装配生物科学到达诊所

StephenW

Assembly Biosciences Reaches The ClinicNov. 16, 2016 11:43 AM ET
|
About: Assembly Biosciences, Inc. (ASMB)


Clinically Sound Investor Follow (1,772 followers)

Biotech, healthcare, tech, event-driven
Send Message|
A Pharmacist Breaks Down Biotech


SummaryThe company's lead product candidate is a potential curative treatment for hepatitis B virus (HBV).
Although ABI-H0731 is behind in development compared to some others, those ahead may provide a blueprint for action.
Since these agents share a similar and highly HBV-specific mechanism of action, a similar nontoxic profile may also be expected.

Assembly Biosciences (NASDAQ:ASMB) is a small biotechnology company (market cap: $223.93 million) developing curative small molecule therapies for chronic hepatitis B virus (HBV) infection and microbiotic therapies for Clostridium difficile infections. The stock has doubled since the beginning of October, perhaps as the market became aware of the company's two September presentations in Asia. Last week, a first-in-man Phase 1a/1b study was initiated for ABI-H0731 (AB-V101), the lead entry from Assembly's proprietary class of oral direct acting antivirals known as Core Protein Allosteric Modifiers (CpAMs). CpAMs bind to Cp and are believed to work by blocking the encapsidation (enveloped in virus-like particle shells) of viral pregenomic RNA (pgRNA, Figure 1). Investors should keep track of any company that has a potential curative drug in HBV, since it will likely be priced in multiples of the annual cost of antivirals that have to be taken lifelong, such as entecavir, which was a multi-year blockbuster for Bristol-Myers Squibb (NYSE:BMY) as one of several preferred treatment options.

Figure 1. Core Protein (Cp) Allosteric Modifiers Cause Interference throughout Hepatitis B Virus Lifecycle

Richard Colonno, who coincidentally was an integral part of the team which discovered and developed entecavir at BMS, is Assembly's Chief Science Officer and gave the China presentation. He retold the possible HBV cure that was initially hoped for with entecavir (approved in 2005), which had cured woodchucks of HBV. But cccDNA hides inside the nuclei of liver cells, out of the reach of the nucleoside (NYSE:NUC) antiviral as well as other current treatments. Years later, it became clear that to achieve clinical HBV cure in humans, therapy must eliminate (or silence) existing covalently closed circular DNA (cccDNA) and prevent new cccDNA formation. One approach is that of Arrowhead Pharmaceuticals' (NASDAQ:ARWR) ARC-520, which silences cccDNA and all HBV gene products, including Cp. Arrowhead is trying to recover after the Food and Drug Administration placed a clinical hold on ARC-520's U.S. trial due to toxicology concerns on the vehicle used to deliver ARC-520 to liver cells.

Dr. Colonno contrasted how entecavir only inhibits reverse transcription activity of the HBV polymerase, which reduces encapsidated HBV DNA, but which actually also increases pgRNA-containing particles and makes them the dominant type of virions circulating in the blood. Serum pgRNA has been confirmed as a useful surrogate marker since it mirrors pgRNA in the liver, which in turn correlates with cccDNA activity persisting in HBV-infected patients. CpAMs reduce pgRNA packaging, which is thought to inhibit rcDNA formation and reduce rcDNA delivery to the nucleus.

The Asian presentations were also the first to show consistent potency of Assembly's candidates over another CpAM. A proof-on-concept trial by Johnson and Johnson (NYSE:JNJ) showed promising results on their Cp inhibitor, NVR 3-778. However, it took a very high dose as monotherapy to get a 1 log 10 reduction in HBV DNA. Assembly has $59 million in cash and has burned an average of $11 million per quarter in 2016. Thus, the funds should last until the trial completes. It will be exciting to see how ABI-H0731 performs solo, and whether the company will pair it with pegylated interferon as JNJ did, or go straight for a NUC combo. As the good doctor says, "We want what we achieved in woodchucks!" We also want a good return on investment, and because ABI-H0731 doesn't need a vehicle, it is likely that the study in healthy individuals will be successful.

Disclosure: I am/we are long ARWR.

I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

StephenW

装配生物科学到达诊所
2016年11月16日上午11:43
关于：Assembly Biosciences，Inc.（ASMB）

该公司的主要产品候选者是乙型肝炎病毒（HBV）的潜在治疗性治疗。

虽然ABI-H0731在发展中落后于其他一些，但前面的可能提供行动的蓝图。

由于这些试剂共享相似的和高度HBV特异性作用机制，因此也可以预期类似的无毒​​性谱。

装配生物科学（纳斯达克：ASMB）是一个小型生物技术公司（市值：2.2393亿美元），开发治疗慢性乙型肝炎病毒（HBV）感染和微生物治疗艰难梭菌感染的治疗小分子治疗。自10月初以来，股价已经翻了一番，也许是因为市场意识到公司在亚洲举行的两个9月演讲会。上周，针对ABI-H0731（AB-V101）开始了第一阶段1a / 1b期研究，该研究是Assembly的专有类口服直接作用抗病毒药物，称为核心蛋白变构修饰剂（Core Protein Allosteric Modifiers，简称CpAM）。 CpAM与Cp结合并且被认为通过阻断病毒前基因组RNA（pgRNA，图1）的衣壳化（包裹在病毒样颗粒壳中）起作用。投资者应该跟踪任何在乙型肝炎病毒中含有潜在的治疗性药物的公司，因为它很可能定价为必须终身使用的抗病毒药物的每年成本的倍数，如恩替卡韦，这是布里斯托尔的一个多年大爆油炸-Myers Squibb（NYSE：BMY）作为几种首选治疗方案之一。

图1.核心蛋白（Cp）变构修饰剂导致整个乙型肝炎病毒生命周期的干扰

理查德·科隆诺，巧合的是团队的一个组成部分，发现和开发恩他卡韦在BMS，是大会的首席科学官，并给中国的演讲。他回顾了最初期望与恩替卡韦（在2005年获得批准）的HBV治愈方法，该方案已经治愈了HBV的土拨鼠。但是cccDNA隐藏在肝细胞的核内，在核苷（NYSE：NUC）抗病毒以及其他当前治疗的范围之外。几年后，显然，为了在人类中实现临床HBV治疗，治疗必须消除（或沉默）现有的共价闭合环状DNA（cccDNA）并防止新的cccDNA形成。一种方法是Arrowhead Pharmaceuticals（NASDAQ：ARWR）ARC-520，其沉默cccDNA和所有HBV基因产物，包括Cp。箭头在试图恢复后美国食品和药物管理局暂时搁置ARC-520的美国试验，由于毒性关注的车辆用于交付ARC-520到肝细胞。

Colonno博士对比了恩替卡韦仅抑制HBV聚合酶的逆转录活性，这减少了衣壳化的HBV DNA，但实际上也增加了含有pgRNA的颗粒，并使其成为在血液中循环的病毒颗粒的主要类型。血清pgRNA已被证实为有用的替代标志物，因为它反映肝脏中的pgRNA，其反过来与持续存在于HBV感染的患者中的cccDNA活性相关。 CpAM降低pgRNA包装，其被认为抑制rcDNA形成并降低rcDNA递送至细胞核。

亚洲演讲也是第一个显示大会候选人与另一个CpAM的一致效力。约翰逊和约翰逊（纽约证券交易所：JNJ）的概念验证试验显示了他们的Cp抑制剂NVR 3-778的有前途的结果。然而，作为单一疗法需要非常高的剂量以获得HBV DNA的1log 10减少。大会有5900万美元的现金，并在2016年平均每季度烧毁1100万美元。因此，资金应持续到试验完成。这将是令人兴奋的，看看ABI-H0731如何执行独奏，以及公司是否会配对它与聚乙二醇干扰素作为JNJ做，或直接为NUC组合。正如好医生说，“我们想要我们在土拨鼠！我们还希望获得良好的投资回报，因为ABI-H0731不需要车辆，健康人的研究很可能会成功。

披露：我/我们是长ARWR。

我自己写这篇文章，它表达了我自己的意见。我没有得到赔偿（除了寻求阿尔法）。我与本文中提到的任何公司的股票没有业务关系。

newchinabok

感谢sw老师分享正能量，能翻译成河南话就更好了。这翻译文章，俺看不中！