新型乙肝治疗显示承诺

StephenW

Novel Hep B Therapies Show Promise
Several new agents reduce virus levels, but reliable cure not yet on horizon

    by Liz Highleyman
    Contributing Writer, MedPage Today

    This article is a collaboration between MedPage Today® and: Medpage Today

Expert Critique
FROM THE AGA Reading Room
Michelle Long Assistant Professor of Medicine, Department of Medicine, Section of Gastroenterology Boston University School of Medicine Boston, MA
With the success of therapy for hepatitis C virus, there has been a renewed interest in the development of treatments for hepatitis B virus (HBV). However, HBV, a DNA virus, is very different from hepatitis C, and it is likely that multiple agents targeting different viral mechanisms as well as medications to boost the immune response will be necessary to achieve a cure. Novel agents are under development, but a reliable cure of HBV for most patients is not yet on the horizon. Currently, medications can halt HBV replication but they are not effective at eliminating HBV DNA from the liver cell, which can be difficult to distinguish from the host. New pipeline medications include agents targeted at HBV transcription, HBV capsid disassembly, interfering with the release of subviral particles, and HBV messenger RNA. The medications currently under development have been tested in only a small number of patients and additional studies are needed.

A number of promising drugs in the pipeline can lower hepatitis B virus (HBV) DNA and antigen levels, and some may offer a functional cure for selected individuals. But agents that offer a reliable cure for most patients are not yet on the horizon, and many experts think a combination strategy will be necessary.

"It is still quite early in the field of HBV therapeutics," Paul Kwo, MD, of Stanford University Medical Center in California, told MedPage Today. "What is obvious is that multiple strategies are going to be required to achieve a so-called functional cure. These will include strategies to inhibit viral replication by multiple pathways, as well as boosting the immune response to help clear hepatitis B."

Kwo presented a summary of several promising hepatitis B pipeline candidates in his viral hepatitis debrief at the conclusion of The Liver Meeting in October, the annual conference of the American Association for the Study of Liver Diseases (AASLD). He said a large number of novel agents are being explored to target various steps of the HBV lifecycle.

Now that chronic hepatitis C virus (HCV) can be cured in almost all patients using well-tolerated direct-acting antivirals taken for 8 or 12 weeks, many researchers and pharmaceutical companies are turning their attention to hepatitis B.

Nucleoside/nucleotide analog antivirals like tenofovir disoproxil fumarate (Viread), tenofovir alafenamide (Vemlidy), and entecavir (Baraclude) can suppress HBV viral load during long-term therapy, but usually do not lead to a cure, as indicated by loss of hepatitis B surface antigen (HBsAg) and possibly anti-HBs seroconversion.

"Everybody wants to be cured," AASLD president Anna Lok, MD, of the University of Michigan in Ann Arbor, told MedPage Today at the conference. "One reason people are getting back into hepatitis B research is that they are hearing from patients: 'You can cure hepatitis C; why can't you cure hepatitis B?' But it's a different virus, and it's more complicated."

Unlike HCV, HBV produces a persistent form of its genetic material, known as covalently closed circular DNA (cccDNA), in the nucleus of infected hepatocytes, and in some cases the virus can integrate into host cell chromosomes. Nucleoside/nucleotide analogs, which block HBV polymerase activity, can stop replication but do not affect the integrated viral blueprint -- meaning that the virus can start multiplying again when antivirals are discontinued.

"We are now seeing data that represent ongoing maturation of approaches designed to influence key steps in the control of the HBV lifecycle outside of the HBV polymerase, which has been the target of FDA-approved agents to date," Raymond Chung, MD, chief of hepatology at Massachusetts General Hospital in Boston, told MedPage Today.

"These include small molecules that work by boosting innate immune responses against HBV, inhibitors designed to block the HBV capsid protein, which is involved in several steps in the viral lifecycle, an inhibitor that prevents release of HBsAg from the infected hepatocyte, and an RNA inhibitory approach that blocks translation of several key viral proteins."
Promising pipeline agents discussed at the Liver Meeting include the following:

    Inarigivir: Inarigivir soproxil, or SB 9200, being developed by Spring Bank Pharmaceuticals, is an oral immune modulator that activates RIG-I (retinoic acid inducible gene I). It appears to both interfere with viral transcription and packaging (encapsidation) and stimulate interferon production. In the phase II ACHIEVE trial, patients who received 25 mg once-daily inarigivir monotherapy for 12 weeks followed by 12 weeks of tenofovir DF had a larger decrease in HBV viral load than those who received a placebo followed by tenofovir, with steeper declines seen in hepatitis B "e" antigen (HBeAg)-negative compared with HBeAg-positive patients. Six of the 16 treated participants had a sustained reduction in HBsAg levels of more than -0.5 log; some also saw declines in HBV RNA and HBeAg levels. Inarigivir was generally safe and well tolerated with no serious adverse events reported. Higher doses are currently being evaluated
    JNJ-56136379: JNJ-379, being developed by Janssen, binds to the HBV core protein, interfering with capsid disassembly when HBV enters cells and assembly of new capsids when the virus multiplies, resulting in production of non-functional viral particles. In a phase I study of 24 treatment-naive mostly HBeAg-negative chronic hepatitis B patients, 75 mg of JNJ-379 taken for 28 days reduced HBV DNA by 2.89 log. Three people who used the 75 mg dose -- but none of those who used a 25 mg dose -- reached an undetectable viral load. HBV RNA levels also declined, but there was no notable change in HBsAg levels. JNJ-379 was also generally safe and well tolerated. A 150 mg cohort is now enrolling
    REP 2139: REP 2139, being developed by Replicor, is a nucleic acid polymer that interferes with assembly and release of subviral particles from HBV-infected hepatocytes. In a phase II study of previously untreated HBeAg-negative chronic hepatitis B patients, eight out of 10 treated with weekly IV infusions of REP 2139 in combination with tenofovir DF and pegylated interferon for 48 weeks achieved HBsAg clearance (<1 IU/mL), increases in anti-HBs antibodies, and liver enzyme flares followed by normalization. This functional control persisted for up to 24 weeks after completing treatment, suggesting a potential cure. A related agent, REP 2165, did not perform as well.
    ARB-1467: ARB-1467, being developed by Arbutus Biopharma, consists of synthetic small interfering RNAs directed against HBV messenger RNAs. In a phase II clinical trial, 36 mostly HBeAg-negative chronic hepatitis B patients on tenofovir DF or entecavir received IV infusions of ARB-1467 or placebo at doses of 0.2 or 0.4 mg/kg once a month or biweekly for 12 weeks. Everyone treated with ARB-1467 saw a reduction in HBsAg, with the higher dose given biweekly producing the greatest decline. Seven of the 11 evaluable patients in the biweekly cohort (64%) were classified as responders and switched to monthly dosing for up to a year. The largest HBsAg decrease was 2.7 log, and five people in this group reached levels below 50 IU/mL; none, however, achieved HBsAg clearance. The researchers concluded that monthly dosing does not appear sufficient to maintain or improve initial HBsAg reductions achieved with biweekly administration and suggesting that combination therapy may be more effective. A forthcoming trial will evaluate ARB-1467 plus tenofovir and pegylated interferon.

While it remains to be seen whether it is possible to completely eradicate cccDNA from infected liver cells, research to date suggests that a functional cure, or sustained undetectable HBV DNA and HBsAg loss after stopping treatment, may be achievable. This would be expected to substantially reduce the likelihood of liver disease progression and the development of hepatocellular carcinoma, although the risk does not fall to zero.

"Each of these approaches offers hope that one or more such strategies could be rationally combined with traditional polymerase inhibitors to enhance the likelihood of functional cure, or sustained loss of HBsAg, in chronically infected persons," Chung said. "However, it remains quite possible that additional approaches to robustly enhance the cellular immune response, which ultimately clears HBV from naturally infected cells, will be needed to achieve this important goal."

StephenW

新型乙肝治疗显示承诺
一些新的药物可以降低病毒水平，但尚未可靠的治疗方法

    由Liz海利曼
    特约作家，MedPage Today

    本文是MedPageToday®和Medpage Today之间的合作

专家评判
来自AGA阅览室
波士顿波士顿大学医学院消化内科医学系助理教授Michelle Long
随着丙型肝炎病毒治疗的成功，对乙型肝炎病毒（HBV）治疗的发展有了新的兴趣。然而，DNA是一种DNA病毒，与丙型肝炎病毒有很大的不同，可能需要针对不同病毒机制的多种药物和促进免疫反应的药物才能达到治愈的目的。新型药物正在开发中，但对大多数患者来说，可靠的HBV治疗尚未出现。目前，药物可以阻止HBV的复制，但是它们不能有效清除肝细胞中的HBV DNA，这很难与宿主区分开来。新的管道药物包括靶向HBV转录，HBV衣壳分解，干扰亚病毒颗粒释放和HBV信使RNA的药物。目前正在开发的药物仅在少数患者中进行了测试，还需要进一步的研究。

一些有前途的药物正在研制中，可以降低乙肝病毒（HBV）的DNA和抗原水平，有些可能为选定的个体提供功能性治疗。但是，为大多数患者提供可靠治疗的药物尚未出现，许多专家认为组合策略是必要的。

加州斯坦福大学医学中心的Paul Kwo医师向MedPage Today表示：“目前在HBV治疗领域还相当早。 “显而易见的是，实现所谓的功能性治愈将需要多种策略，包括通过多种途径抑制病毒复制的策略，以及加强免疫应答以帮助清除乙型肝炎。

Kwo在10月份的肝脏会议结束时，在美国肝病研究协会（AASLD）的年度会议上，他的病毒性肝炎汇报中汇总了一些有前途的乙型肝炎候选药物。他说，正在探索大量的新型代理商，以针对HBV生命周期的各个步骤。

现在，几乎所有使用耐受良好的直接抗病毒药物治疗8或12周的患者都可以治愈慢性丙型肝炎病毒（HCV），但是许多研究人员和制药公司正把注意力转移到乙型肝炎上。

核苷/核苷酸类似物抗病毒药物如替诺福韦二吡呋酯富马酸酯（Viread），替诺福韦艾拉酚胺（Vemlidy）和恩替卡韦（Baraclude）可以在长期治疗期间抑制HBV病毒载量，但通常不会导致治愈，如肝炎B表面抗原（HBsAg）和可能的抗HBs血清转换。

安娜堡密歇根大学的医学博士Anna Lok博士在会上告诉“今日医学杂志”，“每个人都想要治愈”。 “人们重新进入乙型肝炎研究的一个原因是，他们听到病人的消息：”你可以治愈丙肝，为什么你不能治好乙肝呢？但这是一种不同的病毒，而且更复杂。“

与HCV不同，HBV在被感染的肝细胞的细胞核中产生其遗传物质的持久形式，被称为共价闭合环状DNA（cccDNA），并且在一些情况下，病毒可以整合到宿主细胞染色体中。阻断HBV聚合酶活性的核苷/核苷酸类似物可以阻止复制，但不会影响整合的病毒蓝图，意味着当抗病毒药物停止使用时，病毒可以再次开始繁殖。

“我们现在看到的数据代表了不断成熟的方法，旨在影响HBV聚合酶以外的HBV生命周期的关键步骤，这一直是FDA批准的代理商迄今的目标”，Raymond Chung医学博士波士顿马萨诸塞州综合医院肝病科医生告诉MedPage Today。

“这些包括通过加强对HBV的先天性免疫反应而起作用的小分子，用于阻断HBV衣壳蛋白的抑制剂，其涉及病毒生命周期中的几个步骤，阻止从感染的肝细胞释放HBsAg的抑制剂，以及RNA阻止几种关键病毒蛋白翻译的方法“。

在肝脏会议上讨论的有希望的管道代理包括以下内容：

    Inarigivir：由Spring Bank Pharmaceuticals开发的Inarigivir soproxil或SB 9200是口服免疫调节剂，其激活RIG-1（视黄酸可诱导的基因I）。它似乎既干扰病毒转录和包装（capsidation），并刺激干扰素的生产。在II期ACHIEVE试验中，接受25mg每日一次的inarigivir单药治疗12周，然后接受12周的替诺福韦DF的患者比接受安慰剂和替诺福韦治疗的患者有更大的HBV病毒负荷下降，与HBeAg阳性患者相比，乙型肝炎“e”抗原（HBeAg）阴性。 16名接受治疗的受试者中有6名HBsAg水平持续下降超过-0.5log;一些人也看到了HBV RNA和HBeAg水平的下降。 Inarigivir通常安全且耐受性良好，没有报告严重的不良事件。目前正在评估更高的剂量
    JNJ-56136379：由Janssen开发的JNJ-379与HBV核心蛋白结合，当HBV进入细胞时干扰衣壳的分解，并在病毒繁殖时装配新的衣壳，导致产生非功能性病毒颗粒。在一项针对24名初治HBeAg阴性慢性乙型肝炎患者的I期研究中，服用28天的75 mg JNJ-379使HBV DNA降低了2.89 log。三个使用75毫克剂量的人 - 但是没有一个使用25毫克剂量 - 达到了无法检测的病毒载量。 HBV RNA水平也下降，但HBsAg水平没有显着变化。 JNJ-379也一般安全且耐受性良好。一个150毫克的队列现在正在招募
    REP 2139：REP 2139由Replicor开发，是一种干扰HBV感染肝细胞的亚病毒颗粒装配和释放的核酸聚合物。在一项II期临床研究中，以前未经治疗的HBeAg阴性的慢性乙型肝炎患者，每周静脉输注REP 2139联合替诺福韦DF和聚乙二醇干扰素治疗48周后，有8例达到了HBsAg清除率（<1 IU / mL）抗-HBs抗体增加，肝酶闪耀随后归一化。这种功能控制在完成治疗后持续长达24周，提示可能的治疗。一个相关的代理人，REP 2165，表现不佳。
    ARB-1467：Arbutus Biopharma开发的ARB-1467由针对HBV信使RNA的合成小干扰RNA组成。在一项II期临床试验中，替诺福韦DF或恩替卡韦治疗的36例大多数HBeAg阴性慢性乙型肝炎患者接受静脉输注ARB-1467或安慰剂，剂量为0.2或0.4 mg / kg，每月一次，或每两周一次，共12周。每个接受ARB-1467治疗的人都看到了HBsAg的减少，两周以来产生的最高剂量下降幅度最大。双周组中有11名可评价患者中的7名（64％）被归类为应答者，并转换为每月给药长达一年。最大的HBsAg下降为2.7个对数，并且该组中的5个达到低于50IU / mL的水平;但是，没有一个获得HBsAg清除。研究人员得出结论，每月给药似乎不足以维持或改善双周给药所达到的初始HBsAg降低，并提示联合治疗可能更有效。即将进行的试验将评估ARB-1467加替诺福韦和聚乙二醇化干扰素。

虽然从感染的肝细胞是否有可能彻底根除cccDNA尚有待观察，但迄今为止的研究表明，可以实现功能性治愈，或在停止治疗后持续检测不到HBV DNA和HBsAg消失。预计这将大大降低肝病进展和肝细胞癌发展的可能性，但风险不会降至零。

Chung说：“每一种方法都希望一种或多种这样的策略能够与传统的聚合酶抑制剂合理地结合起来，以增强慢性感染者功能性治愈或HBsAg持续丢失的可能性。 “然而，为了实现这一重要目标，仍然有必要采取其他方法来强化增强细胞免疫应答，最终从自然感染的细胞中清除HBV。

StephenW

https://www.medpagetoday.com/rea ... er%20-%20180%20days

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感谢分享，期待新药更多进展