GSK3228836研究进展总结

StephenW

回复 tim889 的帖子

所有研究科学家都相信Rep？正确的. 阅读关于 HBV 功能性治愈的最新研究论文——都承认 REP2139 是一种有效的 HBsAg 释放抑制剂。

我相信你知道约John Travis是谁.
john.tavis
Verified Science Expert
2 Jun

Hi all,

I just want to put in a good word for Andrew’s NAPs.

His studies have achieved the highest level of functional cure that I’ve seen for any HBV therapy so far in Phase I or II clinical trials. Drug discovery/development is high risk, nerve-wracking and expensive, and there is never certainty of success. However, Andrew has pushed this forward through a great deal of adversity over the years. His NAPs have as good a chance as any approach (probably better than almost all) to receive approval and improve therapy for HBV infected people. I wish him and his research the best!

John

好像2020年之后就没啥动静了？
See for yourself:
HBsAg isoform dynamics during NAP-based therapy of HBeAg-negative chronic HBV and HBV/HDV infection
Bazinet M, Anderson M, Pântea V, Placinta G, Moscalu I, Cebotarescu V, Cojuhari L, Jimbei P, Iarovoi L, Smesnoi V, Musteata T, Jucov A, Dittmer U, Gersch J, Holzmayer V, Kuhns M, Cloherty G, Vaillant A.
Hepatology Communications 2022, April 3

In vitro mechanistic evaluation of nucleic acid polymers: A cautionary tale
Vaillant A. Molecular Therapy Nucleic Acids 2022; 28: 168-174.

Analysis of HBsAg Immunocomplexes and cccDNA Activity During and Persisting After NAP-Based Therapy
Bazinet M, Anderson M, Pântea V, Placinta G, Moscalu I, Cebotarescu V, Cojuhari L, Jimbei P, Iarovoi L, Smesnoi V, Musteata T, Jucov A, Dittmer U, Gersch J, Holzmayer V, Kuhns M, Cloherty G, Vaillant A. Hepatology Communications 2021; July 10

Transaminase Elevations during Treatment of Chronic Hepatitis B Infection: Safety Considerations and Role in Achieving Functional Cure
Vaillant A. Viruses 2021 13: 745

Benefit of transaminase elevations in establishing functional cure of HBV infection during nap-based combination therapy
Bazinet M, Pântea V, , Placinta G, Moscalu I, Cebotarescu V, Cojuhari L, Jimbei P, Iarovoi L, Smesnoi V, Musteata T, Dittmer U, Krawczyk A, Vaillant A. Journal of Viral Hepatitis 2021; 5: 817-825

连新的临床也没有了？
From Andrew Vaillant himself:
"It took a long time to get the scientific / medical community to accept NAPs as a legitimate antiviral technology because of their novel biochemistry and potent antiviral responses. NAPs are now well accepted and we have used our previous trials to date to move the drug product to a formulation which is now easy to self administer via subcutaneous injection (SC). The proof of this was only achieved in our last trial with REP 2139-Mg (published in 2020). As for many other companies, the SARS CoV-2 pandemic has had a negative impact on our ability to initiate new clinical development but we have gone ahead to use SC REP 2139-Mg in compassionate use patients in France with very good results (http://replicor.com/wp-content/u ... rt2021-Poster-7.pdf 17) so we hope to be in a position to conduct the final phase IIA trial with SC REP 2139 in the very near future. The delay with the clinical development of NAPs is not because of any problems with the drug or with our science but is due to other unrelated issues. We are working as hard as we can to get REP 2139-Mg to patients as soon as possible."

https://www.hepbcommunity.org/t/ ... yNR3JKwF-47uMl5CSFQ

StephenW

tim889 发表于 2022-9-19 05:46
众所周知NA的target是HBV DNA polyeramse和transcription无关。 没有理由怀疑NA直接silence了transcripti ...

你知道Marc Ghany 和 Anna Lok是谁吗？
Marc Ghany is a Gastroenterologist in Bethesda, Maryland. Ghany is highly rated in 6 conditions, according to our data. His top areas of expertise are Hepatitis, Hepatitis B, Hepatitis C, and Cirrhosis. He is licensed to treat patients in Louisiana.
His clinical research consists of co-authoring 135 peer reviewed articles and participating in 13 clinical trials in the past 15 years.

Anna Suk-Fong Lok (Chinese: 駱淑芳) is a gastroenterologist who studied in Hong Kong and moved to the United States in 1992. She is a Professor of Medicine at the University of Michigan in Ann Arbor and helped the World Health Organization (WHO) and American Association for the Study of Liver Diseases (AASLD) develop guidelines for medical professionals and recommendations for the general public on who should be treated and how treatments should be administered to persons with hepatitis B infections.

newchinabok

StephenW 发表于 2022-9-19 07:14
回复 tim889 的帖子

所有研究科学家都相信Rep？正确的. 阅读关于 HBV 功能性治愈的最新研究论文——都承认 ...

慢慢去做梦，拉些战友一起做梦

tim889

StephenW 发表于 2022-9-18 15:14
回复 tim889 的帖子

所有研究科学家都相信Rep？正确的. 阅读关于 HBV 功能性治愈的最新研究论文——都承认 ...

谢谢分享。

我尊重John的观点。但毕竟也是他个人的观点。我同意看数据本身的确是挺好，而且一直都是好到too good to be true，但就是雷声大雨点小。到现在还机理模糊不清，这也是科学界对这个药的共识。具体有没有用，就看能不能上二期和三期，以及之后的独立验证。至于Andrew Vaillant 说的你就更不知道了到底怎么回事了，他总不可能说我们为了股价做了某些事。

StephenW

tim889 发表于 2022-9-19 05:46
众所周知NA的target是HBV DNA polyeramse和transcription无关。 没有理由怀疑NA直接silence了transcripti ...

"现有的实验（包括Grudda et al.的）只是人体内的相关性而已。不能说明NA直接silence了transcription。"

Read carefully the discussion section of Grudda's paper:

In contrast, NUC treatment did reduce the levels of HBsAg in blood in individuals in whom cccDNA was the predominant source at baseline and we attribute this to cccDNA transcriptional silencing and clearance of infected cells. Our single-cell data largely corroborate these findings but also allow a more granular view of how relative changes in iDNA versus cccDNA transcription within single hepatocytes relate to changes in total HBV transcription. Overall, our results highlight the importance of iDNA transcription in some individuals to sustain elevated HBsAg levels despite NUC treatment of CHB; in those individuals, the relative amount of iDNA- to cccDNA-derived transcription appeared to enrich over time. Thus, transcriptionally active iDNA contributes to circulating HBsAg during NUCs and is therefore a barrier to functional cure.

We and others have reported that NUC therapy is associated with cccDNA transcriptional silencing, which can also be inferred from the decrease in HBV RNA in serum as well as pgRNA in the liver (2, 6, 9, 10, 14, 15). By comparing quantities of pgRNA to cccDNA in people taking NUCs who had decreases in serum HBV DNA, here we confirmed our earlier findings that NUCs are associated with transcriptional silencing of cccDNA (14, 15), rather than the alternative hypothesis that HBV transcription is reduced during NUCs strictly because of an overall reduction in the number of infected cells. cccDNA transcriptional silencing during NUCs is likely to be transient, since treatment interruption is frequently associated with virologic rebound. After HBV DNA is no longer detectable in serum and HBV RNA has declined, substantial HBsAg quantities remain in the majority of NUC-treated persons, even if diminished (2, 3, 8, 13, 21). Our data offer a potential explanation for this previously unexplained observation in that the individuals who transcribed S mostly from cccDNA had significant HBsAg declines coupled with decreases in cccDNA transcription on NUC therapy, whereas those who transcribed mostly from iDNA did not have substantial declines in HBsAg levels. These findings suggest that NUC therapy may modulate HBsAg levels in cccDNA transcriptionally dominant individuals but not in iDNA transcriptionally dominant individuals. A recent study by van Buuren et al. showed a similar phenomenon in individuals treated with NUC plus PEG-IFN-α; iDNA-derived transcription was enriched when HBsAg levels remained stable, although the group was unable to determine whether this was an effect of PEG-IFN-α or NUCs since all participants received PEG-IFN-α (12). We now demonstrate enrichment of iDNA transcription relative to cccDNA transcription with NUCs, especially when cccDNA-derived transcription is progressively diminished. These observations may impact treatment strategies for people with CHB, as currently NUC therapy is required lifelong to suppress HBV DNA and HBV RNA levels in serum. Our findings establish that the subset of people with HBsAg deriving mainly from iDNA may never achieve further declines in HBsAg from prolonged NUC therapy alone since NUCs are not known to inhibit transcription from iDNA, although they likely interrupt new integration events. We predict that the subset of individuals with primarily iDNA-derived HBsAg will require novel therapies targeting iDNA-derived S mRNAs or the cells that produce them.

tim889

StephenW 发表于 2022-9-18 15:36
你知道Marc Ghany 和 Anna Lok是谁吗？
Marc Ghany is a Gastroenterologist in Bethesda, Maryland. Gha ...

我知道是谁，你也不用拿这俩名字来压我。scientist从来不会因为某个人是该领域是专家，就搞独裁不让人说话。

如果你有能力读原文，麻烦去读了文章，再来就事论事的讨论。我甚至连哪张图哪个实验都告诉你了，如果想讨论就好好讨论，看不懂文章就不要来搞这套。

StephenW

tim889 发表于 2022-9-19 05:46
众所周知NA的target是HBV DNA polyeramse和transcription无关。 没有理由怀疑NA直接silence了transcripti ...

"因为Grudda et al.的supplementary Figure 3中的transcription index已经是normalize by total cccDNA了。"

This is the caption to Supplementary Figure 3:
Figure S3. Assay efficiencies when measuring synthetic DNA input. Lyophilized, synthetic
gBlock DNA from the manufacturer was hydrated, quantified by Nanodrop, and diluted to within
the dynamic range of our assays. Dilutions where run on ddPCR with a minimum of 10
replicates for each assay to assess PCR efficiencies. Each replicate is represented as a unique
point and error bars mark the spread of two standard deviations from the mean of replicates.
Comparable efficiencies were shown for each assay

Where is the reference to a transcription index and normalized by total cccDNA?

tim889

StephenW 发表于 2022-9-18 15:51
"现有的实验（包括Grudda et al.的）只是人体内的相关性而已。不能说明NA直接silence了transcription。"
...

跟你讲了你这样搞成篇复制黏贴没意思的。

哪篇paper哪个实验那张图证明了NA直接silence了transcription,你发过来，我愿意读。文中cite的几篇我已经看过了。只是人体内的相关性而已。不能说明NA直接silence了transcription。

tim889

StephenW 发表于 2022-9-18 15:54
"因为Grudda et al.的supplementary Figure 3中的transcription index已经是normalize by total cccDNA了 ...

真的，我建议你好好读完这篇paper再来讨论吧。连横纵坐标是啥意思都看不明白，就要跟我来讨论，纯粹在浪费大家时间。

StephenW

tim889 发表于 2022-9-19 07:53
我知道是谁，你也不用拿这俩名字来压我。scientist从来不会因为某个人是该领域是专家，就搞独裁不让人说 ...

"就搞独裁不让人说话。" - 他们不让人说话?  领域专家的说话比你的更重.