看Oncore生物吧，总感觉这家公司能成。。

作者: newchinabok 时间: 2014-10-10 12:24

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

作者: StephenW 时间: 2014-10-10 13:15

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.

作者: StephenW 时间: 2014-10-10 13:19

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.

作者: newchinabok 时间: 2014-10-10 13:40

把myrcludex动物试验数据对比一下现在数据看看

作者: StephenW 时间: 2014-10-10 14:21

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.

作者: lgs1 时间: 2014-10-10 14:58

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

作者: newchinabok 时间: 2014-10-10 20:01

本帖最后由 newchinabok 于 2014-10-10 20:02 编辑

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

作者: newchinabok 时间: 2014-10-10 20:03

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

作者: newchinabok 时间: 2014-10-10 20:06

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

欢迎光临肝胆相照论坛 (http://hbvhbv.info/forum/)