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标题: Arrowhead v Assembly: 股市观点 [打印本页]

作者: StephenW    时间: 2019-11-22 15:12     标题: Arrowhead v Assembly: 股市观点

Investors eagerly awaiting updates from the American Association for the Study of Liver Diseases (AASLD) Annual Meeting, simply referred to as the Liver Meeting, weren't disappointed when presentations began publishing online in mid-November. Some of the most intriguing drug candidates in the pharmaceutical industry's pipeline, treating conditions ranging from fatty liver disease to chronic hepatitis B (CHB), were on display.

Arrowhead Pharmaceuticals (NASDAQ:ARWR) and Assembly Biosciences (NASDAQ:ASMB) were two companies that stoked investor interest heading into the meeting. Each is developing a treatment for CHB. Both had promising potential based on results published before the meeting. But investors appear to have coalesced around one of the drug candidates now that the meeting has ended.

Investors can easily find themselves lost in the clinical jargon of hepatitis B drug development, so it helps to explain several terms.

It starts by considering the structure of the infectious particle. The hepatitis B virus (HBV) is encapsulated within two shells: The outermost layer is the viral envelope, while the innermost layer is the nucleocapsid core. Researchers diagnose the viral infection and determine its activity level by detecting the presence of certain viral proteins produced on or within one of these layers. Therefore, the effectiveness of a drug candidate is determined by measuring the reduction of HBV proteins from baseline levels, which suggests HBV particles are being cleared from the body faster than they can be replenished.

Viral Antigen
   

Location
   

Significance

Hepatitis B surface antigen (HBsAg)
   

Found on the outermost layer (the viral envelope) of an HBV particle, secreted into the blood.
   

Used to diagnose an individual with CHB, even if they have no symptoms.

Hepatitis B envelope antigen (HBeAg)
   

Found between the inner and outer layer of an HBV particle, secreted into the blood.
   

A sign that HBV is replicating, suggesting an individual can pass it to another person.

Hepatitis B core-related antigen (HBcrAg)
   

Found within the innermost layer of an HBV particle, not easily detected in blood.
   

A sign that HBV is replicating, suggesting an individual can pass it to another person.

Data source: Liang 2009.

Researchers also look for HBV DNA and HBV RNA fragments to determine if the virus is replicating and whether a patient is responding to treatment. However, an individual is considered "functionally cured" if HBsAg can no longer be detected in blood tests, which makes the measurement of the surface antigen the gold standard in determining if a drug candidate is effective.

While nucleos(t)ide analogs (NA) are the current standard of care for CHB, it's estimated that no more than 3% of individuals receiving treatment for five years achieve a functional cure. Most individuals taking an NA never achieve a clinically meaningful reduction in HBsAg antigen, but the drug candidates from Arrowhead Pharmaceuticals and Assembly Biosciences both reported promising reductions.

What makes this hepatitis B drug candidate the winner?

One look at the divergent charts of the two pharma stocks says it all. Shares of Assembly Biosciences have fallen 21% since the beginning of November, while shares of Arrowhead Pharmaceuticals gained 18% in that span. Stretch back to the beginning of October and shares of Assembly Biosciences gained as much as 75% just before the meeting. What happened?

The updates for both hepatitis B drug candidates were promising, but the update from Arrowhead Pharmaceuticals and its collaborator Johnson & Johnson (NYSE:JNJ) was better when it comes to reductions in HBsAg.

The pair are developing a combination therapy comprising an NA and JNJ-3989, a drug candidate based on RNA interference (RNAi). The goal is to develop the foundation for a functional cure defined by reductions in HBsAg. By contrast, Assembly Biosciences is developing a combination therapy comprising an NA and ABI-H0731, which is a core inhibitor thought to work by disrupting viral replication and the innermost layer of an HBV particle. That's why the company has prioritized reductions in HBV RNA levels rather than HBsAg.

While stacking up the results side by side provides an imperfect comparison, it helps demonstrate why investors are beginning to favor JNJ-3989:  

Drug Candidate
   

HBsAg Reduction
   

HBeAg and HBcrAg Reductions
   

Data Cutoff

JNJ-3989 + NA
   

31 of 32 patients achieved at least 90% reduction
   

Generally less robust than HBsAg reductions
   

16 weeks

ABI-H0731 + NA
   

11 of 21 patients achieved at least 80% reduction
   

Generally more robust than HBsAg reductions
   

48 weeks

Data source: Poster presentation from AASLD and press release.

As the table above makes clear, investors have good reason to favor JNJ-3989 in the race for developing a functional cure for CHB. Any arguments about the superior efficacy of ABI-H0731 as measured by reductions in envelope and core antigens is quickly snuffed out by data presented for a triple-combination therapy being developed by Arrowhead Pharmaceuticals and Johnson & Johnson.

The triple-combination therapy comprises an NA, JNJ-3989, and JNJ-6379. The third asset is a capsid assembly modulator, which means it disrupts the formation of the innermost protective layer of an HBV particle. The hypothesis is that such a combination will lead to robust reductions in HBsAg (from JNJ-3989), as well as HBeAg and HBcrAg (from JNJ-6379). Early results suggest that the hypothesis may prove correct.

In an ongoing phase 1 study of the triple-combination therapy, all 12 patients available for evaluation achieved reductions of at least 90% for both HBsAg and HBeAg after 16 weeks of treatment. By contrast, the double-combo involving ABI-H0731 achieved HBeAg reductions of at least 80% in only 11 of the 21 patients after 48 weeks of treatment.


The cure for hepatitis C, developed in the last decade, sparked renewed hope that the milestone can be duplicated in hepatitis B. While it's too soon to declare that the triple-combination therapy from Johnson & Johnson and Arrowhead Pharmaceuticals will provide that long-awaited victory and potentially save more than 1 million lives per year, it does appear to be the most promising CHB drug in the industry's pipeline based on limited data collected to date.

That explains why shares of Arrowhead Pharmaceuticals have soared since the beginning of November despite the early-stage nature of the results. It stands to earn up to $1.6 billion in milestone payments from Johnson & Johnson, plus royalties on future sales, for JNJ-3989 (formerly ARO-HBV). It could receive up to $1.9 billion in additional royalties for other drug candidates involved in the broad collaboration.

That also explains why investors are less impressed with the otherwise solid results from Assembly Biosciences. However, that doesn't mean Johnson & Johnson and Arrowhead are free from competition. A new partnership between Dicerna Pharmaceuticals and Roche promises to combine a potentially superior RNAi drug candidate with a novel capsid assembly modulator. While the new challengers won't have data until 2020, their presence should keep investors grounded.


作者: StephenW    时间: 2019-11-22 15:13

当演讲在11月中旬开始在线发布时,渴望等待美国肝病研究协会(AASLD)年会(简称为肝会议)的最新消息的投资者并不感到失望。展出了一些制药行业最吸引人的候选药物,这些药物可以治疗从脂肪肝到慢性乙型肝炎(CHB)的各种疾病。

Arrowhead Pharmaceuticals(NASDAQ:ARWR)和Assembly Biosciences(NASDAQ:ASMB)是两家引起投资者兴趣的公司。每个人都在开发一种治疗CHB的方法。根据会议前公布的结果,双方都有潜力。但是,由于会议已经结束,投资者似乎已经合并了一名候选药物。

投资者可以轻松地在乙型肝炎药物开发的临床术语中发现每一个损失,因此有助于解释几个术语。

乙型肝炎病毒(HBV)封装在两个壳中:最外层是病毒包膜,而最内层是核衣壳核心。研究人员通过检测在这些层之一上或其中产生的某些病毒蛋白的存在来诊断病毒感染并确定其活性水平。候选药物的有效性是通过测量HBV蛋白从基线水平的降低来确定的,这表明HBV从体内清除微粒的速度超过了可以补充的速度。

病毒抗原


地点


意义

乙型肝炎表面抗原(HBsAg)


发现于HBV颗粒的最外层(病毒被膜),分泌到血液中。


用于诊断患有CHB的患者,即使他们没有症状。

乙型肝炎包膜抗原(HBeAg)


发现在HBV颗粒的内层和外层之间,分泌到血液中。


乙肝病毒正在复制的迹象,表明一个人可以将其传递给另一个人。

乙型肝炎核心相关抗原(HBcrAg)


发现在HBV颗粒的最内层,在血液中不易检测到。


乙肝病毒正在复制的迹象,表明一个人可以将其传递给另一个人。

数据来源:Liang 2009。

研究人员还寻找HBV DNA和HBV RNA片段,以确定病毒是否正在复制以及患者是否对治疗有反应。但是,如果无法在血液测试中检测到HBsAg,则认为该人“功能治愈”,这使表面抗原的测量成为确定候选药物是否有效的金标准。

虽然核苷酸(t)化物类似物(NA)是目前CHB的护理标准,但据估计,接受治疗五年的个体中,只有3%的人能够达到功能治愈。大多数服用NA的个体从未达到临床意义的HBsAg抗原降低,但Arrowhead Pharmaceuticals和Assembly Biosciences的候选药物均报告了有希望的降低。

是什么使这种乙型肝炎候选药物成为赢家?

一看这两家制药公司股票的走势图就可以了。自11月初以来,Assembly Biosciences的股价下跌了21%,而Arrowhead Pharmaceuticals的股价在此期间上涨了18%。可以追溯到10月初,在会议召开之前,Assembly Biosciences的股价上涨了75%。发生了什么?

两种乙肝药物候选药物的更新都是有希望的,但是就减少HBsAg而言,Arrowhead Pharmaceuticals及其合作者强生公司(纽约证券交易所:JNJ)的更新更好。

两人正在开发一种组合疗法,其中包括NA和JNJ-3989,这是一种基于RNA干扰(RNAi)的候选药物。目标是为减少HBsAg的功能定义奠定基础。相比之下,Assembly Biosciences正在开发一种包含NA和ABI-H0731的联合疗法,ABI-H0731是一种核心抑制剂,被认为通过破坏病毒复制和HBV颗粒的最内层起作用。这就是为什么该公司优先考虑降低HBV RNA水平而不是降低HBsAg。

虽然并排累加结果并不完美,但它有助于说明投资者为何开始青睐JNJ-3989:

候选药物


减少HBsAg


减少HBeAg和HBcrAg


数据截止

JNJ-3989 +不适用


32位患者中的31位至少减少了90%


通常不如HBsAg降低那么有力


16周

ABI-H0731 + NA


21位患者中的11位至少减少了80%


通常比减少HBsAg更有效


48周

数据来源:AASLD的海报展示和新闻稿。

如上表所示,在开发CHB功能性固化剂的竞赛中,投资者有充分的理由支持JNJ-3989。通过包膜和核心抗原的减少来衡量的有关ABI-H0731优越功效的任何论点,很快就被Arrowhead Pharmaceuticals和Johnson&Johnson提出的三联疗法的数据所掩盖。

三联疗法包括NA,JNJ-3989和JNJ-6379。第三个资产是衣壳装配调节剂,这意味着它会破坏HBV颗粒最内层保护层的形成。假设是这样的组合将导致HBsAg(来自JNJ-3989)以及HBeAg和HBcrAg(来自JNJ-6379)的强烈降低。早期结果表明该假设可能是正确的。

在一项正在进行的三联疗法的1期研究中,所有16名患者在治疗16周后均可评估HBsAg和HBeAg至少降低90%。相比之下,在治疗48周后,涉及ABI-H0731的双重联合疗法在21例患者中仅11例实现了HBeAg降低至少80%。


过去十年中开发出的丙型肝炎治疗方法,再次激发了人们希望该里程碑可以在乙型肝炎中复制的希望。尽管现在宣布强生和Arrowhead Pharmaceuticals的三联疗法将提供期待已久的为时过早胜利,每年可能挽救超过一百万的生命,根据迄今为止收集的有限数据,它似乎是该行业中最有前途的CHB药物。

这就是为什么尽管结果具有初期性质,但箭头制药公司的股票自11月初以来却一直飙升的原因。它有望从强生公司获得高达16亿美元的里程碑付款,外加未来销售的特许权使用费,用于购买JNJ-3989(原ARO-HBV)。它可能会为参与广泛合作的其他药物候选者获得多达19亿美元的额外特许权使用费。

这也解释了为什么Assembly Biosciences否则会给坚实的业绩给投资者留下不小的印象。但是,这并不意味着强生和Arrowhead可以摆脱竞争。 Dicerna Pharmaceuticals与罗氏(Roche)建立了新的合作伙伴关系,有望将具有潜在优势的RNAi药物候选人与新型衣壳装配调节剂相结合。尽管新的挑战者要到2020年才能获得数据,但他们的存在应使投资者保持扎根。
作者: StephenW    时间: 2019-11-22 15:13

https://www.fool.com/investing/2 ... r-winner-among.aspx
作者: newchinabok    时间: 2019-11-22 16:20

可以通过阻断RNA和核心颗粒的复制来阻断HBV的复制周期。早在NAs应用于临床之前,我们就曾使用过核衣壳抑制剂和衣壳蛋白调节剂来抗HBV。小分子干扰RNAs(siRNAs)也可能用于治疗HBV感染,其可以有效地阻断如表面抗原和e抗原等蛋白的生成。虽然上述药物能够使HBsAg水平快速下降,但是需要经皮下或经血管注射,不能口服治疗。如果患者使用上述方法后达到了HBsAg的阴转,但没有相应的免疫应答激活,这种治疗应答是否具有持续性仍不确定。虽然患者达到HBsAg清除,但一旦停止治疗,可能导致病毒复发
作者: newchinabok    时间: 2019-11-22 16:21

但没有相应的免疫应答激活,这种治疗应答是否具有持续性仍不确定。虽然患者达到HBsAg清除,但一旦停止治疗,可能导致病毒复发
作者: 平凡之路123    时间: 2019-11-22 16:40

回复 newchinabok 的帖子

我看有些母婴遗传的,持续抗病毒几年后,到了六七十岁,会出现表面抗体。
作者: 齐欢畅    时间: 2019-11-22 20:51


作者: aiyayao    时间: 2019-11-23 00:08

需要纠正一点的是楼主这篇文章里关于箭头的3联用药:在一项正在进行的三联疗法的1期研究中,所有16名患者在治疗16周后均可评估HBsAg和HBeAg至少降低90%

美肝会箭头的pdf数据:Reductions in HBeAg and HBcrAg were generally less pronounced during the dosing period

可以看到实际箭头的3联对于 HBeAg 效果并不明显,所以这篇文章说HBeAg降低90是错误的
作者: 平凡之路123    时间: 2019-11-23 11:53

所以说,资本市场比我们更敏锐。

为什么说乙克没有成功?因为华丽家族的股票半死不活。如果乙克效果很好,最起码科研人员知道,早就大规模购买股票了。
作者: dxd2017    时间: 2019-11-25 08:33

回复 aiyayao 的帖子

请问为什么对HBeAg效果不好?3个药这么强的药,连HBeAg都没作用,怎么治愈?谢谢!
作者: ICABC    时间: 2019-11-26 23:05

不晓得箭头是不是有什么消息了,今天股票涨得特别好!
作者: c1v8x8hqnhkvmuz    时间: 2019-12-1 17:28

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