Replicor提出关于REP的安全性和有效性基于2139ca合治疗慢性

HBVCURER

StephenW 发表于 2015-11-6 23:55
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I think you are talking rubbish again!

“Interferon used to be described as immune-moderator, but now research indicated, post REP9AC,  that it may achieve some of its effect because it can also lower HBsAg!”

IFN能降低HBsAg，真的真的不是现在才发现的。IFN是研究的最多也可能是最久的一种抗病毒药物了，它的作用机制非常丰富，但是最早发现的经典抗病毒机制之一，就是IFN能激活2-5OAS/RNase L，降解病毒mRNA， 从而降低病毒抗原，自然包括HBsAg（也还有其他机制可以降低HBsAg，这些年来逐步被更清晰地阐明）。这一点在当初开发IFN以及peg-IFN用于治疗HBV的时候，有大量的文献阐述，而这些文献，都早于replicor。

你说的在美国定量HBsAg没有被广泛采用，这是事实。但在欧洲早就被当作是金标准了。事实上HBV的基础和临床研究，欧洲一直都是主力。同时，即便是非定量的HBsAg检测（除了早期的+/-这种两对半结果，早已被淘汰），也不是看不到HBsAg的降低，只不过缺少线性关系而已。但对于临床上的趋势观察而言，早已经足够了。

最后，我觉得我有必要说一句，讨论问题基本点是相互尊重。那怕你说的再错，基本观点似是而非，我也不会说出“you are talking rubbish”这种rubbish来的。

HBVCURER

MP4 发表于 2015-11-7 00:04
你还没看明白我说的吗？市场大就一定意味着能占市场份额？我也知道可乐市场大技术要求还没制药高啊，可我 ...

我原帖说的很清楚了，不仅仅病毒载体，也包括质粒DNA载体（你到底是看不见还是看不懂哦啊？？）。在用于基因治疗的时候，因为使用剂量很高，有可能出现整合到基因组上所带来的风险，所以这一方案也同样受到黑天鹅事件的严重影响。确切点说，当年只要是基因治疗概念，无论是哪种技术路线，统统受到严重影响。即使这么多年过去了，这种影响也还没完全消除，基因治疗的推广还是受到很大的阻力。当然，和2008年的一片漆黑是完全不同的，现下已经看到曙光了。

StephenW

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As I said before, show me the evidence to support what you mentioned as "facts".

有哪些学术论文，是引用了REP9AC的论文或结果作为该观点的来源的？这么说够明确吗？
Read carefully what I said - REP9AC is the first compound that demonstrated  HBsAg inhibit HBV specific immune functions in humans - the keyword here is "humans".

是REP9AC引发了后续的新策略例如siRNA，
I don't know whether you want to mislead intentionally - REP9Ac has nothing to do with RNAi, you know and I know. But the clinical trials of REP9AC showed that reduction in serum HBsAg MAY lead to a cure for HBV. Since ARC520 cannot reduce hbvdna efficiently as NUCS, REP9AC allows ARC520 to seek a second life. Show facts that I am wrong on this and I will apologize.

一样会有以降低HBV DNA的同时抑制HBsAg进而实现血清学转换的说法, 这个说法不是replicor的原创，
In humans, REP9AC is the first one to demonstrate that.
"Replicor’s first discovery has been to demonstrate in patients that Replicor’s NAPs can reduce circulating surface antigen to undetectable levels over a 20 week treatment. NAPs target the assembly and release of subviral particles (SVPs) from infected liver cells. Almost all surface antigen (HBsAg) circulating in the blood comes from SVPs (for every infectious HBV virus there are more than 10,000 non-infectious SVPs). Circulating HBsAg interferes with the ability of the immune system to fight the virus and eventually overwhelms the patient’s immune response, allowing the infection to become chronic. For some patients the removal of HBsAg is enough to allow their immune system to completely suppress and establish control of their infection off treatment. This state is referred to as having a Sustained Virological Response (SVR).

The second discovery has been to understand the role of surface antigen. Replicor’s hypothesis, which has now been proven in four separate human clinical trials, is that by reducing and eliminating surface antigen with NAPs, the immune system is allowed to recover and regain control of the infection. More importantly, in those patients where removing HBsAg was not enough to restore immune control, the elimination of HBsAg greatly improved their response to immunotherapy compared to patients receiving immunotherapy without the benefit of HBsAg removal. This combination treatment of NAP-based HBsAg removal and concomitant immunotherapy results in high rates of restoration of immune control over HBV infection off treatment."

事实上Replicor已经关注到了HBsAg的肝脏聚集问题并着手优化新的NAP了
Please  show me evidence for this fact? What exactly is the problem of 肝脏聚集?
优化新的NAP了 to reduce the accumulation of HBsAg and at the same time blocking its release? Please explain.

也足足够产生你所担心的HBsAg epitopes in MHC class I complex了。这么说够明确吗？Proof? You think .001 % is enough? I need to see the evidence, not your suggestion based on what?

Name me the textbooks that show evidence serum HbsAg inhibit HBV immune functions. Even Arrowhead cannot and did not know of such textbooks.

HBVCURER

StephenW 发表于 2015-11-7 00:04
回复 guilin2013 的帖子

没人怀疑ARC-520,没人怀疑ABX203? 你看他们的股价？

这是不同的怀疑。

对ARC520, ASX203的怀疑是是否能达到预想的治疗效果。当初对Replicor的怀疑是，数据本身的可靠性。对我而言，什么时候能标准化流程重复出当年单药诱发高比例的HBsAg血清学转换的结果来，才能打消我对当初其数据可靠性的怀疑。

HBVCURER

MP4 发表于 2015-11-7 00:17
FDA啥时候批准的不重要，他们是2008年发新闻稿说开始做一期临床试验的就对了。 ...

FDA在黑天鹅之前批准了，然后黑天鹅了，然他们开始了，然后就嗝屁没下文了。

对了，500例临床安全的数据，在哪里呢？

StephenW

guilin2013 发表于 2015-11-7 00:32
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股价是因为对这两药的效果还没有太明确的说法，但这两药是稳步推进，未来实验显示强 ...

但这两药是稳步推进 - 为什么 4mg? 为什么FDA不赞成多剂量递增？为什么ARC521？
未来实验显示强大的效果 - 你可以看到未来?

还在在一个不知那里的国家做临 - 同ABX203的国家.

你的怀疑基于什么？基于没有上市计划??

MP4

补充下
Nucleonics在2008年解散后，IP(知识产权)卖给了Alnylam，之后Alnylam主要目标是肝癌，与国内世方药业联盟。据闻Alnylam打算今年尾启动乙肝临床试验
以下转

大公司像Novartis和Merk都像Gilead一样在抛弃这种技术。但小公司Arrowhead却捡起来。前段时间Arrowhead刚从Novartis花3500万买了一些RNAi资产，这些RNAi资产其实是2005年Novartis从RNAi专长的Alnylam ($ALNY)花5600万买去的。十年过去了，显然Novartis在这方面一事无成。难怪Alnylam对最近这笔交易即嘲笑Novartis的无能，也对Arrowhead不看好。Alnylam自认为自己在RNAi方面造诣深厚，也在积极的用RNAi gene silencer技术的药ALN-HBV去加入对付HBV的大战中

MP4

HBVCURER 发表于 2015-11-7 01:09
FDA在黑天鹅之前批准了，然后黑天鹅了，然他们开始了，然后就嗝屁没下文了。

对了，500例临床安全的数据 ...

补充下
Nucleonics在2008年解散后，IP(知识产权)卖给了Alnylam，之后Alnylam主要目标是肝癌，与国内世方药业联盟。据闻Alnylam打算今年尾启动乙肝临床试验

StephenW

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IFN能降低HBsAg，真的真的不是现在才发现的。Please read carefully what I wrote - I did not say post REP9AC it has been shown that IFN能降低HBsAg! But it is a fact that post REP9AC, IFN能降低HBsAg is one of the reasons why it modulates the immune system!

这一点在当初开发IFN以及peg-IFN用于治疗HBV的时候，有大量的文献阐述，而这些文献，都早于replicor。Yes, but did they attribute this effect of Interferon because it can reduce HBsAg? So you are talking rubbish.

事实上HBV的基础和临床研究，欧洲一直都是主力。Yes, but clinical trials in new HBV drugs, 欧洲一直都是主力?

I am very blunt, when I see frequent misrepresentations or mistake, I call a spade a spade. You may not say I am not talking rubbish, but you do say it, indirectly, just the same. As I say, show me your evidence that I am wrong, I will apologize, directly.

HBVCURER

StephenW 发表于 2015-11-7 01:03
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As I said before, show me the evidence to support what you mentioned as "facts ...

“REP9AC is the first compound that demonstrated HBsAg inhibit HBV specific immune functions in humans”

我实在不能理解，为什么HBsAg inhibits HBV specific immune functions in humans需要REP9AC来demonstrate？在患者体内的免疫学研究早就证明了。好吧，你说是第一个compound，但不总能说，第一个compound支持了之前的理论，就认为其后所有的compound都是学习它吧。他们都是一个师傅，出师有早晚罢了。

“REP9AC allows ARC520 to seek a second life.” 这个只是你的臆测罢了。ARC为什么要REP9AC 来教他只有降低HBsAg才有出路？制药界都知道只有降低了HBsAg才有出路，他们都是REP9AC的徒弟？太好笑了吧？假如大家都在学replicor，为啥没人直接去走replicor的技术路线呢？又不复杂。

“Circulating HBsAg interferes with the ability of the immune system to fight the virus and eventually overwhelms the patient’s immune response, allowing the infection to become chronic.” 这并不是replicor教会大家的新知识，我要说多少遍？

“事实上Replicor已经关注到了HBsAg的肝脏聚集问题并着手优化新的NAP了”。这个replicor的主页上就有，自己看吧。

“You think .001 % is enough? I need to see the evidence, not your suggestion based on what?” 这是免疫学基本常识。即便是很低表达量的抗原，也会被HLA提呈倒细胞表面，只要特异性的T细胞足够活化，就可以杀伤。理论上讲，细胞表面有一个暴露的表位就足够了。同时，HBsAg的降低也不是瞬间就降到最低，有一个逐步降低的过程，而在这个过程中HBsAg的抗原表位一直在被提呈中。这其实和HBsAg在被清除之后会逐步产生抗体一个道理。如果按类似你的理解，既然血清中没有HBsAg了，也就没有了免疫原，那么针对HBsAg的抗体又是怎么产生的？


病毒学的经典教科书，Fields virology，里面有专门的HBV一章。