对arc520治疗的探讨

9病成医

齐欢畅2 发表于 2015-10-2 21:46
我看好520，我个人认为如果520和长效干扰素联用，超过一半的人可以治愈，但未必所有人都可以治愈。不过还有 ...

这话俺爱听。

重韧

一般药物如是到了2B效果还不明朗的话，那这个药也基本上希望不大了。所以还是期待520

HBVCURER

siRNA/RNAi抗病毒，机制其实比NUC还要简单直接，那就是直接抑制所有病毒mRNA的产生（导致其降解），没有了病毒的mRNA，自然就没有了病毒的蛋白，自然就没有了病毒的一切，这个是分子生物学里最核心但也是最简单的所谓“中心法则”。

由于siRNA/RNAi靶向的是病毒mRNA，而不是病毒复制的根源cccDNA，所以从direct antiviral的角度讲，siRNA/RNAi并不能直接清除病毒，所以所有单针注射的黑猩猩在一段时间后都会反弹，这是必然的。但从indirect antiviral的角度，siRNA/RNAi的最大亮点是可以显著降低HBsAg的载量，而高HBsAg载量正是业界认为造成慢性乙肝患者无法通过自身免疫系统彻底清除病毒的最主要原因。

临床上早就发现，HBsAg载量越低的患者，对干扰素/NUC治疗的效果就越明显，而HBsAg载量逐年显著下降的患者，实现功能性治愈的可能性就越大。但有研究表明，HBsAg载量下降多少个log，可能并不能直接反映预后，而下降到多少个IU，才是关键。至于低到什么水平以下，就能极大概率实现功能性治愈，目前还不确切知道，需要后续更大规模的临床研究。

ARC520已经走出了最重要的第一步，那就是先尽可能的把HBsAg载量降下来（需要多次给药）。但很明显这还不够，因为T/B细胞免疫反应的恢复和重建需要时间，更需要合适的刺激。通过多次连续的治疗将HBsAg载量维持在很低的水平上，再给予免疫调节剂的联合，比如干扰素，或者治疗性疫苗，相信会有很高的几率最终实现功能性治愈。

菲凡

谢谢

newchinabok

Arrowhead Reports Peak Reduction in HBsAg of Up to 99% (1.9 log) After a Single Dose with Hepatitis B Candidate ARC-520 in Treatment Naïve Cohort of Phase 2a Study

PASADENA, Calif.--(Business Wire)--Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical company developing targeted RNAi therapeutics, is hosting an analyst day today in New York, with a presentation starting at 11:00 a.m. EDT to discuss top-line findings from the Heparc-2001 Phase 2a clinical study of ARC-520, its candidate for the treatment of chronic hepatitis B infection. Additionally, the company will discuss findings from a study of 9 chimpanzees that have been treated monthly with ARC-520 for between 6 and 11 months with a background therapy of nucleotide/nucleoside analog inhibitors (NUCs) tenofovir and/or entecavir.
Key findings:

Arrowhead’s proprietary DPC™ platform can effectively and consistently knock down target genes in humans
HBV E-antigen positive (HBeAg-positive) patients on a background of chronic entecavir receiving a 4 mg/kg single-dose of ARC-520 showed a mean maximal 92% (1.2 log) reduction in circulating HBeAg and a best reduction of 98% (1.7 log). Similar mean maximal reductions were also demonstrated in HBV core-related antigen (HBcrAg) from both HBeAg-negative and -positive patients. ARC-520 is designed to silence all gene products expressed by HBV cccDNA, so this data suggests that it may be substantially disrupting additional viral functions.

ARC-520 achieves significant HBV s-Antigen (HBsAg) reductions in humans, particularly in treatment naïve, HBeAg-positive patients
In a cohort of NUC-naïve, HBeAg-positive patients, best peak HBsAg reduction has been 99% (1.9 log) and the mean maximum HBsAg reduction has been 1.05 log through 15 days post ARC-520 treatment. This open-label cohort is fully enrolled; data collection is ongoing and will be continued through Day 85 post ARC-520 treatment. These reductions are substantially higher than results from NUC treatment-experienced cohorts.

Arrowhead identifies a large target HBV population for ARC-520 and describes a new paradigm for the HBV lifecycle
Arrowhead’s long-term chimp study and findings from the clinical study suggest that HBV cccDNA decreases during the HBV lifecycle, especially with the transition from HBeAg-positive to -negative. HBV DNA integrated into host DNA appears to maintain significant HBsAg production as cccDNA declines. This process is accelerated with NUC treatment. ARC-520 specifically targets cccDNA, and NUC-naïve HBeAg-positive patients are expected to be richest in cccDNA. It is estimated in the U.S. that 95% of people chronically infected with HBV are currently NUC-naïve and at least 50% of them are likely to be HBeAg-positive. While it is unknown what impact ARC-520’s broad based effects on HBV biology will have on the sero-clearance process in any of the HBV subgroups, the effect on HBsAg in NUC-naïve HBeAg-positive patients makes this group especially attractive to study and a key focus for multi-dose studies going forward.

ARC-520 induces deep HBsAg reduction in chronically HBV infected chimps and 1 of 4 HBeAg-positive chimps demonstrated signs of immune reactivation during therapy
9 chimps were first suppressed with NUCs and then treated with 6 – 11 monthly doses of ARC-520. 4 HBeAg-positive chimps demonstrated 99% (2 log) mean peak reduction in HBsAg, and 1 of the 4 experienced signs of immune reactivation during therapy; 4 HBeAg-negative chimps demonstrated 81% (0.7 log) mean peak reduction in HBsAg; and 1 chimp transitioning from HBeAg-positive to HBeAg-negative demonstrated peak HBsAg reduction of 87% (0.9 log).

ARC-520 has been well tolerated
84 humans have received ARC-520 and to date no adverse events have been rated as serious or severe, no discontinuations have occurred due to an adverse event, and no laboratory results have indicated any end organ toxicity. Additionally, 9 chimps received 6-11 monthly doses of ARC-520 and no safety

newchinabok

箭头报道HBsAg的峰值下降99%(1.9日志)与乙肝候选人单剂量后弧- 520治疗天真的第二阶段研究
加州帕萨迪纳市(业务线),箭头研究公司(纳斯达克:ARWR),生物制药公司开发有针对性的RNAi疗法,是在纽约举办今天的分析师,与演讲在美国东部时间上午11:00开始讨论收入发现heparc - 2001第二阶段的临床研究电弧- 520,它的候选治疗慢性乙型肝炎感染。此外,该公司将讨论结果从9黑猩猩的研究,治疗与arc - 520每月6 - 11个月的背景治疗核苷酸/核苷模拟抑制剂(NUCs)替诺福韦和恩替卡韦。
主要结论:
箭头的专有DPC™平台能有效且一致地击倒目标基因在人类身上
乙肝病毒E-antigen积极(HBeAg-positive)患者慢性恩替卡韦的接收4毫克/公斤单剂弧- 520显示平均最大92%(1.2日志)减少流通e抗原,最好减少98%(1.7日志)。类似的意思是最大的减少也在乙肝病毒core-related抗原(HBcrAg)HBeAg-negative和艾滋病患者。arc - 520是为了沉默HBV cccDNA表达的基因产物,所以这些数据表明它可能会扰乱得额外病毒功能。
arc - 520实现重大HBV s-Antigen(HBsAg)减少人类,尤其是在治疗天真,HBeAg-positive病人
HBeAg-positive病人在一群NUC-naive,最佳峰值HBsAg减少了99%(1.9日志)和平均最大HBsAg减少1.05日志通过arc - 520治疗后15天。这种开放性队列完全登记;数据收集正在并将继续通过一天85后弧- 520治疗。这些削减是大大高于结果NUC treatment-experienced军团。
箭头标识一个大弧- 520年目标人口乙肝病毒和乙肝病毒的生命周期描述了一种新的范式
箭头的长期黑猩猩研究和临床研究的结果表明,HBV cccDNA降低乙肝病毒的生命周期期间,特别是从HBeAg-positive过渡到负面。乙型肝炎病毒DNA整合到宿主DNA似乎保持重要HBsAg生产cccDNA下降。这个过程是加速NUC治疗。arc - 520专门针对cccDNA,NUC-naive HBeAg-positive病人预计将cccDNA的富有。据估计,95%的人在美国慢性乙型肝炎病毒感染目前NUC-naive和至少50%的人可能是HBeAg-positive。虽然是未知的什么影响电弧- 520的广泛影响乙肝病毒生物学将基于sero-clearance过程的乙肝病毒子组,对HBsAg的影响在NUC-naive HBeAg-positive病人让这个群体尤其有吸引力的研究重点多剂量研究向前发展。
arc - 520引发深HBsAg减少慢性HBV感染的黑猩猩和1的4 HBeAg-positive黑猩猩证明免疫治疗期间复活的迹象
9只黑猩猩被首先抑制NUCs然后处理6 - 11月剂量的弧- 520。4 HBeAg-positive黑猩猩显示日志(2 99%)意味着减少HBsAg的高峰,和1的4免疫激活的迹象在治疗;4 HBeAg-negative黑猩猩了81%(0.7日志)意味着减少峰值HBsAg,和1黑猩猩过渡从HBeAg-positive HBeAg-negative证明HBsAg峰值降低87%(0.9日志)。
arc - 520已经耐受良好
84人收到了arc - 520和到目前为止没有评为严重或严重不良事件,没有中止发生由于不良事件,并没有实验室结果表明任何器官毒性。此外,9黑猩猩收到6尺11寸的月度剂量的弧- 520和不安全

newchinabok

提供了一个信息，大猩猩在治疗中有免疫激活的现象

zgct

感谢！

菲凡

多谢，希望人体也有这样的效果

newchinabok

我用替诺换拉米夫定时，以前肝功正常，在半年之内肝功能剧烈波动，说明了当病毒强抑制时，免疫系统有变化无疑。arc520用在大猩猩上，免疫恢复是有可能的