再次关注乙型肝炎新进展

StephenW

Renewed Attention Sees New Progress For Hepatitis B.

By Anjani Shah

August 31, 2017 | Hepatitis B is a serious liver infection, caused by the hepatitis B virus (HBV), with indications ranging from a mild illness lasting a few weeks to a life-long, chronic liver infection. There is a prophylactic hepatitis B vaccine for infants and children, but with an estimated 257 million people living with a hepatitis B virus infection, the virus is still an active target for drug discovery.

The HBV field has seen increased attention from industry research in the past few years, influenced by the success of new hepatitis C virus (HCV) therapies. Aftercientized HCV could be cured, they turned their attention to hepatitis B, hoping to develop a cure for it also.

There are major differences between the two viruses. The HBV worldwide incidence is twice that of HCV's, and research into HBV is at the stage that hepatitis C research was about 10 years ago. HBV is more challenging because the virus has a unique way of controlling the host response; often a reservoir of hepatitis B virus remains even after treatment.

I spoke recently with Mike Sofia, Ph.D., chief science officer and co-founder of Arbutus Pharmaceuticals, about the latest HBV research. Sofia was one of the pioneering researchers of the recently launched new class of hepatitis C virus inhibitors when he was senior VP of chemistry at Pharmasset, a company now part of Gilead, and has now turned his attention to HBV.

"The two main approaches [for targeting HBV] are immune modulators and direct-acting antivirals (DAA)," Sofia told me.

These classes of drugs have been used for years. The original immune modulator class refers to interferon-based therapies and came into use in the early 1990s. -specific to the virus, they have significant side effects such as causing depression, fatigue and making one more prone to infections.

Ten years later, in the early 2000s, the other main class of drugs for HBV were launched-nucleoside analogs (NUCs such as lamivudine) which are considered because they directly inhibit the virus' replication machinery. NUCs are oral drugs, thus more convenient for the patient than weekly (or more frequent) interferon-based injections. However, while they reduce the production of HBV in the infected cells, they do not completely cure the patient; some virus still remains and these medicines need to be for for life Moreover, a subset of patients develop resistance to the NUCs, so it 's clear that more therapeutic options are necessary.

"Today," Sofia explained, "we believe a combination of therapies will likely be most successful in fully eradicating the virus, and will need to involve reducing viral replication, activating host responses, and finally clearing the viral DNA reserve from the nucleus."

"Of the DAA approaches, short interfering (siRNA) is leading the way with Arbutus' therapies in phase II clinical trials," Sofia said.

Arbutus 'siRNA aim to inhibit viral replication, cleave HBV transcripts, and lower all viral antigens. Arrowhead Pharmaceuticals also has siRNAs in development designed to silence all of the HBV gene products by intervening upstream of the virus' reverse transcription step. The hope for all siRNA approaches is that once once production of the virus is diminished, the body's natural immune defense will have a chance to clear the virus and lead to a permanent cure, most likely in combination with current therapies.

Inhibitors against specific HBV proteins is another DAA strategy. Johnson & Johnson's capsid inhibitors are the farthest along using that approach but others are rapidly catching up. Inhibiting the capsid protein disrupts assembly of the HBV particle which suppresses its replication.

"Immunomodulator approaches, but interferon, are still in the early stages of research," Sofia said. "A promising line of investigation includes reactivating tolerized T cells via pattern recognition receptors. Some of the 'T cell reactivating' molecules are studied are STING, RIG1, PD1, PD-L1, TIN3 and Lag3. "

In addition to these oral-based therapies for HBV, progress is also being made on the vaccines front and other therapeutic modalities as well. It's an exciting time to be involved in this field, especially with the increased understanding of liver-related diseases such as fibrosis and fatty liver disease, which often appear in conjunction with HBV.

CORRECTION 9/8/17: Sofia's job title was corrected in paragraph 4. He is co-founder and CSO of Arbutus, not CEO.

Anjani Shah, Ph.D. is a conference director at Cambridge Healthtech Institute, the parent company of Bio-IT World. Dr. Shah has planned a symposium on Sept. 25 on drug development for Hepatitis B to be held at the upcoming Discovery On Target event in Boston, Mass. Sept 25-29, 2017.

StephenW

再次关注乙型肝炎新进展

由Anjani Shah

2017年8月31日|乙型肝炎是一种由乙型肝炎病毒（HBV）引起的严重肝脏感染，适应症从持续几周的轻度疾病到终身慢性肝脏感染。婴儿和儿童接种了预防性乙肝疫苗，但估计有2.57亿人感染乙型肝炎病毒，但这种病毒仍然是药物发现的积极对象。

在过去的几年中，HBV领域受到了新的丙型肝炎病毒（HCV）治疗成功的影响，因此越来越受到业界研究者的关注。丙型肝炎治愈后，将注意力转向乙型肝炎，希望能够治愈。

这两种病毒有很大的不同。 HBV在世界范围内的发病率是HCV的两倍，对HBV的研究正处于丙型肝炎研究大约10年前的阶段。 HBV更具挑战性，因为病毒具有控制宿主反应的独特方式;即使在治疗后，仍然存在乙型肝炎病毒库。

我最近与科学家，首席科学家兼杨梅制药公司的共同创始人Mike Sofia博士谈了最新的HBV研究。索非亚是最近推出的新一代丙型肝炎病毒抑制剂的先驱研究人员之一，他是现在隶属于Gilead公司Pharmasset的高级化学副总裁，现在已将注意力转向了HBV。

“针对HBV的两种主要方法是免疫调节剂和直接作用抗病毒药物（DAA），”索非亚告诉我。

这些类药物已经使用了多年。最初的免疫调节剂类是指基于干扰素的疗法，并在20世纪90年代初开始使用。对于病毒而言，它们具有显着的副作用，例如引起抑郁症，疲劳以及使得更容易感染。

十年后的二十一世纪初，另一类主要的HBV药物 - 核苷类似物（拉米夫定等）被认为是直接抑制病毒复制的机制。 NUC是口服药物，因此比每周（或更频繁）基于干扰素的注射更方便患者。但是，尽管它们减少了感染细胞中HBV的产生，但并不能完全治愈患者，一些病毒仍然存在，这些药物需要终身服用。而且，一部分患者对NUCs产生耐药性，因此显然需要更多的治疗选择。

索非亚解释说：“今天，我们相信联合治疗可能会最有效地彻底根除病毒，并且需要减少病毒复制，激活宿主反应，最终从病毒核中清除病毒DNA储备。”

Sofia说：“在DAA方法中，短干扰（siRNA）在Arbutus的II期临床试验中处于领先地位。

Arbutus的siRNA旨在抑制病毒复制，切割HBV转录本，降低所有病毒抗原。箭头制药公司还开发了siRNA，旨在通过介入病毒逆转录步骤的上游来沉默所有的HBV基因产物。所有siRNA方法的希望是，一旦病毒产生减少，人体的天然免疫防御将有机会清除病毒并导致永久治愈，最有可能与当前的治疗相结合。

针对特定HBV蛋白的抑制剂是另一种DAA策略。强生公司的衣壳抑制剂是使用这种方法最远的，但也有一些正在迅速赶上。抑制衣壳蛋白破坏抑制其复制的HBV颗粒的组装。

索非亚说：“免疫调节剂的方法，但干扰素，仍处于研究的早期阶段。 “一项很有前途的研究包括通过模式识别受体重新激活耐受的T细胞，研究的一些”T细胞活化“分子包括STING，RIG1，PD1，PD-L1，TIN3和Lag3。

除了这些用于HBV的口服疗法之外，在疫苗方面和其他治疗方式方面也正在取得进展。参与这个领域是一个激动人心的时刻，尤其是随着人们对肝纤维化和脂肪肝等肝病相关疾病的认识加深，而这些疾病往往与HBV联合出现。

更正9/8/17：索非亚的职位在第4段中得到纠正。他是Arbutus的联合创始人兼CSO，而非首席执行官。

Anjani Shah博士Bio-IT World的母公司Cambridge Healthtech Institute的会议总监。 2017年9月25日至29日在马萨诸塞州波士顿举行的Discovery On Target活动中，Shah博士计划于9月25日召开乙型肝炎药物研发研讨会。

windu

文中提到强生走得最远的衣壳抑制剂应该是3778吧？