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标题: arc520 好资料必看 [打印本页]

作者: newchinabok 时间: 2015-11-10 09:26 标题: arc520 好资料必看

http://files.shareholder.com/dow ... ster_2015_Final.pdf

作者: fs2002 时间: 2015-11-10 10:28

看不懂，好心人翻译一下呗

作者: newchinabok 时间: 2015-11-10 10:29

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文字可复制，去百度翻译译吧

作者: jinabest 时间: 2015-11-10 13:03

结论：arc520对大三阳猩猩降低表抗效果明显，对小三阳猩猩效果不明显。arc520在4mg剂量仍然是耐受的。多种证据表明整合dna是产生表抗的主要来源，尤其对于小三阳。

作者: ivanich 时间: 2015-11-10 16:34

人还是猩猩

作者: 齐欢畅2 时间: 2015-11-10 21:17

jinabest 发表于 2015-11-10 13:03
结论：arc520对大三阳猩猩降低表抗效果明显，对小三阳猩猩效果不明显。arc520在4mg剂量仍然是耐受的。多种 ...

整合dna是产生表抗的主要来源，

作者: StephenW 时间: 2015-11-10 21:28

齐欢畅2 发表于 2015-11-10 21:17
整合dna是产生表抗的主要来源，

整合dna是产生表抗的主要来源 - 整合dna是产生表抗一个来源, 不是主要来源.

作者: 齐欢畅2 时间: 2015-11-10 21:34

ARC-520 will continue development including focus on the significant market of e-antigen positive treatment-naïve chronic HBV patients. ARC-521 is being developed to target cccDNA and also, integrated DNA, which appears to be a more significant producer of HBsAg in patients who have been treated with NUCs or who are e-antigen negative. In HBeAg-negative chimps predicted to have higher levels of integrated DNA, administration of the integrant-targeted siRNA in ARC-521 led to 99% (2 logs) of additional HBsAg reduction. The Company expects to file an IND or equivalent for ARC-521 by mid-2016.

作者: 齐欢畅2 时间: 2015-11-10 21:35

ARC-521

administration of the integrant-targeted siRNA in ARC-521 led to 99% (2 logs) of additional HBsAg reduction. The Company expects to file an IND or equivalent for ARC-521 by mid-2016.

作者: 齐欢畅2 时间: 2015-11-10 21:36

StephenW 发表于 2015-11-10 21:28
整合dna是产生表抗的主要来源 - 整合dna是产生表抗一个来源, 不是主要来源. ...

作者: 齐欢畅2 时间: 2015-11-10 21:37

重要来源

作者: newchinabok 时间: 2015-11-10 21:51

马克

作者: 齐欢畅2 时间: 2015-11-10 21:55

个人意见：降低表抗可以产生免疫反应，我确信，但一定要降低到很低，我认为是万分之一左右，也就是0.0001,4个数量级的降低，如果还不能激发免疫反应，就上干扰素和乙肝疫苗吧，或者古巴新药也可以，很期待arc521，同时抑制cccdna和整合dna，以大三阳患者为例，获得了99%的表抗降低，那么姑且算剩余的1%是由整合dna所产生的，那么如果可以将整合dna也抑制的程度降低到99%，那么就刚好可以达到万分之一的要求，那么激发免疫系统产生免疫反应就可以实现，所以，对于arc521,战胜乙肝，已不是不可能的了，我认为arc521至少可以解决超过50%的乙肝，加上联合用药的话，乙肝攻克只是时间问题。

作者: 齐欢畅2 时间: 2015-11-10 21:57

ARC-520 will continue development including focus on the significant market of e-antigen positive treatment-naïve chronic HBV patients. ARC-521 is being developed to target cccDNA and also, integrated DNA, which appears to be a more significant producer of HBsAg in patients who have been treated with NUCs or who are e-antigen negative. In HBeAg-negative chimps predicted to have higher levels of integrated DNA, administration of the integrant-targeted siRNA in ARC-521 led to 99% (2 logs) of additional HBsAg reduction. The Company expects to file an IND or equivalent for ARC-521 by mid-2016.
个人意见：降低表抗可以产生免疫反应，我确信，但一定要降低到很低，我认为是万分之一左右，也就是0.0001,4个数量级的降低，如果还不能激发免疫反应，就上干扰素和乙肝疫苗吧，或者古巴新药也可以，很期待arc521，同时抑制cccdna和整合dna，以大三阳患者为例，获得了99%的表抗降低，那么姑且算剩余的1%是由整合dna所产生的，那么如果可以将整合dna也抑制的程度降低到99%，那么就刚好可以达到万分之一的要求，那么激发免疫系统产生免疫反应就可以实现，所以，对于arc521,战胜乙肝，已不是不可能的了，我认为arc521至少可以解决超过50%的乙肝，加上联合用药的话，乙肝攻克只是时间问题。

作者: StephenW 时间: 2015-11-10 22:07

齐欢畅2 发表于 2015-11-10 21:37
重要来源

这一点，我个人不同意, 即使这是Locarnini教授他的解释.

出发点是: arc520对大三阳猩猩降低表抗效果明显，对小三阳猩猩效果不明显.
Locarnini教授他的解释:
1. arc520靶标是cccDNA, 大三阳猩猩有很大的cccDNA量, 降低表抗效果明显.小三阳猩猩具有非常小的cccDNA, 但效果不明显, 因此，必须有另一种乙肝表面抗原源. 此源必须是整合dna.
2. 设计arc521靶标乙肝表面抗原基因在整合dna和cccDNA. arc521对小三阳猩猩效果明显.

疑问:
1. arc521是否对大三阳猩猩降低表抗效果明显?如果是的话，问题是arc520，不是整合dna.
2.小三阳猩猩具有大量整合dna吗? 从活检证据?
3. 猩猩的证据可以应用到人吗?

作者: 齐欢畅2 时间: 2015-11-10 22:12

合理怀疑。
但我个人觉得整合dna可以通过某种形式制造表抗，虽然我也不知道具体原因。

作者: 齐欢畅2 时间: 2015-11-10 22:33

考虑人体细胞核dna，他们是可以表达蛋白质的，这个高中生物就学习过
所以乙肝整合dna可以表达蛋白质也不足为奇，但不是说一定可以得到表达。
cccdna是一个环状dna稳定性很强强，而且可以通过不断的解旋来表达hbsag，这个是一个cccdna高效生产表抗的机制，比整合dna肯定要快。
曾经有一个药物，在论坛掀起轩然大波，就是蔡荣的奎纳克林-----这个药物可以对cccdna产生抑制作用，因为奎纳克林分子可以和cccdna分子，利用氢键结合，从而抑制cccdna的解旋和再螺旋化，通过战友的药物试验，结果也显示确实有抑制乙肝病毒的作用。
箭头公司的关于整合dna的解释，我个人还是赞成的，但也是具有疑点的，因为没有很明确的给出机理解释。
但从其已发表的论文来看，arc521确实显示了更强的抑制表抗的作用。个人观点，仅供参考。

作者: HBVCURER 时间: 2015-11-10 22:47

回复 StephenW 的帖子

1. ARC521本质上就是在ARC520基础上增加一个可以靶向整合DNA的siRNA trigger，这个trigger同样也可以靶向cccDNA，不存在只靶向整合DNA不靶向cccDDA的siRNA。从这个原理讲，ARC521对大三阳应该同样有效。我也很奇怪目前ARC公司的下一步研发策略。全力开发ARC521包治大小三阳即可。不放弃ARC520原因可能是不愿放弃先前的在520上付出的所所有努力。
2.小三阳黑猩猩患者，根据RNAseq数据的推断，存在大量整合，但这是间接证据，AASLD期间，相信会看到完整证据。
3. 黑猩猩是最真实接近人类的动物模型，目前关于乙肝和丙肝的很多认识，最初都来自黑猩猩，和人类感染存在重大区别的地方，似乎还不多见。

关于ARC520和Rep9ac降HBs的区别，我有个问题想问一下：为什么你说rep9ac只抑制Hbs分泌，而不以抑制病毒颗粒的分泌？我觉得解释不通

作者: StephenW 时间: 2015-11-11 00:29

本帖最后由 StephenW 于 2015-11-11 00:36 编辑

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我觉得解释不通
你自己看:
http://replicor.com/science/hepatitis-b/
http://replicor.com/science/nap-technology/

作者: StephenW 时间: 2015-11-11 00:29

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我觉得解释不通
你自己看:

作者: jaylongli 时间: 2015-11-11 14:27

关键还是在猩猩身上，这么久了

作者: ivanich 时间: 2015-11-11 15:01

那次发布的消息不是人身上么

作者: HBVCURER 时间: 2015-11-11 23:48

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你给的单纯网页上的这些背景信息，我其实一早就清楚的。

而我的问题是，如果NAPs仅仅只抑制SVP的分泌而不抑制Viral Pariticle分泌的话，如何能解释仅仅在治疗12周的时候，serum HBV DNA（以及RNA）就已经显著下降了，非常接近LLD；而这时HBsAg仍然是显著阳性的。很明显这是无法用"restoration of immune function"来解释的。

这其实也一直是我对Replicor的一大疑惑和不解。不知道你是怎么考虑的。

作者: StephenW 时间: 2015-11-12 00:19

本帖最后由 StephenW 于 2015-11-12 00:23 编辑

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This is what Replicor posted on clinical.gov website regarding their new clinical trial. It should answer all your questions. Please read carefully[the red highlight is by me]

"Nucleic acid polymers (NAPs) utilize the sequence independent properties of phosphorothioated oligonucleotides to target apolipoprotein interactions involved in the formation of HBV subviral particles (SVPs) which are comprised mainly of the hepatitis B surface antigen protein (HBsAg). The effect of NAPs is to block the formation of SVPs inside infected hepatocytes which prevents their secretion. As SVPs account for > 99.99% of HBsAg in the blood, NAPs are an effective approach for clearing HBsAg from the serum of HBV infected patient.

Previous clinical trials have demonstrated that treatment with the NAP REP 2139 (REP 2139-Ca) results in the rapid and effective clearance ofHBsAg from the blood. This HBsAg removal has the immediate effect of unmasking the underlying, pre-existing anti-HBsAg (anti-HBs) response, allowing clearance of HBV virus from the blood.

HBsAg has important immunosuppressive effects in HBV infection which have been shown to block both adaptive and innate immune processes. Removal of HBsAg from the blood of patients removes this immunosuppressive effect.

Thus, an important additional effect of removal of HBsAg from the blood is to greatly enhance the effect of immunotherapeutic agents like pegylated interferon alpha 2a and thymosin alpha 1. It is expected that elimination of serum HBsAg with REP 2139-Mg or REP 2165-Mg will lead to creation of a favourable immunological activation in the absence of HBsAg, appearance of free anti-HBs, clearance of HBV virions in the blood and synergistic immunostimulation with conventional dosing of pegylated interferon alpha-2a or thymosin alpha-1 and improved control of HBV infection in the presence of tenofovir disoproxil fumarate (TDF). All patients will receive 24 weeks of monotherapy with TDF prior to entry into experimental or active comparator arms."

TDF (reduces replication and hence release of new viral particles) + REP9AC (inhibits the formation of Sub Viral Particles and hence release of 99.99 % HBsAg, since HBsAg can only be released from infected liver cells in the forms of SVP or surface coat of viral particles) = removal of serum HBsAg = unmasking of HBsAb, freeing these HBsAb to bind to any serum viral particles, hence allow removing of all serum viral particles.

In this ideal situation of no immunosuppression by serum HBsAg and viral particles, immunostimulation with Interferon may allow revival of immune system sufficiently to permanently control the infection when treatment (TDF + REP9AC) is stopped.

作者: HBVCURER 时间: 2015-11-12 00:57

本帖最后由 HBVCURER 于 2015-11-12 01:04 编辑

StephenW 发表于 2015-11-12 00:19
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This is what Replicor posted on clinical.gov website regarding their new clini ...

很遗憾，这些并没有回答到我的问题。

我的疑问很明确：在治疗12周的时候，这时HBV DNA已经非常接近LLD了，而这时的HBsAg还没有被remove，其滴度仍然较高，因此，显然不能用标红部分所谓的pre-existing anti-HBsAg (anti-HBs) 以及任何“removes this immunosuppressive effect”来解释。

我不知道我说了两次，说清楚了没有。

作者: HBVCURER 时间: 2015-11-12 01:00

这里是原始数据

作者: StephenW 时间: 2015-11-12 09:03

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Oh, I see. You referred to the abstract presented at EASL 2015:

SERUM HBV-RNA LEVELS DECLINE SIGNIFICANTLY IN CHRONIC HEPATITIS B PATIENTS DOSED WITH THE NUCLEIC-ACID POLYMER REP2139-CA
Louis Jansen* 1, 2, Andrew Vaillant3, Femke Stelma1, 2, Neeltje A. Kootstra2, Michel Bazinet3, M. Al-Mahtab4, Hendrik W. Reesink1, 2
1Gastroenterology and Hepatology, 2Experimental Immunology, Academic Medical Centre, University of Amsterdam., Amsterdam, Netherlands, 3REPLICor Inc., Montreal, Canada, 4Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh

Corresponding author’s email: l.***@****

Background and Aims: Treatment of chronic hepatitis B (CHB) patients with the HBsAg release inhibitor REP2139-Ca may be a promising new option for achieving therapy-induced HBsAg loss (functional cure), however its effect on circulating hepatitis B pregenomic RNA (HBV-RNA) is not known. For this, we determined HBV-RNA levels during treatment with REP2139-Ca and compared these with HBV-DNA and HBsAg levels.
Methods: 12 Patients with HBeAg positive CHB (mean HBV-DNA 8.21 logC/mL) participating in a phase 2 study were dosed with the nucleic-acid based amphipathic polymer REP2139-Ca for 20-38 weeks. Responders to REP2139 (defined as decline in serum HBsAg) were subsequently treated with add-on peginterferon alpha-2a and/or thymosin alpha-1. HBsAg (Architect), HBV-DNA, and HBV-RNA levels were determined in baseline serum samples, after 20-24 weeks of REP2139-Ca monotherapy, and either during a treatment-free follow-up (for responders) or during entecavir treatment (for non-responders). HBV-RNA isolated from 140 µL of plasma was quantified by RT-qPCR using HBV-specific primers. Lower limit of quantification of RNA was set at 3.00 logC/mL. Variables were evaluated with a paired T-test.
Results: HBV-RNA was detectable in all 12 patients before treatment (mean 6.70 (SD 0.83) logC/mL), and was significantly associated with HBsAg (r2 0.33, p=0.049) and HBV-DNA (r2 0.74, p<0.001). After 20-24 weeks of REP2139-Ca treatment, mean HBV-RNA, HBV-DNA, and HBsAg levels declined significantly compared to baseline (-2.54, -3.34, and -3.12 logC or IU/mL, respectively, all p<0.001). At week 20-24, HBV-RNA was undetectable in 8/12 patients. In 7 of these 8 patients, HBV-RNA remained undetectable during the treatment-free follow-up period (mean 21.9 weeks, range 7-27). HBsAg loss and anti-HBs seroconversion was achieved in 4/8 patients during treatment-free follow-up (anti-HBs range 200-766 U/L).

=============================================
In 12 HbeAg POSITIVE patients, 20-24 week treatment with REP2139-CA, mean HBV-RNA, HBV-DNA, and HBsAg levels declined significantly compared to baseline. Replicor attributed the decline in HbsAg to REP2139-CA, but they OBSERVED also decline in HBVDNA and HBV-RNA. Replicor offered no explanation, and I of cause cannot offer an explanation.
If you believe it is due to the blocking of release of new viral particles by REP2139-CA, that is your business. If you don't believe REP92139-CA caused decline in HBsAg, that is your business. To me, the decline in both HBVDNA and HBsAg in HBeAg positive patients by REP2139-CA is a very encouraging result if can be repeated in a larger cohart of patients. An explanation of the mechanism that lead to decline in HBVDNA would be nice, but it can wait.

As to masking of HbsAb, it is well known that chronic HBV patients do produce HBsAb(pre-existing) but in far less quantity than HBsAg, hence they are "masked" and cannot be detected .
As to removal of "immunosuppressive" effect, it is believed that the immunosuppressive effect does not have to wait until HBsAg = 0 to be removed, but may start to wane after the decline of HBsAg to a certain threshold level, maybe 1,000 iu/ml.

作者: HBVCURER 时间: 2015-11-12 11:33

本帖最后由 HBVCURER 于 2015-11-12 11:35 编辑

StephenW 发表于 2015-11-12 09:03
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Oh, I see. You referred to the abstract presented at EASL 2015:

出现了这么明显和其基本机制并不相吻合的临床结果，Replicor并没有能给出任何解释。当然你也无法解释，你可以觉得这不重要；但对Replicor而言，面对质疑就不是像你来这么一句“that is your business”就能化解的了。事实上，业界的质疑从最早的这张poster中所展示的数据就开始了。而其中部分患者体内HBsAg，HBsAb和HBV DNA之间很难解释的相互动态变化关系，一直是质疑的焦点。而在replicor后续的所有数据展示中，干脆就直接省略了12周以内的HBV DNA（以及RNA）的检测结果。

As to removal of "immunosuppressive" effect, it is believed that the immunosuppressive effect does not have to wait until HBsAg = 0 to be removed, but may start to wane after the decline of HBsAg to a certain threshold level, maybe 1,000 iu/ml.

可以说，这明显是缺乏临床数据支持的。我同意无需等到HBsAg降为0，事实上也不可能降为0，但要到可以到开始removal of "immunosuppressive" effect的程度，replicor和ARC520的数据都并不支持你认为的1000的这个所谓额阈值，同样也和很多年来的干扰素治疗相关的临床观察不相吻合。更何况，我们这里讨论的是，HBsAb的产生及其对HBV DNA/HBsAg的影响，这种影响绝不可能从1000IU的水平开始。

Replicor一直使用masking这个词来形容HBsAg和HBsAb之间的相互关系，其实有一个更直接的词，neutralizing，中和。CHB患者体内可能存在微量的HBsAb，但会立即中和HBsAb形成抗原抗体复合物并被机体清除。当体内还存在高滴度HBsAg的时候，除非是突变的HBsAg或某些极为特殊的情况，否则不可能检测到游离状态的HBsAb的。此外，ARC的数据也清晰地提示，即使HBsAg下降到较低的水平，HBsAb也很可能并不会自发产生。这和replicor所谓的“masking”效应，只要HBsAg显著降了，即使不降到0，也会释放出pre-existing HBsAb的解释，是不相吻合的，同样和多年的临床实践不相吻合。

好了，我觉得和你关于replior的讨论确实可以告一段落了。说到底，选择相信什么，不相信什么，确实是个人的选择。

作者: ivanich 时间: 2015-11-12 12:55

大神水平的确是火星级！

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