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标题: 寻找治疗乙型肝炎的新机制 [打印本页]

作者: StephenW 时间: 2018-9-19 20:22 标题: 寻找治疗乙型肝炎的新机制

Looking for new mechanisms to cure hepatitis B

Madeleine Armstrong

            A genome editing tie-up between Gilead and Precision Biosciences, and promising early data with Arrowhead’s RNA interference project, are two novel approaches in hep B.

                                                Yesterday’s preclinical-stage deal between Gilead and Precision Biosciences shows the renewed interest in finding a functional cure for hepatitis B. But the project, which aims to eliminate hep B via Precision’s Arcus genome-editing technology, is far from the closest to market.
Arrowhead's RNA interference candidate ARO-HBV, for which last week the company reported promising phase I/II data, is much closer to approval. But Arrowhead is not the only group with a mid-stage project, with big players including Glaxosmithkline and Johnson & Johnson, as well as Gilead, also in the race.
The current mainstay of hepatitis B treatment is antiviral therapy with pegylated interferons or oral nucleoside/nucleotide analogues, which are also used in HIV. These drugs can suppress viral replication but patients must be treated chronically, and adherence can be low – hence the need for a functional cure.
[td]

Selected mid-stage novel hep B projects
Project	Company	Mechanism of action	Ongoing trial(s)	Primary completion
ARO-HBV	Arrowhead Pharmaceuticals	Hep B polymerase RNAi therapeutic	NCT03365947	Reported
ARB-1467	Arbutus Biopharma	Hep B polymerase RNAi therapeutic	NCT02631096	Reported
Inarigivir	Spring Bank/ Gilead	RIG1 agonist	NCT03434353, Achieve (NCT02751996)	End 2018
REP 2139	Replicor	Hep B surface antigen inhibitor	NCT02565719	Sep 2018
REP 2165	Replicor	Hep B surface antigen inhibitor	NCT02565719	Sep 2018
IONIS-HBV-LRx	Ionis Pharmaceuticals/ Glaxosmithkline	HBV ligand conjugated antisense	NCT03020745	Nov 2018
IONIS-HBVRx	Ionis Pharmaceuticals/ Glaxosmithkline	HBV antisense	NCT03020745, NCT02981602	Nov 2018, Dec 2018
ABI-H0731	Assembly Biosciences	Capsid assembly modulator	NCT03576066, NCT03577171	Mar 2019, Apr 2019
GS-9688	Gilead Sciences	TLR 8 agonist	NCT03491553, NCT03615066	Apr 2019, Oct 2019
JNJ-6379	Johnson & Johnson	Capsid assembly modulator	NCT03361956	Oct 2019
Myrcludex B	Myr Pharma/ Hepatera	Viral entry inhibitor	NCT02888106	Dec 2019
Source: EvaluatePharma.

All eyes are now on Arrowhead after the company’s presentation last week at the World Gastroenterologists Summit in Auckland, New Zealand. But it is worth noting that the results, which sent the group’s stock up 38%, came in only eight patients treated with the first two doses of ARO-HBV: 100mg and 200mg.
The trial found a reduction in serum hepatitis B surface antigen (HBsAg) of 2.0 log in the 100mg cohort and 1.4 log in the 200mg cohort. HBsAg is a viral protein used to assess a patient’s response to therapy, and its permanent suppression is regarded as an important step towards achieving a functional cure.
Arrowhead said activity was seen in all patients, including those who were negative for hepatitis B e-antigen (HBeAg) – notable because the company’s older RNAi project, ARC-520, did not show an effect in this group.
The results look promising, but investors will be waiting to see if a dose response emerges with data from the higher-dose cohorts; there are a total of 10 cohorts in the trial. Arrowhead hopes to present more comprehensive results from the study at the AASLD Liver Meeting in San Francisco in November, and has also said that a combination approach would likely be needed to produce a functional cure for hep B.
The ARO-HBV data set up a battle with Arbutus Biopharma, Arrowhead’s closest competitor in hep B RNAi.
Early data with Arbutus’s ARB-1467, evaluating monthly dosing, were disappointing (Arbutus slides on poor results in hep B, 30 September 2016). But biweekly dosing led to an average serum HBsAg reduction of 1.4 log, in line with the ARO-HBV results.
Arbutus is now carrying out a phase II trial of longer-term biweekly therapy with ARB-1467 plus Gilead’s antiviral Viread and pegylated interferon, and interim data are expected in the fourth quarter.
Triple combos?
The most valuable novel hepatitis B project, with forecast 2024 sales of $995m according to EvaluatePharma sellside consensus, is Spring Bank Pharmaceuticals’ oral Rig-1 agonist inarigivir, which targets a modulator of antiviral immune defence. Gilead is involved in its development, and is testing the project in combination with its marketed antiviral Vemlidy.
Interestingly, Arrowhead highlighted inarigivir during its World Gastroenterologists Summit presentation last week, leading to speculation that ARO-HBV could be added to this combo. Indeed, Spring Bank has said that it expects inarigivir to be included in a triple combination with an RNA interference project “or a different mechanism”, with clinical trials set to begin in the first half of 2019.
Last month, Spring Bank reported data from the third dosing cohort of the ongoing Achieve trial, which appeared to support a dose response with inarigivir monotherapy. Topline results from the final, highest-dose cohort are expected by the end of the year.
At the same time, the company announced that the Gilead-funded study of inarigivir plus Vemlidy would enrol two new higher-dose cohorts; this will allow Spring Bank to skip the planned phase IIb portion of the Achieve trial and go straight into phase IIb/III in early 2019.
Meanwhile, Gilead has its own project, the TLR 8 agonist GS-9688, in two phase II trials – one in treated and one in treatment-naive patients – that are due to complete next year.
TLR agonists are thought to activate patients’ innate immune response against the hepatitis B virus. Roche has been investigating a similar mechanism with the TLR 7 agonist RO6864018, but its status is currently unclear after a phase II trial was completed last year.
And, in another sign that all might not be rosy with the TLR approach, Gilead appears to have shifted its attention to HIV with its TLR 7 agonist GS-9620, which was once in development for hepatitis B.
CAM on
Still, there are plenty more approaches being tested. At the World Gastroenterologists Summit, Arrowhead also made a nod to JNJ-6379, a capsid assembly modulator (CAM), triggering rumours that partnership with J&J could also be in the offing.
Data from the phase I HPB1001 trial of JNJ-6379 were presented at the same conference, showing a reduction in HBV DNA versus placebo – but no changes in HBsAg. A phase II study of JNJ-6379 is due to complete next year.
CAMs are designed to disrupt the “shell” around the virus, thereby blocking replication. Other groups looking at this mechanism include Assembly Biosciences, whose first-generation project, ABI-H0731, should yield phase II data next year.
Arbutus also has the next-gen capsid inhibitors AB-423 and AB-506 in phase I development, according to its website.
Meanwhile, other mechanisms being tested include an antisense approach, by Ionis and Glaxosmithkline, and targeting HBsAg, where Replicor is active.
Myr Pharma’s Myrcludex B takes yet another approach, aiming to inhibit entry of the hepatitis B virus into a patient’s cells, and the company claims that this is the only hepatitis B project in development to work in this way.
Gilead’s latest deal might show a lack of confidence in its more advanced approaches – or perhaps the group is just hedging its bets. Then again, if Arrowhead is right and combos are the way forward, maybe Gilead wants all the components in house.
Curing hepatitis C might not have made good business sense, but Gilead seems determined to repeat the same trick in hep B.

作者: StephenW 时间: 2018-9-19 20:25

寻找治疗乙型肝炎的新机制

玛德琳阿姆斯特朗

Gilead和Precision Biosciences之间的基因组编辑联系，以及Arrowhead RNA干扰项目的早期数据，是两种新方法。
乙型肝炎病毒的例证在蓝色的

昨天Gilead和Precision Biosciences之间的临床前阶段交易显示了人们对寻找乙型肝炎功能性治疗方法的新兴趣。但该项目旨在通过Precision的Arcus基因组编辑技术消除hep B，远离市场最近。

箭头的RNA干扰候选物ARO-HBV，上周该公司报告了有希望的I / II期数据，更接近批准。但箭头并不是唯一一个拥有中期项目的团体，包括葛兰素史克和强生公司在内的大型玩家以及吉利德也在竞选中。

乙肝治疗目前的主要支柱是用聚乙二醇化干扰素或口服核苷/核苷酸类似物进行抗病毒治疗，这些治疗也用于HIV。这些药物可以抑制病毒复制，但患者必须长期治疗，并且依从性可能很低 - 因此需要功能性治愈。
选择中期新颖的乙肝项目
项目公司行动机制正在进行的试验初步完成
ARO-HBV箭头药物Hep B聚合酶RNAi治疗NCT03365947报道
ARB-1467 Arbutus Biopharma Hep B聚合酶RNAi治疗NCT02631096报道
Inarigivir Spring Bank / Gilead RIG1激动剂NCT03434353，Achieve（NCT02751996）2018年底
REP 2139 Replicor Hep B表面抗原抑制剂NCT02565719 Sep 2018
REP 2165 Replicor Hep B表面抗原抑制剂NCT02565719 Sep 2018
IONIS-HBV-LRx Ionis Pharmaceuticals / Glaxosmithkline HBV配体偶联反义NCT03020745 2018年11月
IONIS-HBVRx Ionis Pharmaceuticals / Glaxosmithkline HBV反义NCT03020745，NCT02981602 2018年11月2018年12月
ABI-H0731组装生物科学衣壳组装调节器NCT03576066，NCT03577171 2019年3月，
2019年4月
GS-9688 Gilead Sciences TLR 8激动剂NCT03491553，NCT03615066 Apr 2019，Oct 2019
JNJ-6379 Johnson＆Johnson Capsid组装调节器NCT03361956 Oct 2019
Myrcludex B Myr Pharma / Hepatera病毒进入抑制剂NCT02888106 Dec 2019
资料来源：EvaluatePharma。

该公司上周在新西兰奥克兰举行的世界胃肠病学家峰会上发表演讲后，目前所有的目光都集中在箭头上。但值得注意的是，结果导致该组股票增加了38％，仅有8名接受前两剂ARO-HBV治疗的患者：100mg和200mg。

该试验发现，100mg组中血清乙型肝炎表面抗原（HBsAg）降低2.0log，200mg组降低1.4log。 HBsAg是一种病毒蛋白，用于评估患者对治疗的反应，其永久性抑制被认为是实现功能性治愈的重要一步。

Arrowhead表示，所有患者均有活动，包括乙型肝炎e抗原阴性者（HBeAg） - 值得注意的是，该公司较老的RNAi项目ARC-520在该组中没有显示出效果。

结果看起来很有希望，但投资者将等待观察剂量反应是否来自高剂量队列的数据;试验中总共有10个队列。 Arrowhead希望在11月份在旧金山举行的AASLD肝脏会议上提供更全面的研究结果，并且还表示可能需要采用联合方法来生产针对肝脏B的功能性治疗方法。

ARO-HBV数据与Arrowhead在hep B RNAi中最接近的竞争对手Arbutus Biopharma展开了一场战斗。

Arbutus ARB-1467的早期数据，评估每月剂量，令人失望（Arbutus在2016年9月30日的HB B结果不佳）。但每两周一次给药导致血清HBsAg平均降低1.4 log，与ARO-HBV结果一致。

Arbutus目前正在进行一项II期临床试验，即使用ARB-1467加上Gilead的抗病毒Viread和聚乙二醇化干扰素进行长期双周治疗，预计第四季度将提供中期数据。

三重组合？

根据EvaluatePharma卖方的共识，最有价值的新型乙型肝炎项目，预测2024年销售额为9.95亿美元，是Spring Bank Pharmaceuticals的口服Rig-1激动剂inarigivir，其目标是抗病毒免疫防御调节剂。吉利德参与其开发，并与其上市的抗病毒药物Vemlidy一起测试该项目。

有趣的是，Arrowhead在上周的世界胃肠病学家峰会上发表了强调inarigivir，导致人们猜测ARO-HBV可能被添加到这个组合中。事实上，Spring Bank已经表示，它希望将inarigivir纳入与RNA干扰项目“或不同机制”的三重组合中，临床试验将于2019年上半年开始。
上个月，Spring Bank报告了正在进行的Achieve试验的第三个剂量组的数据，该试验似乎支持了使用inarigivir单药治疗的剂量反应。最终的最高剂量队列的最终结果预计将在今年年底完成。

与此同时，该公司宣布，吉利德资助的inarigivir加Vemlidy研究将招募两个新的高剂量队列;这将允许Spring Bank跳过Achieve试验计划的IIb期部分，并在2019年初直接进入IIb / III期。

与此同时，吉利德在两个阶段的试验中有自己的项目，即TLR 8激动剂GS-9688，其中一个在治疗中，一个在治疗初治患者中 - 将于明年完成。

TLR激动剂被认为激活患者针对乙型肝炎病毒的先天免疫应答。罗氏一直在研究与TLR 7激动剂RO6864018类似的机制，但在去年完成II期试验后，其状态目前尚不清楚。

并且，另一个迹象表明TLR方法可能并不乐观，吉利德似乎已经将其注意力转移到艾滋病病毒的TLR 7激动剂GS-9620上，该病毒曾一度用于乙型肝炎。

CAM上

不过，还有很多方法正在测试中。在世界胃肠病学家峰会上，Arrowhead还向JNJ-6379致敬，这是一种衣壳组件调节器（CAM），引发了与J＆J的合作关系也可能即将到来的传闻。

来自JNJ-6379的I期HPB1001试验的数据在同一会议上呈现，显示HBV DNA与安慰剂相比减少 - 但HBsAg没有变化。 JNJ-6379的第二阶段研究将于明年完成。

CAM旨在破坏病毒周围的“外壳”，从而阻止复制。其他正在研究这种机制的团体包括Assembly Biosciences，其第一代项目ABI-H0731将在明年产生第二阶段数据。

根据其网站，杨梅还在第一阶段开发中具有下一代衣壳抑制剂AB-423和AB-506。

同时，正在测试的其他机制包括Ionis和Glaxosmithkline的反义方法，以及Replicor活跃的HBsAg靶向。

Myr Pharma的Myrcludex B采取了另一种方法，旨在抑制乙型肝炎病毒进入患者细胞，该公司声称这是唯一正在开发的乙型肝炎项目。

吉利德的最新协议可能表明对其更先进的方法缺乏信心 - 或者该集团可能正在对冲其赌注。再说一次，如果箭头是正确的，而组合是前进的方向，那么基列可能想要内部的所有组件。

治愈丙型肝炎可能没有很好的商业意义，但吉利德似乎决心在肝脏B中重复相同的技巧。

作者: newchinabok 时间: 2018-9-19 20:40

StephenW 发表于 2018-9-19 20:25
寻找治疗乙型肝炎的新机制

玛德琳阿姆斯特朗

好文，马克and中

作者: newchinabok 时间: 2018-9-19 20:47

本帖最后由 newchinabok 于 2018-9-19 21:11 编辑

Arbutus目前正在进行一项II期临床试验，即使用ARB-1467+Viread+干扰素进行长期双周治疗，预计第四季度将提供中期数据。

作者: 齐欢畅 时间: 2018-9-19 21:47

亚盛的新药，我倒很感兴趣。
新机制越多越好。我觉得可以在老药新用中找找灵感。

作者: Hepbest 时间: 2018-9-20 11:23

回复 newchinabok 的帖子

总感觉能够带上干扰素的方案，都是挺原始的。
毕竟很多战友不适用于干扰素啊

作者: 齐欢畅 时间: 2018-9-20 11:55

干扰素是比较成熟的药物，联用是需要这样的药物的。

作者: 齐欢畅 时间: 2018-9-20 12:06

请问贵公司提交的替芬泰二期临床方案是否被302医院否决了？
贵州百灵：
由于军改对部队医院的影响，解放军302医院已就替芬泰相关的合作进行讨论和审批，但不构成对该项目二期临床试验的影响，相关工作正常进行，公司将及时进行项目后续进展的信息披露工作。谢谢

作者: newchinabok 时间: 2018-9-20 12:06

本帖最后由 newchinabok 于 2018-9-20 12:08 编辑

Hepbest 发表于 2018-9-20 11:23
回复 newchinabok 的帖子

总感觉能够带上干扰素的方案，都是挺原始的。

干挠素今后会被其它免疫药替代。一定。首先验证一下，RNAi药有没有作用，单用肯定无用的。没有免疫药，RNA！药就是无用之药

作者: 齐欢畅 时间: 2018-9-20 12:06

替芬泰二期、三期临床申请资料已编制完成，三家已通过，仅解放军302医院在审，请问按照规定这个审核期限多久？现在国家要求简政放权，连国家食药监审核新药都已经简化流程，开通绿色通道，现在一家医院居然官僚作风浓厚，审核了几年没动静，请问：1、公司在合作过程中是否完全没有主动权？2、这次申请临床是二期、三期一起上报，食药监审核后2、3期临床试验一起执行吗？
贵州百灵：
感谢您对公司的关注，关于替芬泰项目申请后续临床试验的相关准备工作，公司和合作研究机构会积极的进行沟通和交流，争取项目早日向相关部门进行提交。目前替芬泰项目后续二期、三期临床试验的申报资料已编写完成，如项目审批顺利，预计相关审批部门会同时下发二期、三期临床试验的临床批件，但最终将以正式收到的相关文件为准。谢谢！

作者: 齐欢畅 时间: 2018-9-20 12:08

股吧的信息。未验证。

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