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标题: 研究人员说，HBV 治愈回到绘图板 [打印本页]

作者: StephenW 时间: 2022-7-7 20:46 标题: 研究人员说，HBV 治愈回到绘图板

研究人员说，HBV 治愈回到绘图板

萨拉弗里曼

2022 年 7 月 5 日
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伦敦——根据欧洲肝脏研究协会赞助的年度国际肝脏大会上的一份报告，目前正在开发的药物很难实现对乙型肝炎病毒 (HBV) 的功能性治愈.

“在 ILC 2022 上展示了有趣的结果，必须仔细解释，”法国克雷泰伊的 Henri Mondor 医院的医学博士 Jean-Michel Pawlotsky 在会议闭幕日的病毒性肝炎亮点会议上说。

“新的 HBV 药物开发看起来比最初预期的要复杂，其目标和战略需要重新定义和重新定位，”他补充说

“这确实来自我们在会议期间以及走廊上的讨论，”Pawlotsky 补充道。 “我们知道这将很困难；我们必须重新设置、重新启动——不是从零开始，而是从不多——并修改我们的战略，”他建议道。

Pawlotsky 说，有许多针对 HBV 的新药正在研究中，并指出会议上提交的研究数量让人想起在发现丙型肝炎的功能性治愈方法之前的一系列活动。 “很高兴看到乙肝病毒再次发生这种情况，”他说。

事实上，有许多新的直接作用的抗病毒药物、免疫调节剂或其他方法正在测试中，一些更先进的研究“教给我们一些东西，可能提出的问题多于得到答案，”Pawlotsky 说。
B-CLEAR 研究

其中一项研究是在后期会议期间提出的 2b 期 B-CLEAR 研究。这项研究涉及反义寡核苷酸 bepirovirsen，并测试了其在接受或停止稳定核苷（酸）类似物 (NA/NUC) 治疗的慢性乙型肝炎病毒感染患者中的疗效和安全性。

相似比例（分别为 28% 和 29%）的患者在 24 周治疗结束时达到低于量化下限的乙型肝炎表面抗原 (HBsAg) 水平。然而，对 HBsAg 的影响因治疗组而异，改变剂量或改用安慰剂表明，当治疗停止或减少剂量时，效果可能会减弱。

“有趣的是，观察到 ALT 升高与大多数 HBsAg 下降有关，”Pawlotsky 指出。 “我认为我们仍然必须确定这是否是好的耀斑/坏耀斑，好兆头/坏兆头，以及之后会发生什么。”
珊瑚礁研究

另一种强调的方法是在第 2 期 REEF-1 和 REEF-2 研究中将沉默或小干扰 RNA (siRNA) JNJ-3989 与衣壳组装调节剂 (CAM) JNJ-6379 相结合。

REEF-1 是在乙型肝炎 e 抗原 (HBeAg) 阳性或阴性且未接受 NA/NUC 治疗或 NA/NUC 抑制的患者中进行的，显示出剂量依赖性，但在个体患者中可能存在不同的影响预计在 48 周治疗结束时。这持续到第 72 周，即停止治疗后 24 周的随访。
然而，Pawlotsky 指出，“我认为最重要的部分是，如果在 siRNA 上添加 CAM，则不会提高对 HBsAg 水平的影响。”

然后是 REEF-2 研究，测试相同的组合，但仅在标准 NA/NUC 治疗的 NA 抑制或 HBeAg 阴性的患者中进行。作为第一个报告的新型联合治疗试验，这基本上是一个停止试验，Kosh Agarwal, BMedSci (Hons), MBBS, MD，该研究的一名研究人员在媒体简报会上单独解释说。

Agarwal 说，患者（n = 130）接受了 48 周的治疗，然后停止了所有治疗（包括 NA/NUC），并在停药后进行了 48 周的随访。伦敦国王学院医院。他提供了治疗结束后前 24 周的数据。

在治疗结束时，该组合导致 HBsAg 平均降低 1.89 log10 IU/mL，而在本试验中作为对照组的仅 NA/NUC 组降低了 0.06。但是“在这项研究中，没有患者失去了他们的表面抗原，也就是说，他们的乙型肝炎在积极组或对照组中被治愈，”阿加瓦尔说。

“我们没有治愈，但很大一部分人处于‘受控’的病毒阶段，”阿加瓦尔说。事实上，在他介绍研究结果期间，他表明在停止联合用药后，大多数 (72%) 患者的 HBsAg 抑制作用得以维持。

虽然没有达到试验的主要终点，但“这是一项非常重要的研究，”阿加瓦尔说。他观察到：“这项 [研究] 在 COVID 时代完成并交付，因此许多患者都得到了欧洲站点的非常仔细的照顾。”

预计该试验会进一步跟进，阿加瓦尔表示，随后的讨论将“带我们回到绘图板上，思考我们是否需要更好的抗病毒治疗，或者我们是否需要考虑不同的组合，以及是否真的停止治疗每次治疗都是正确的策略。”

Agarwal 和 Pawlotsky 都在试验中标记了一名患者的病例，该患者曾在对照组中并经历了需要肝移植的严重 HBV 再激活。

“这个病人是一个警告信号，”Pawlotsky 在他的演讲中建议道。 “当我们考虑停止 NUC 时，我们必须考虑 HbsAg 损失方面的潜在益处以及潜在风险。”

虽然 Agarwal 曾指出，它强调“仔细设计再治疗标准对于评估 NA/NUC 停止概念的研究很重要”。
单克隆抗体大有可为

其他组合可能涉及 siRNA 和免疫调节剂，在会议的海报会议上，Agarwal 还展示了正在进行的 1 期研究的数据，该研究使用了一种名为 VIR-3434 的新型中和单克隆抗体。

这种单克隆抗体是新颖的，因为它被认为具有多种作用方式，首先通过与 HBV 结合并影响其进入肝细胞，然后通过将病毒呈递给 T 细胞并刺激“疫苗”或免疫效应，然后通过帮助清除 HBsAg 并将病毒递送至树突状细胞。

在这项研究中，发现单剂量的 VIR-3434 耐受性良好，并能迅速降低 HBsAg，使用的最高剂量（300 毫克）在第 8 周内产生最大和最持久的效果。

VIR-3434 也在 3 月 2 期试验中与其他药物联合进行测试。其中一种组合是 VIR-3434 和一种名为 VIR-2218 的研究 siRNA。在 ILC 2022 上展示的临床前工作表明，与单独使用任何一种药物相比，这种组合似乎能够在更大程度上降低 HBsAg。
重新思考治愈的策略

当然，VIR-3434 是几种正在开发的免疫调节化合物之一。有治疗性疫苗、针对先天免疫反应的药物、其他单克隆抗体、T细胞受体、检查点抑制剂和PD-L1抑制剂。然后还有其他化合物，例如进入抑制剂、凋亡诱导剂和法尼醇 X 受体激动剂。

“我在结束这次会议时提出的问题多于答案，”Pawlotsky 说。 “增强特异性抗 HBV 免疫的正确目标是什么？体内诱导的免疫反应是否会转化为对 HBV 感染的任何有益效果？治疗性疫苗会在病毒感染中起作用吗？”

此外，他问道，“我们如何避免增强多种复杂的非特异性免疫反应的副作用？治疗引起的耀斑是好的耀斑还是坏的耀斑？所有这些都是真正没有答案的问题，我们必须得到答案答案在不久的将来。”

B-CLEAR 研究由葛兰素史克赞助。 REEF-2 研究由 Janssen Research & Development 赞助。 VIR-3434 研究由 Vir Biotechnology 资助。

作者: StephenW 时间: 2022-7-7 20:47

HBV Cure Going Back to the Drawing Board, Researchers Say

Sara Freeman

July 05, 2022
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LONDON – Achieving a functional cure for hepatitis B virus (HBV) is not going to be easily achieved with the drugs that are currently in development, according to a presentation at the annual International Liver Congress sponsored by the European Association for the Study of the Liver.

"Intriguing results have been presented at ILC 2022 that must be carefully interpreted," said Jean-Michel Pawlotsky, MD, PhD, of Henri Mondor Hospital in Créteil, France, during the viral hepatitis highlights session on the closing day of the meeting.

"New HBV drug development looks more complicated than initially expected and its goals and strategies need to be redefined and refocused," he added

"This is really something that came from the discussions we had during the sessions but also in the corridors," Pawlotsky added. "We know it's going to be difficult; we have to reset, restart – not from zero, but from not much – and revise our strategy," he suggested.

There are many new drugs under investigation for HBV, Pawlotsky said, noting that the number of studies being presented at the meeting was reminiscent of the flurry of activity before a functional cure for hepatitis C had been found. "It's good to see that this is happening again for HBV," he said.

Indeed, there are many new direct-acting antiviral agents, immunomodulatory, or other approaches being tested, and some of the more advanced studies are "teaching us a few things and probably raising more questions than getting answers," Pawlotsky said.
The B-CLEAR Study

One these studies is the phase 2b B-CLEAR study presented during the late-breaker session. This study involved bepirovirsen, an antisense oligonucleotide, and tested its efficacy and safety in patients with chronic hepatitis B virus infection who were either on or off stable nucleos(t)ide analogue (NA/NUC) therapy.

A similar proportion (28% and 29%, respectively) of patients achieved an hepatitis B surface antigen (HBsAg) level below the lower limit of quantification at the end of 24 weeks treatment. However, the effect on HBsAg varied according to the treatment arm, with changes to the dosing or switching to placebo indicating that the effect might wane when the treatment is stopped or if the dose is reduced.

"Interestingly, ALT elevations were observed in association with most HBsAg declines," Pawlotsky pointed out. "I think we still have to determine whether this is good flare/bad flare, good sign/bad sign, of what is going to happen afterward."
The REEF Studies

Another approach highlighted was the combination of the silencing or small interfering RNA (siRNA) JNJ-3989 with the capsid assembly modulator (CAM) JNJ-6379 in the phase 2 REEF-1 and REEF-2 studies.

REEF-1, conducted in patients who were either hepatitis B e antigen (HBeAg) positive or negative who were not treated with NA/NUC or were NA/NUC suppressed, showed a dose-dependent, but variable effect among individual patients as might be expected at the end of 48 weeks' treatment. This was sustained at week 72, which was 24 weeks' follow-up after stopping treatment.
However, pointed out Pawlotsky "I think the most important part of this is that if you add a CAM on top of the siRNA, you do not improve the effect on HBsAg levels."

Then there is the REEF-2 study, testing the same combination but in only patients who were NA suppressed or HBeAg negative alongside standard NA/NUC therapy. As well as being the first novel combination treatment trial to report, this was essentially a stopping trial, Kosh Agarwal, BMedSci (Hons), MBBS, MD, one of the study's investigators explained separately at a media briefing.

Patients (n = 130) were treated for 48 weeks, then all treatment – including NA/NUC – was discontinued, with 48 weeks of follow-up after discontinuation, said Agarwal, who is a consultant hepatologist based at the Institute of Liver Studies at King's College Hospital, London. He presented data from the first 24 week period after treatment had ended.

At the end of treatment, the combination had resulted in a mean reduction in HBsAg of 1.89 log10 IU/mL versus a reduction of 0.06 for the NA/NUC-only group, which acted as the control group in this trial. But "no patient in this study lost their surface antigen, i.e., were cured of their hepatitis B in the active arm or in the control arm," Agarwal said.

"We didn't achieve a cure, but a significant proportion were in a 'controlled' viral stage," said Agarwal. Indeed, during his presentation of the findings, he showed that HBsAg inhibition was maintained in the majority (72%) of patients after stopping the combination.

While the trial's primary endpoint wasn't met, "it's a really important study," said Agarwal. "This [study] was fulfilled and delivered in the COVID era, so a lot of patients were looked after very carefully by sites in Europe," he observed.

Further follow-up from the trial is expected, and Agarwal said that the subsequent discussion will "take us back to the drawing board to think about whether we need better antiviral treatments or whether we need to think about different combinations, and whether actually stopping treatment with every treatment is the right strategy to take."

Both Agarwal and Pawlotsky flagged up the case of one patient in the trial who had been in the control arm and had experienced severe HBV reactivation that required a liver transplant.

"This patient is a warning signal," Pawlotsky suggested in his talk. "When we think about NUC stopping, we have to think about the potential benefit in terms of HbsAg loss but also the potential risks."

While Agarwal had noted that it highlights that "careful design of retreatment criteria is important in studies assessing the NA/NUC-stopping concept".
Monoclonal Antibody Shows Promise

Other combinations could involve an siRNA and an immunomodulatory agent and, during the poster sessions at the meeting, Agarwal also presented data from an ongoing phase 1 study with a novel, neutralizing monoclonal antibody called VIR-3434.

This monoclonal antibody is novel because it is thought to have several modes of action, first by binding to HBV and affecting its entry into liver cells, then by presenting the virus to T cells and stimulating a 'vaccinal' or immune effect, and then by helping the with the clearance of HBsAg and delivery of the virus to dendritic cells.

In the study, single doses of VIR-3434 were found to be well tolerated and to produce rapid reductions in HBsAg, with the highest dose used (300 mg) producing the greatest and most durable effect up to week 8.

VIR-3434 is also being tested in combination with other drugs in the phase 2 MARCH trial. One of these combinations is VIR-3434 together with an investigational siRNA dubbed VIR-2218. Preclinical work presented at ILC 2022 suggests that this combination appears to be capable of reducing HBsAg to a greater extent than using either agent alone.
Rethinking the Strategy to Get to a Cure

Of course, VIR-3434 is one of several immunomodulatory compounds in development. There are therapeutic vaccines, drugs targeting the innate immune response, other monoclonal antibodies, T-cell receptors, checkpoint inhibitors and PD-L1 inhibitors. Then there are other compounds such as entry inhibitors, apoptosis inducers, and farnesoid X receptor agonists.

"I finish this meeting with more questions than answers," Pawlotsky said. "What is the right target to enhance specific anti-HBV immunity? Does in vivo induction of immune responses translate into any beneficial effect on HBV infection? Will therapeutic vaccines every work in a viral infection?"

Moreover, he asked, "how can we avoid the side effect of enhancing multiple and complex nonspecific immune responses? Are treatment-induced flares good flares or bad flares? All of these are questions that are really unanswered and that we'll have to get answers to in the near future."

The B-CLEAR study was sponsored by GlaxoSmithKline. The REEF-2 study was sponsored by Janssen Research & Development. The VIR-3434 studies were funded by Vir Biotechnology. Pawlotsky has received grant and research support, acted as a consultant, adviser, or speaker, and participated in advisory boards for multiple pharmaceutical and biotechnology companies. This news organization was unable to verify Agarwal's ties to Vir Biotechnology, but he presented one of the posters on VIR-3434 at the meeting and has been involved in the phase 1 study that was reported.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

作者: StephenW 时间: 2022-7-7 21:38

我对
1. 贝匹罗韦森(bepirovirsen) 的解读:

它显然是一种非常有效的 RNAi（反义）能够减少 HBsAg 的产生。它似乎没有 Replicor 的 NAP 强大，但至少可以解释它的工作原理。为了提供功能性治疗，它必须与免疫调节剂一起使用，就像 NAP 一样。

2. 衣壳组装调节剂 (CAM) JNJ-6379 在第 2 期 REEF-1 和 REEF-2 研究中:

衣壳组装调节剂 (CAM) 和NA一起 , 非常显着减少hbvdna，减少hbvdna和cccDNA更快.

3. 单克隆抗体Monoclonal Antibody :

HBSAg单克隆抗体可以 a) 降低血清 HBsAg； b) 刺激 T 细胞的产生？
有许多 HBSAg 单克隆抗体。我们的版主是专家.

看来我们可以试试下面的组合:

NA + JNJ-6379(CAM) + bepirovirsen(RNAI) + VIR-3434(Monoclonal antibody); 或者

NA + JNJ-6379(CAM) + NAP(Replicor) + PegInfn(90mcg/m, not the standard 180 mcg/mL)

作者: 齐欢畅 时间: 2022-7-16 20:03

作者: lancas 时间: 2022-7-16 22:14

都是联合治疗~~联合的药也越来越多~

作者: newchinabok 时间: 2022-7-17 08:01

lancas 发表于 2022-7-16 22:14
都是联合治疗~~联合的药也越来越多~

看起来新药轰轰烈烈，其实没有卵用

作者: 乙肝人1949 时间: 2022-7-17 23:19

不知道标题啥意思

作者: newchinabok 时间: 2022-7-18 17:07

乙肝人1949 发表于 2022-7-17 23:19
不知道标题啥意思

意思是不打干挠素就是自杀，呵呵

作者: 乙肝人1949 时间: 2022-7-19 12:26

哈哈哈。都是搞笑，抓眼球。乙肝治疗和绘图板啥关系？为了增加抓眼球

作者: 乙肝人1949 时间: 2022-7-19 12:27

newchinabok 发表于 2022-7-18 17:07
意思是不打干挠素就是自杀，呵呵

哈哈哈

作者: tim889 时间: 2022-7-19 12:42

乙肝人1949 发表于 2022-7-18 20:26
哈哈哈。都是搞笑，抓眼球。乙肝治疗和绘图板啥关系？为了增加抓眼球

Back to the Drawing Board 英文意思是得另起炉灶了

作者: tim889 时间: 2022-7-19 12:45

mRNA疫苗要是能用于开发乙肝治疗性疫苗就好了可惜不知道为什么moderna和bioNtech都没有在做多数pipeline都去搞covid了

作者: 乙肝人1949 时间: 2022-7-19 13:24

tim889 发表于 2022-7-19 12:45
mRNA疫苗要是能用于开发乙肝治疗性疫苗就好了可惜不知道为什么moderna和bioNtech都没有在做多数pipeline ...

逐利

作者: tim889 时间: 2022-7-19 13:35

乙肝人1949 发表于 2022-7-18 21:24
逐利

有这个因素，但应该也不全是。biontech有不少癌症疫苗的管线，hbv的市场其实也不小

作者: 乙肝人1949 时间: 2022-7-19 13:43

tim889 发表于 2022-7-19 13:35
有这个因素，但应该也不全是。biontech有不少癌症疫苗的管线，hbv的市场其实也不小 ...

难度系数大，开发乙肝药？

作者: tim889 时间: 2022-7-19 13:52

乙肝人1949 发表于 2022-7-18 21:43
难度系数大，开发乙肝药？

其实不只是我。我今天出于好奇，关键词搜了下文献，也有别的科研人员提到了相关方向。是难度的问题，还是免疫效果不好还是别的问题就不得而知。也可能这些药厂私底下开始搞了，只是未对外公布。希望是后者。唉苦命啊

作者: lancas 时间: 2022-7-19 18:00

HBV市场是不小，可能都集中在较为贫穷的亚洲和东南亚地区吧~~= =~~
我想企业优先的研发顺序还是经济比较好的地区疾病吧

作者: tim889 时间: 2022-7-20 01:32

lancas 发表于 2022-7-19 02:00
HBV市场是不小，可能都集中在较为贫穷的亚洲和东南亚地区吧~~= =~~
我想企业优先的研发顺序还是经济比较好 ...

lancas兄说的这个因素很有道理，毕竟穷地方药也卖不出太高的价格

作者: 乙肝人1949 时间: 2022-7-20 10:06

哈哈哈，看来资夲主义逐利夲质。人权，为了全人类。哈哈哈哈哈，搞笑不。为了全人类

作者: tim889 时间: 2022-7-20 10:30

乙肝人1949 发表于 2022-7-19 18:06
哈哈哈，看来资夲主义逐利夲质。人权，为了全人类。哈哈哈哈哈，搞笑不。为了全人类 ...

逐利没有错。逐完利还能像当年默克给中国送乙肝疫苗那样做点善事就已经很伟大了。

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