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标题: ILC：在与竞争对手竞争的同时寻找功能性解决方案，Vir和Alnyl [打印本页]

作者: StephenW 时间: 2020-8-29 12:20 标题: ILC：在与竞争对手竞争的同时寻找功能性解决方案，Vir和Alnyl

ILC: Searching for a functional cure while battling rivals, Vir and Alnylam post hep B data peek
by Ben Adams | Aug 28, 2020 10:45am
hepatitis B virus
Hepatitis B virus (Institute for Molecular Virology - University of Wisconsin–Madison)

The battle to be the first RNAi to help cure hepatitis B is heating up as Vir Biotechnology and partner Alnylam release ongoing data and rivals line up with their own results at the International Liver Congress (ILC) 2020.

We’ve had to wait: ILC 2020 was meant to happen back in April in London, but COVID-19 chaos caused its delay and digitization until this week.

And while nonalcoholic steatohepatitis remains a key focus for investors out of this event (and Gilead Sciences is dropping some new data on Saturday), hepatitis B, a condition that affects 300 million people worldwide and can cause long-term liver damage if left untreated, still remains a major disease target.

It’s been a tough nut to crack, with the likes of Roche and Arbutus falling to the wayside in recent years after flops and safety worries. In clinical terms, a functional cure for hep B would cut levels of the virus’s surface antigen and DNA to undetectable levels—and keep them there six months after the patient finished treatment.

What Gilead managed in hepatitis C with Sovaldi and Harvoni, both of which can effectively cure people of the disease, a number of big-name biotechs and pharmas are now aiming to achieve with hepatitis B.

There are already several antivirals approved to treat chronic hepatitis B, including Roche’s Pegasys, a pegylated interferon, but nothing as successful as what we now have to treat hepatitis C.

The new hope is coming from RNA technology and its potential to cure this disease. George Scangos’ Vir and partner Alnylam, an RNA specialist (and the first company to even have an RNA drug approved), alongside phoenix from the flames Arrowhead and partner Johnson & Johnson, are leading the hep B RNA race.

With Vir battling to find a treatment for COVID-19, its work in hep B is being largely ignored by investors, with its Alnylam partnership also now extending to COVID-19; however, it still remains a major part of the pair’s R&D pipeline.

All four companies presented at ILC 2020 today, with Vir and Alnylam unveiling a peek at their ongoing phase 2 of its RNA hopeful VIR-2218 in patients with chronic hepatitis B virus (HBV) on nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs), the current standard of care.

Their therapy is designed to target a conserved region in the HBV X gene. This drug, originally called ALN-HBV-02 before Alnylam licensed it to Vir in 2017, came as part of an infectious disease deal worth up to $1 billion.

VIR-2218 is designed to silence all HBV transcripts, from both cccDNA and integrated DNA, across all 10 HBV genotypes.

The main thrust of Vir’s study is focused on lowering the levels of a surface antigen called HBsAg, one of four hep B transcripts the virus used to duplicate and rebound.

It found that in the ongoing test of 24 patients, a subset of patients in the 50-mg dose level “have achieved maximal decline in HBsAg levels at Week 12,” with a mean decline of 1.5 log10 from baseline in VIR-2218 treated patients.

Vir said that declines in HBsAg “continue in other cohorts with at least two patterns observed: an early response and a delayed response.” The test did not raise any safety scares.

In July, Vir also kick-started a phase 2 combo test of VIR-2218 and pegylated interferon-alpha, with these sorts of cocktails the likely best way of creating that functional cure. An initial data drop from this is “anticipated in 2021”, Vir said.

Its key rivals using a similar RNA approach are Arrowhead and partner J&J, which a few years back penned a pact with the biotech worth a few hundred million dollars upfront, but with a major $3.5 billion biobucks for the RNAi hep B program.

They both also released data at ILC 2020 today. Investigators here administered three doses of JNJ-3989 to participants in 56 days to evaluate whether giving the RNAi therapy in combination with an existing treatment can degrade viral RNA and inhibit DNA formation to reduce levels of HBsAg.

The study then tracked the subjects for 48 weeks after the administration of the final dose of JNJ-3989.

By the end of the follow-up, 15 of the 38 patients who initially responded to JNJ-3989 still had a -1.0 log10 IU/mL or greater reduction in HBsAg. The average 392-day reduction in HBsAg among the 15 sustained responders was around -2.0 log10 IU/mL.
Bigger and longer-term studies will be needed for both Vir/Alnylam and J&J/Arrowhead, but with safety seemingly not an issue and HBsAg levels generally in the right direction, all four will be hopeful bigger tests will also see positive results.

All four had also been battling another RNAi hopeful, Arbutus, but last year this biotech canned its Roivant-backed oral capsid inhibitor AB-506 in chronic hepatitis B after two healthy people in a phase 1 study ended up developing the very disease the drug was supposed to treat.

Swiss major Roche also ditched an antisense hep B drug back in January but then rebounded after it snagged a $200 million deal with Dicerna and its phase 1 effort DCR-HBVS, another RNAi therapy designed to knock down genes needed to make HBV mRNA and get the virus into liver cells.

The drug, now known as RG6346, is further behind its rivals. And Dicerna reported positive data in early August from its phase 1, with Roche now taking over for its midstage tests.

作者: StephenW 时间: 2020-8-29 12:21

ILC：在与竞争对手竞争的同时寻找功能性解决方案，Vir和Alnylam公布了乙肝数据
本·亚当斯| 2020年8月28日上午10:45
乙型肝炎病毒
乙型肝炎病毒（威斯康星大学麦迪逊分校分子病毒研究所）

随着Vir Biotechnology和合作伙伴Alnylam发布持续的数据并且竞争对手在2020年国际肝病大会（ILC）上获得他们自己的结果，成为第一个帮助治愈乙型肝炎的RNAi的斗争正在升温。

我们不得不等待：ILC 2020原定于4月在伦敦发生，但COVID-19混乱导致其延迟和数字化，直到本周。

尽管非酒精性脂肪性肝炎仍然是投资者关注的焦点（并且吉利德科学公司在周六发布了一些新数据），但乙型肝炎仍在全球范围内影响着3亿人，如果不及时治疗，可能导致长期肝损害，仍然是主要的疾病目标。

这是一个很难克服的难题，近年来，由于失败和安全隐患，罗氏（Roche）和杨梅（Arbutus）之类的产品跌入了困境。从临床的角度来看，对乙肝的功能性治疗可以将病毒的表面抗原和DNA的水平降低到无法检测的水平，并在患者完成治疗六个月后将其保留在那里。

吉利德利用Sovaldi和Harvoni共同治疗丙型肝炎的方法可以有效治愈人们的疾病，许多著名的生物技术公司和制药公司现在的目标是实现乙型肝炎。

已经有几种抗病毒药被批准用于治疗慢性乙型肝炎，包括罗氏公司的Pegasys（聚乙二醇化干扰素），但没有像现在治疗丙肝那样成功。

新的希望来自RNA技术及其在治疗该疾病中的潜力。乔治·斯坎戈斯（George Scangos）的维尔（Vir）和合作伙伴RNA专家Alnylam（也是首家获得RNA药物批准的公司）以及烈焰箭头公司的凤凰和合伙人强生公司（Johnson＆Johnson）共同领导了乙肝RNA竞赛。

随着Vir努力寻找COVID-19的治疗方法，其在乙肝领域的工作被投资者大大忽略了，其Alnylam合作伙伴关系现在也扩展到了COVID-19；但是，它仍然是双方研发渠道中的主要部分。

所有四家公司都在今天的ILC 2020上进行了展示，Vir和Alnylam揭开了他们正在进行的RNA有望进行中的VIR-2218阶段2的预告，该阶段是通过核苷酸/核苷酸逆转录酶抑制剂（NRTIs）治疗慢性乙型肝炎病毒（HBV）患者的。当前的护理标准。

他们的治疗旨在针对HBV X基因的保守区域。该药物最初被称为ALN-HBV-02，在2017年Alnylam将其许可给Vir之前，是一项价值高达10亿美元的传染病交易的一部分。

VIR-2218旨在沉默所有10种HBV基因型中来自cccDNA和整合DNA的所有HBV转录物。

Vir研究的主要重点是降低表面抗原HBsAg的水平，HBsAg是该病毒用于复制和反弹的四个Hep B转录物中的一种。

研究发现，在进行中的24名患者的测试中，剂量为50 mg的部分患者“在第12周已达到HBsAg水平的最大下降”，在接受VIR-2218治疗的患者中，平均下降了1.5 log10 。

Vir说，HBsAg的下降“在其他队列中继续存在，至少观察到两种模式：早期反应和延迟反应。”该测试没有引起任何安全恐慌。

7月，Vir还启动了VIR-2218和聚乙二醇化干扰素-α的第2阶段组合测试，这些类型的混合物可能是实现该功能性固化的最佳方法。维尔说，由此产生的最初数据下降是“预计在2021年”。

它使用类似RNA方法的主要竞争对手是Arrowhead和合作伙伴强生公司（J＆J），几年前与该生物技术公司签署了一项价值几亿美元的协议，但为RNAi heb B计划提供了35亿美元的巨额生物资金。

他们俩还在今天的ILC 2020上发布了数据。研究人员在56天内向参与者施用了三剂JNJ-3989，以评估将RNAi治疗与现有治疗结合使用是否可以降解病毒RNA并抑制DNA形成以降低HBsAg水平。

然后，该研究追踪了最终剂量JNJ-3989给药后48周的受试者。

在随访结束时，最初对JNJ-3989产生反应的38例患者中有15例HBsAg仍降低了-1.0 log10 IU / mL或更高。 15位持续缓解者中HBsAg平均减少392天约为-2.0 log10 IU / mL。
Vir / Alnylam和J＆J / Arrowhead都需要进行更大范围和更长期的研究，但是似乎安全性不是问题，并且HBsAg水平通常朝着正确的方向发展，所有这四个领域都有望获得更大的测试，从而获得积极的结果。

所有这四个人都还在与另一个有希望的RNAi对抗，即Arbutus，但是去年，在一项1期研究中的两个健康人最终研发出这种药物所致的疾病之后，该生物技术公司将其Roivant支持的口服衣壳抑制剂AB-506罐装在慢性乙型肝炎中。应该治疗。

瑞士少校罗氏（Roche）也在1月份放弃了一种反义乙肝药物，但在与Dicerna达成了一笔2亿美元的交易及其第一阶段研究成果DCR-HBVS之后，又出现了反弹。病毒进入肝细胞。

现在被称为RG6346的这种药物进一步落后于其竞争对手。 Dicerna于8月初报告了第一阶段的积极数据，现在罗氏（Roche）接管了其中期测试。

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