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标题: 核心蛋白抑制剂：最终HBV治愈的关键？恩替卡韦加上新型核 [打印本页]

作者: StephenW 时间: 2019-4-15 16:13 标题: 核心蛋白抑制剂：最终HBV治愈的关键？恩替卡韦加上新型核

Core Protein Inhibitor: A Key to Eventual HBV Cure? Entecavir plus novel core protein inhibitor led to dramatic declines in hepatitis B DNA, RNA

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by Molly Walker, Staff Writer, MedPage Today April 14, 2019
This article is a collaboration between MedPage Today® and:

VIENNA -- A combination therapy with nucleoside/nucleotide analogues plus a novel core protein inhibitor was associated with a significant reduction in the decline of hepatitis B (HBV) DNA and HBV RNA compared with nucleoside/nucleotide monotherapy, a researcher said here.
In treatment-naive, viremic patients with chronic HBV infection, treatment with entecavir (Baraclude) plus novel core protein inhibitor, ABI-H0731 (731), was associated with significant declines in both HBV DNA, as well as HBV RNA compared to entecavir alone, reported Jacob Lalezari, MD, of Quest Clinical Research in San Francisco.
Moreover, in patients with chronic HBV who were virally suppressed on current standard-of-care therapy, adding ABI-H0731 was associated with further declines in HBV RNA. And they proved this by creating an assay that measured declines in viremia below detection of 2-5 IU/mL.
Could the results of this small late-breaking trial be a small, promising step towards a cure for HBV? Lalezari expressed cautious optimism during a press conference at the European Association for the Study of the Liver (EASL) annual meeting.
"One of the messages from this conference is that cure is not possible as long as there is residual virus present. To go further and start talking about cure rates, we need to prevent new reservoir virus from being generated; we need to eliminate residual virus that remains...we expect once DNA and RNA are cleared, viral antigens will follow," he said.
EASL press conference moderator Francesco Negro, MD, of the University Hospital of Geneva, called the approach "extremely promising...and extremely logical. Under the threshold, viremia is very interesting, I've never seen that data before," he told MedPage Today.
Lalezari explained that current standard-of-care therapy for HBV is effective at reducing HBV DNA, but where it falls short is that "it doesn't eliminate the virus to zero," and residual viremia generates new reservoir virus.
The core protein inhibitors are different, he said, because they act at multiple steps of the viral life cycle. Most importantly, they appear to block the formation of covalently closed circular (ccc)DNA, which is "a key step necessary to get to a cure."
This was an interim analysis of two phase IIa studies -- one with treatment-experienced patients with chronic HBV who were virally suppressed on nucleoside/nucleotide analogue therapy, and one with treatment-naive HBV e antigen (HBeAg)-positive patients. After 24 weeks of treatment, patients could roll over into an open-label study to get both drugs together for <1 year, Lalezari said.
In Study 202, 25 HBeAg-positive viremic patients were randomized 1:1 to receive entecavir or entecavir plus core protein inhibitor, 731. Primary endpoint was a log10 decline in HBV DNA at weeks 12 and 24. At the time of analysis, 24 patients had crossed the week 12 threshold and 12 were at week 24.
Overall, patients on the combination therapy experienced greater log10 declines in HBV DNA versus patients on entecavir alone at week 12 (-4.54 vs -3.29, respectively, P<0.011) and week 24 (-5.94 vs -3.99, respectively, P<0.005). But patients on the combination regimen also experienced significant declines in HBV RNA at both time points.
In Study 201, 47 HBeAg-positive patients and 26 HBeAg-negative patients were randomized 3:2 to receive standard of care nucleoside/nucleotide analogue therapy or current therapy plus 731. At the time of analysis, 65 patients had crossed the week 12 threshold and 11 were at week 24. Primary endpoint was a log10 decline at week 24 of hepatitis B s antigen (HBsAg) or HBeAg.
At week 24, patients on the combination therapy experienced significantly larger declines in HBV RNA compared to those on monotherapy (-2.20 vs -0.15, P=0.012).
Researchers then examined a subgroup of patients in study 201 who entered the study with viremia <20 IU/mL, and developed a semi-quantitative assay for a level of detection of 2-5 IU/mL. They looked at serial samples of these patients, and found that in five of six patients, detectable virus had declined to below the level of detection of the assay, at weeks 8-16 compared to zero patients on monotherapy.
"This work is completely novel -- no one has ever shown that you can move residual virus ... past the level of current detection," Lalezari said. "This confirms what's being more broadly understood at this meeting -- that patients on a 'Nuc' monotherapy have ongoing viremia, which explains why we don't get a cure with the current drugs because we're not actually getting rid of the virus."
The therapy was also safe, he noted, with treatment-emergent adverse events (such as rash) generally mild or moderate and transient.
But Lalezari also said that this was an interim analysis, and the manufacturer is actually developing more potent compounds, "because it gives patients a little bit of wiggle room in terms of compliance."
Negro told MedPage Today this study appeared to be a "proof-of concept," and "it is something they want to study in more detail."
"I don't understand that [decision]," he said, when asked if he was surprised that this compound was not moving into phase III trials.
Lalezari said that the mood in the HBV space may be shifting from a cure that could take years to one that might take around 6 months -- a "finite process" rather than "an indefinite process with no end in sight."
"It might not be [hepatitis C virus], where you stop viral replication, and 8 weeks later, patients have cleared out all virus, but this isn't HIV either," he said.

作者: StephenW 时间: 2019-4-15 16:14

核心蛋白抑制剂：最终HBV治愈的关键？
恩替卡韦加上新型核心蛋白抑制剂导致乙型肝炎DNA，RNA的急剧下降

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作者：Molly Walker，撰稿人，MedPage Today
2019年4月14日

本文是MedPageToday®与Medpage Today的合作

维也纳 - 研究人员表示，与核苷/核苷酸单药治疗相比，核苷/核苷酸类似物与新型核心蛋白抑制剂的联合治疗与乙型肝炎（HBV）DNA和HBV RNA的下降显着减少有关。

在治疗初期，慢性HBV感染的病毒血症患者，恩替卡韦治疗（Baraclude）加上新型核心蛋白抑制剂ABI-H0731（731），与单用恩替卡韦相比，HBV DNA和HBV RNA均显着下降。据旧金山Quest Clinical Research的医学博士Jacob Lalezari报道。

此外，在目前标准治疗中病毒性抑制的慢性HBV患者中，加入ABI-H0731与HBV RNA的进一步下降有关。他们通过创建一种测定病毒血症下降低于2-5 IU / mL的检测证明了这一点。

这项小型晚期试验的结果能否成为治愈HBV的一小步，有希望的一步？ Lalezari在欧洲肝脏研究协会（EASL）年会的新闻发布会上表达了谨慎的乐观态度。

“这次会议的一个消息是，只要存在残留的病毒，就不可能治愈。为了进一步开始讨论治愈率，我们需要防止产生新的病毒;我们需要消除残留的病毒仍然......我们预计一旦DNA和RNA被清除，病毒抗原就会随之而来，“他说。

EASL新闻发布会主持人，日内瓦大学医院的医学博士Francesco Negro称这种方法“极具前景......而且非常符合逻辑。在阈值之下，病毒血症非常有趣，我以前从未见过这些数据，”他告诉他MedPage Today。

Lalezari解释说，目前HBV的标准治疗方法可有效降低HBV DNA，但不足之处在于“它不会将病毒消除为零”，残留的病毒血症会产生新的病毒。

他说，核心蛋白抑制剂是不同的，因为它们在病毒生命周期的多个步骤中起作用。最重要的是，它们似乎阻止了共价闭合环状（ccc）DNA的形成，这是“达到治愈所必需的关键步骤”。

这是对两项IIa期研究的中期分析 - 一项是治疗经验丰富的慢性HBV患者，他们在核苷/核苷酸类似物治疗中被病毒抑制，另一项是治疗初期HBV e抗原（HBeAg）阳性患者。 Lalezari说，经过24周的治疗，患者可以进行开放性研究，将两种药物一起服用<1年。

在研究202中，25名HBeAg阳性病毒血症患者以1：1随机接受恩替卡韦或恩替卡韦加核心蛋白抑制剂731.主要终点是第12周和第24周时HBV DNA的log10下降。在分析时，24名患者超过了第12周的门槛，12个是第24周。

总体而言，联合治疗的患者HBV DNA的log10下降与第12周单独使用恩替卡韦的患者相比（分别为-4.54 vs -3.29，P <0.011）和第24周（-5.94 vs -3.99，P <0.005））。但是联合方案的患者在两个时间点也经历了HBV RNA的显着下降。

在研究201中，47名HBeAg阳性患者和26名HBeAg阴性患者按3：2随机分组接受标准治疗核苷/核苷酸类似物治疗或现有治疗加731.在分析时，65名患者已超过第12周阈值在第24周时，主要终点是乙型肝炎病毒抗原（HBsAg）或HBeAg在第24周时log10下降。

在第24周，与单药治疗相比，联合治疗的患者HBV RNA下降幅度明显更大（-2.20 vs -0.15，P = 0.012）。

研究人员随后检查了研究201中的患者亚组，他们以≥20IU / mL的病毒血症进入该研究，并开发了半定量分析，检测水平为2-5 IU / mL。他们观察了这些患者的系列样本，发现6名患者中有5名患者的可检测病毒在8-16周时降至低于检测水平，而单药治疗则为零。

“这项工作是完全新颖的 - 没有人表明你可以移动残留的病毒...超过目前的检测水平，”Lalezari说。 “这证实了在这次会议上更广泛理解的内容 - 'Nuc'单药治疗的患者持续发生病毒血症，这解释了为什么我们无法治愈目前的药物，因为我们实际上并没有摆脱病毒“。
他指出，治疗也是安全的，治疗后出现的不良事件（如皮疹）通常是轻度或中度和短暂的。

但Lalezari还表示，这是一项中期分析，制造商实际上正在开发更有效的化合物，“因为它给患者提供了一定程度的依赖性摆动空间。”

黑人告诉MedPage Today这项研究似乎是一个“概念验证”，“这是他们想要更详细研究的东西。”

“我不明白[决定]，”当被问及是否对这种化合物没有进入III期试验感到惊讶时，他说道。

Lalezari表示，HBV领域的情绪可能正在从可能需要数年的治疗转变为可能需要6个月左右的治疗 - 一个“有限的过程”，而不是“无限期的无限期过程”。

“它可能不是[丙型肝炎病毒]，你停止病毒复制，8周后，患者已经清除所有病毒，但这也不是艾滋病毒，”他说。

作者: newchinabok 时间: 2019-4-15 16:32

残余cccdna和基因整合hbv靠免疫剂。如果靠肝细胞新陈代谢，有点幻想

作者: sir 时间: 2019-4-15 18:59

回复 StephenW 的帖子

The decision that this compound was not moving into phase 3 trail,我没理解错的话意思是指ABI-H0731不会继续推进到三期临床？目前好像没看到官方的消息，难道又是打算放弃第一代开发第二代CAMPs？

作者: newchinabok 时间: 2019-4-15 19:20

本帖最后由 newchinabok 于 2019-4-15 19:28 编辑

sir 发表于 2019-4-15 18:59
回复 StephenW 的帖子

The decision that this compound was not moving into phase 3 trail,我没理解错的 ...

联系上下文看，不是你理解的那样。我的理解目前没有进三期计划，需要更多研究，概念验证。最起码弄个联合治疗，搞个短期治愈。推三期有什么意义？公司好像不急于推三期。其实二期有很多疑问要解决，比如多久耗尽cccdna，残留cccdna和基因整合hbv如何清除，是联合免疫药还是肝细胞自己新陈代谢？

作者: newchinabok 时间: 2019-4-15 19:30

只要存在残留的病毒，就不可能治愈。为了进一步开始讨论治愈率，我们需要防止产生新的病毒;我们需要消除残留的病毒仍然.

作者: fuke 时间: 2019-4-15 19:38

“我不明白[决定]，”当被问及是否对这种化合物没有进入III期试验感到惊讶时，他说道。

作者: newchinabok 时间: 2019-4-15 19:42

本帖最后由 newchinabok 于 2019-4-15 19:43 编辑

fuke 发表于 2019-4-15 19:38
“我不明白[决定]，”当被问及是否对这种化合物没有进入III期试验感到惊讶时，他说道。 ...

黑人告诉MedPage Today这项研究似乎是一个“概念验证”，“这是他们想要更详细研究的东西。更详细研究就是说二期还要做其它内容

作者: newchinabok 时间: 2019-4-15 19:46

https://www.medpagetoday.com/meetingcoverage/easl/79222

作者: StephenW 时间: 2019-4-15 20:20

回复 sir 的帖子

我不知道，你可能是对的.
目前，ABI-H0731只有一项2期延期研究(Phase 2 extension)
A Multi-center, Open-label, Long-term Extension Study of ABI-H0731 + Nucleos(t)Ide as Finite Treatment for Chronic Hepatitis B Patients
Actual Study Start Date : December 20, 2018
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2023
https://www.clinicaltrials.gov/c ... sciences&rank=2

作者: fuke 时间: 2019-4-15 23:42

回复 StephenW 的帖子

如果真是这样，那就太狗血了。

作者: windu 时间: 2019-4-16 11:09

别社会主义的核衣壳都上市了，资本主义的还在临床，那就更搞笑了

作者: newchinabok 时间: 2019-4-16 11:15

本帖最后由 newchinabok 于 2019-4-16 11:22 编辑

windu 发表于 2019-4-16 11:09
别社会主义的核衣壳都上市了，资本主义的还在临床，那就更搞笑了

有可能，强生核衣壳在中国试验。但是社会主义的药都是批着狼皮的羊，如乐复能之流

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