对REP9AC、DV601等治愈乙肝科学研究的看法

StephenW

[studyforhope]
Myrcludex blocks the entry of HBv into hepatocytes. That is all it does. Over time, that should indirectly reduce the pool of infected cells, by whatever means this reduction is operative, mainly the ongoing erosive immune attack, that causes the ALTs to be elevated. The question is really right now, how effective will the planned dose of Myrcludex of 1mg/day be in achieving this effect.

If the reduction of infected cells and therefore the cccDNA has come down to a level, where the surface antigen disappears from the circulation, then permanent immune control of the infection is likely, even after stopping myrcludex.

Myrcludex and Replicor would beautifully complement each other, since the effects are on entirely different aspects of the viral mechanisms.

Replicor blocks the release of the surface antigen particle from infected hepatocytes, not of any virions. It does that with great reliability and apparently very little side effects.
That effect per se however is not blocking the virus from replicating or directly reduces the cccDNA. What happens now is that the removal of the surface antigen allows the immune system to focus its anti surface effector cells on the liver and that will lead to an increased removal of infected cells, plus reduction in viral replication and transcription by noncytolytic mechanisms and ,unless the virus is able to respond evasivly, to a reduction of the infected cell number and the cccDNA to a level where permanent immune control of the remnant amounts will be possible, without outside medications.
Myrcludex would help in the speed of this process by preventing reinfection, speeding up clearance and, quite importantly, prevent any immunologically resistant subpopulation from spreading, thus ensuring the success of the REP9A treatment.

Myrcludex阻止乙肝病毒进入肝细胞的条目。这是它所做的一切。随着时间的推移，这应该间接地减少感染的细胞池，通过任何手段减少操作，主要是持续的糜烂性免疫攻击，导致升高的异常低价竞标。问题是真的，现在，如何有效地将1mg/day Myrcludex计划剂量达到这种效果。

如果减少感染的细胞，因此cccDNA的已回落到一定程度，表面抗原从流通中消失，然后永久感染的免疫控制是可能的，即使停药后myrcludex。

Myrcludex和Replicor精美相得益彰，因为病毒的机制是完全不同的方面的影响。

Replicor块释放从被感染的肝细胞的表面抗原颗粒，而不是任何病毒粒子。它具有高可靠性，显然是很少的副作用。
然而，这本身的影响是不阻止病毒复制，或直接降低了cccDNA的。现在会发生什么是表面抗原的清除，允许免疫系统，以集中其抗表面效应细胞对肝脏和，这将导致增加感染细胞的清除，再加上在减少病毒复制，并通过非溶细胞机制转录和，除非病毒是能够回应闪烁其词，没有一个被感染的细胞数量的减少和cccDNA的水平将有可能永久的残余量的免疫控制外药物。
Myrcludex将有助于这一进程的速度，防止再感染，加快通关，很重要的是，防止火势蔓延任何免疫抗亚群，从而保证了成功的REP9A治疗。

kaorusai

StephenW 发表于 2011-10-3 15:38
[studyforhope]
Myrcludex blocks the entry of HBv into hepatocytes. That is all it does. Over time, t ...

Myrcludex和REP9A联合用药？？？

kaorusai

Mycrludex本身是不够治愈？？
这真是个不幸的消息啊

StephenW

kaorusai 发表于 2011-10-3 16:10
Mycrludex本身是不够治愈？？
这真是个不幸的消息啊

很难说, Mycrludex，防止感染和再感染, 会帮助我们的免疫系统来清除所有的感染的肝细胞（与其cccDNA）。加上REP9AC，HBsAg水平下降，免疫系统可以集中精力清除感染的肝细胞（与其cccDNA），因此会很快治愈。这是理论，我们必须等待，看看它是否是真正的,临床试验后。

kaorusai

但愿这个理论能变为现实
Mycrludex到底是德国那个公司的？临床1期需要一年，临床2期需要2年，三期好像需要三年，通过FDA还要两年。那么就要等到2020年了.....太漫长了！

StephenW

kaorusai 发表于 2011-10-3 17:16
但愿这个理论能变为现实
Mycrludex到底是德国那个公司的？临床1期需要一年，临床2期需要2年，三期好像需要 ...

如果一种药物是好的，SDF可以快车道(fast track).
德国MYR GmbH, 非常小的公司

About the MYR GmbH
The company located in Burgwedel near Hannover was founded in 2010 and holds the world-wide exclusive product rights for Myrcludex. Currently, the company has 2 employees who are focused on the coordination of the network of academic partners and vendors involved in the Myrcludex development. Dr. Alexander Alexandrov, MYR CSO: „We have established a very successful public-private partnership giving birth to a promising and efficient Biotech-company“.
投资公司Gründerfonds
About High-Tech Gründerfonds
High-Tech Gründerfonds invests venture capital in promising technology companies that turn innovative concepts into viable businesses. Seed financing aims to help start-ups guide their innovation to the prototype or proof-of-concept stage or to market launch. High-Tech Gründerfonds provides seed financing of approximately €500,000. It supports high-tech companies by way of its investment managers and its highly-qualified network of coaches, investors and specialists. In individual cases it can invest up to a total of €2 m per company. The investors in this public private partnership are the German Federal Ministry for Business and Technology, the KfW Banking Group as well as the six industrial groups of BASF, Deutsche Telekom, Siemens, Robert Bosch, Daimler and Carl Zeiss. High-Tech Gründerfonds has an investment volume totalling approx. €272 m.

kaorusai

StephenW 发表于 2011-10-3 17:37
如果一种药物是好的，SDF可以快车道(fast track).
德国MYR GmbH, 非常小的公司

也是小公司啊......看来小公司能出好产品

2012痊愈

赶紧上市，造福人类

StephenW

Myrcludex演示文稿 - 旧金山, 肝病学会2011
[posted by studyforhope]

Myrcludex presentation at the San Francisco liver conference.

The entry inhibitor Myrcludex-B efficiently blocks viral spreading in vivo in human liver chimeric uPA/SCID mice previously infected with Hepatitis B Virus
M. Lutgehetmann1, 2; J. Petersen3; T. Volz1; L. Allweiss1; A. W. Lohse1; S. Urban4; M. Dandri1
1. Internal Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany.
2. Medical Microbiology, University Hospital Hamburg Eppendorf, Hamburg, Germany.
3. Asklepiosklinik St. Georg, Liver Center Hamburg IFI Institute, Hamburg, Germany.
4. Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany.


  
Currently approved antiviral treatments based on interferon alpha or inhibitors of the hepatitis B virus (HBV) polymerase are generally not curative and additional therapeutic strategies interfering with other HBV replication steps are needed. We previously demonstrated prevention of de novo HBV infection by pre-treating uPA mice with Myrcludex-B, a lipopeptide derived from the preS1 domain of the HBV envelope (Nat. Biotech.2008). Aim of this study was to investigate the ability of this HBV entry inhibitor to block viral spreading post-infection, at a time when viremia is already detectable but only few human hepatocytes are infected. Experimental design: human liver chimeric uPA/SCID mice were injected with HBV-infectious serum (5x10E7 HBV DNA copies/mouse) and treatment with Myrcludex-B (2 mg/Kg/day; s.c. injection) was initiated either 3 days (group A, n=8) or 3 weeks (group B, n=7) post HBV-inoculation, while 8 sham-treated mice were used as control. Mice were analyzed serologically (HBV-DNA, HBsAg) and intrahepatically by quantitative RT-PCR measurements (cccDNA) and immunohistochemistry (human CK-18, HBcAg) at baseline, after 3 and 6 weeks of treatment. Results: In the first experimental setting, Myrcludex-B administration initiated 3-days after HBV-inoculation efficiently prevented viral spreading from the few initially infected human hepatocytes, as demonstrated by immunohistochemistry. Viremia and HBsAg levels remained below 10E5 HBV-DNA/ml and <10 IU/ml, respectively, while in untreated control mice median viremia increased to 3x10E7 and the majority of human hepatocytes stained HBcAg-positive within six weeks post-infection. Occurrence of viral spreading was also demonstrated in 2 mice after therapy discontinuation. Furthermore, Myrcludex-B blocked viral spreading even when treatment was first initiated at 3-weeks post-infection, at a time when median viremia was 2x10E6 HBV-DNA/ml. Notably, levels of viremia, HBsAg and intrahepatic cccDNA loads did not increase significantly after 6 weeks of treatment. Conclusions: Myrcludex-B showed strong capacities to prevent HBV spreading in vivo. Since maintenance of chronic HBV infection involves a dynamic turnover between cells that are cleared by the immune system and cells that become newly infected, the use of drugs preventing hepatocyte re-infection, possibly in combination with other HBV-drugs, may represent a new effective antiviral concept also in the setting of chronic infection.

StephenW

REP 9AC论文摘要 - 旧金山, 肝病学会2011
[posted by studyforhope]

Here is the current abstract for REP9AC at the upcoming San Francisco AASLD liver conference 2011:
REP 9AC: A potent HBsAg release inhibitor that elicits durable immunological control of chronic HBV infection.
M. A. Mahtab2; M. Bazinet1; A. Vaillant1
1. REPLICor Inc., Montreal, QC, Canada.
2. Bangabandhu Sheikh Mujib University, Dhaka, Bangladesh.

BACKGROUND: HBsAg plays a critical role in suppressing the immune system and is the likely mechanism for the chronicity of HBV infection. REP 9AC is a nucleic acid-based amphipathic polymer (NAP) which inhibits the release of HBsAg from infected hepatocytes. Previous interim clinical data has shown that REP 9AC rapidly clears serum HBsAg in infected patients and allows patients to regain durable immunological control over their HBV infection. An updated progress report of the ongoing phase I/II study on the safety and efficacy of REP 9AC in patients with chronic HBV (CHB) infection is presented.
METHODS: All patients were HBsAg+ with pre-treatment HBV DNA titers between 106 and 1012 copies/ml. Additionally, all patients were shown to have significant liver fibrosis as assessed by pre-treatment liver biopsy. Patients with CHB were subjected to parenteral REP 9AC therapy. Safety and virologic response (HBV DNA [Roche Cobas ™], HBsAg, anti-HBs [Immunilite]) were assessed weekly at the trial site/. Off site confirmatory testing of HBsAg, HBeAg, anti-HBs, anti-HBe was conducted using the using the Architect ™ platform.
RESULTS: Interim data shows that 7 out of 8 patients treated to date have either cleared or have only residual levels of serum HBsAg and anti-HBsAg antibodies have been observed in all patients. Clearance of HBsAg and development of anti-HBs have been observed as early as 7 days and no later than 32 weeks. At the time of abstract submission, 6 out of 7 patients with serum HBsAg reductions had achieved a 3 to 7 log reduction in their HBV DNA titers from pre-treatment levels after 7-13 weeks of treatment. Additionally, three of these seven patients have achieved a complete control of their infection with 20-27 weeks of treatment (HBV DNA < 400cpm-, HBsAg -, HBeAg -, anti-HBs +, anti-HBe +) and are being followed off treatment. These three patients have demonstrated durable immunological control over their infections, having SVRs of 18 months, 12 months and 10.5 months after cessation of treatment.
CONCLUSIONS: These results demonstrate that REP 9AC can rapidly and effectively clear HBsAg from the serum of infected patients. This rapid HBsAg seroclearance appears to allow the restoration of an effective immune response, as evidenced by substantial reductions in serum HBV DNA, seroconversion for HBsAg and HBeAg, and the achievement of SVRs in three patients to date. These results suggest that REP 9AC may become an important new tool in the treatment of chronic hepatitis B.