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EASL 2019 - 研究提醒了B公牛,进展缓慢 [复制链接]

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发表于 2019-4-15 16:07 |只看该作者 |倒序浏览 |打印
      EASL 2019 – Research reminds hep B bulls that progress will be slow            
  •                                                                                  
  •         Amy Brown

  
     
                Presentations from Assembly Biosciences and Spring Bank Pharmaceuticals could disappoint those hoping to see more definitive steps towards a functional cure for hepatitis B.
                        

                                                  Updates from the hepatitis B field at the EASL conference this year underlined just how much more of a challenge this virus presents compared with hepatitis C. Progress is being made towards a hep B cure, but is unlikely to unfold quite as dramatically as it did with hep C, as presentations from Assembly Biosciences and Spring Bank showed.
Fresh data from Assembly are likely to disappoint those hoping to see more definitive progress. The company's core protein modifier ABI-H0731 has yet to show any reduction in surface antigen, a marker that can indicate whether a patient is on the way to a cure. Separately, Spring Bank’s immune booster inarigivir caused some head-scratching over dose response.
Ironically, perhaps the most dramatic results came from a trial that combined Hepatera/Myr Pharma’s viral entry inhibitor Myrcludex with interferon. The need for this old drug with toxicity issues might dismay those hoping for progress with novel mechanisms, yet the companies presented evidence of functional cures in very hard-to-treat patients with hepatitis B and D co-infection.
Taking with one hand...
First to Assembly, though, which presented interim data from two ongoing phase II studies of ABI-H0731. Data from a handful of subjects treated for 24 weeks were shown for the first time, and investors had hoped that by this stage an impact on surface antigen, or HBsAg, would be seen.
For a patient to achieve a functional cure viral DNA and HBsAg must be suppressed, as the hep B virus needs both to trigger rebound infections. However, ultimately the virus's life source is believed to be cccDNA, a minichromosome that it deposits in liver cells.
Researchers believe that if viral DNA, RNA and HBsAG is suppressed for long enough cccDNA will start to decay and a functional cure will be achieved. Integrated viral DNA is likely to remain, however, though this is not thought capable of reviving an infection, hence the use of the term “functional cure”.
Nucleoside analogues (nucs) like Gilead’s Vemlidy can suppress DNA effectively while patients remain on therapy, though they are rarely able to clear HBsAg. Hence the search for new mechanisms to use in combination with a nuc backbone.
Encouragingly, Assembly presented data showing a dramatic loss of viral DNA in a small group of patients; 11 patients had been treated out to 24 weeks, and are presumably the subject of the slide below. No other group has managed to show a reduction in viral DNA to below detectable levels, according to Dr Jacob Lalezari, presenter of the study at EASL; Dr Lalezari was involved in the studies and acts as a consultant for Assembly.

            

                                      Assembly EASL presentation                                                               

                                          EASL 2019.
               
                                  He predicted that declines in surface antigen should follow. “We still need to drive RNA lower, then what will follow is decay of cccDNA, and then we will see those surface antigens disappear,” he said.
Describing the data as early but encouraging, he believes that the project is moving in the right direction. However, many investors were hoping to see much clearer evidence of ABI-H0731’s activity on HBsAG. Presentation of the full data, probably at AASLD later this year, is now a huge event for the company.
Dose response?
Spring Bank, meanwhile, is focusing on a different mechanism with inarigivir, an immune system booster that works by activating Rig-1. The company was at EASL presenting full results from the phase II Achieve study, which included a first proper look at the highest 200mg dose.
Although this higher dose promoted much stronger reductions in HBV DNA than lower doses, on other measures such as HBV RNA the dose response was less clear. HBsAg loss was also detected in more patients given the lower dose, which the company suggested might be explained by varying responses to different hepatitis B genotypes.
This jury is certainly still out on inarigivir, and will probably remain so until two large phase IIb studies testing a higher 400mg dose report, sometime next year. The fact that Gilead is sponsoring a phase II trial in combination with Vemlidy is something of a vote of confidence in the project. That could report later this year, and the fate of inarigivir arguably rests in any decision the big biotech makes after it sees the data.  

               
        
                  

                                      Spring Bank EASL presentation                                                               

                                          EASL 2019.
               
                                  Finally, Myr Pharma showed highly encouraging data in co-infected patients; a prior infection with hep B is necessary to contract hep D, which rarely responds to antiviral treatment. As well as leaving 40% of patients with undetectable hep D virus at 72 weeks, 27% of patients had undetectable HBsAg, suggesting the combination is acting on both viruses, a very unexpected and encouraging finding.  
Red flags include the fact that the trial was conducted in Russia, and an apparent lack of dose response, with the lowest dose apparently having a disproportionate effect. However the data impressed doctors at the conference.
“[Interferon] is not something we are trying to increasingly incorporate in our treatment regimens, but if it turns out to be a necessary component, there are worse things to have,” Professor Markus Peck-Radosavljevic, a hepatologist at Klinikum Klagenfurt in Austria, told Vantage. “And it’s still a big advance over not having anything [for hepatitis D].”
Dr Heiner Wedemeyer, who presented the Myrcludex data at EASL, suggested that the therapy could also be curative for hepatitis B alone, and said that Myr intends to investigate this. However, in this setting any need for an interferon backbone could make this a non-starter, given progress elsewhere, though this project has at least shown it is worth following.
Rising tide
Other mechanisms like RNAi were also on show at EASL. An update on previously presented data from Johnson & Johnson/Arrowhead’s JNJ-3989 showed very deep HBsAg reductions in a big proportion of patients, although the presence of rebounds when therapy was withdrawn highlights that much work needs to be done to find optimum regimens.
“The more you learn about hep B, the harder it looks,” Anuj Gaggar, vice-president of Gilead’s liver disease therapeutic area, told Vantage. “We have a lot of important data sets coming in the next year, internally and externally, and they will determine what happens next. Our hope is in the next five years we can get something out there [to start to offer a cure].”
Investors hoping to ride the next hepatitis wave will be hoping for success stories much sooner. However, the data at EASL suggest that progress in hep B will look more like a gently rising tide.

               
        
                  

         

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发表于 2019-4-15 16:09 |只看该作者
EASL 2019  - 研究提醒了B公牛,进展缓慢

    艾米布朗

来自Assembly Biosciences和Spring Bank Pharmaceuticals的演讲可能让那些希望看到更明确的乙型肝炎功能性治疗步骤的人失望。
EASL 2019走廊

今年EASL会议上乙型肝炎领域的最新情况强调了这种病毒与丙型肝炎相比有多大挑战。肝脏B治愈的进展正在取得进展,但不太可能像来自Assembly Biosciences和Spring Bank的演示文稿显示了肝脏C.

大会的最新数据可能会让那些希望看到更明确进展的人失望。该公司的核心蛋白质修饰剂ABI-H0731尚未显示表面抗原的任何减少,表面抗原可以指示患者是否正在治愈。另外,Spring Bank的免疫增强剂inarigivir对剂量反应造成了一些头痛。

具有讽刺意味的是,也许最引人注目的结果来自于将Hepatera / Myr Pharma的病毒进入抑制剂Myrcludex与干扰素结合起来的试验。对具有毒性问题的这种旧药物的需求可能会令那些希望在新机制方面取得进展的人感到沮丧,但这些公司提供了在非常难以治疗的乙肝和丁型肝炎合并感染患者中功能性治愈的证据。

用一只手......

然而,首先是大会,它提出了ABI-H0731正在进行的两项II期研究的临时数据。首次展示了少数接受24周治疗的受试者的数据,投资者希望在此阶段可以看到对表面抗原或HBsAg的影响。

对于患者实现功能性治愈,必须抑制病毒DNA和HBsAg,因为乙型肝炎病毒需要同时引发反弹感染。然而,最终病毒的生命来源被认为是cccDNA,一种存在于肝细胞中的微染色体。

研究人员认为,如果病毒DNA,RNA和HBsAG被抑制足够长的时间,cccDNA就会开始腐烂并实现功能性治愈。然而,整合的病毒DNA可能仍然存在,尽管这被认为不能恢复感染,因此使用术语“功能性治愈”。

像Gilead的Vemlidy这样的核苷类似物(nucs)可以在患者继续接受治疗的同时有效地抑制DNA,尽管他们很少能够清除HBsAg。因此寻找与nuc骨架结合使用的新机制。

令人鼓舞的是,大会提供的数据表明,一小部分患者的病毒DNA显着减少; 11名患者已经治疗了24周,并且可能是下面幻灯片的主题。根据EASL研究的主持人Jacob Lalezari博士的说法,没有其他人能够将病毒DNA降低到可检测水平以下。 Lalezari博士参与了这项研究,并担任大会顾问。
装配EASL演示文稿
EASL 2019。

他预测表面抗原的下降应该随之而来。 “我们仍然需要降低RNA,然后接下来会发现cccDNA的衰变,然后我们会看到那些表面抗原消失,”他说。

他认为数据尽早但令人鼓舞,他认为该项目正朝着正确的方向发展。然而,许多投资者希望看到更清楚的证据表明ABI-H0731对HBsAG的活动。可能在今年晚些时候在AASLD上发布完整数据,现在对公司来说是一件大事。

剂量反应?

与此同时,Spring Bank正专注于与inarigivir不同的机制,即通过激活Rig-1起作用的免疫系统助推器。该公司在EASL展示了第二阶段成就研究的全部结果,该研究包括首次正确观察最高200mg剂量。

尽管这种较高的剂量促使HBV DNA的降低比较低的剂量强得多,但对于其他措施如HBV RNA,剂量反应不太清楚。给予较低剂量的更多患者也检测到HBsAg丢失,该公司建议可能通过对不同乙型肝炎基因型的不同反应来解释。

这个陪审团当然仍然没有参加inarigivir,并且可能会继续这样做,直到两个大型IIb期研究测试更高的400mg剂量报告,明年某个时候。吉利德与Vemlidy一起赞助一项II期试验这一事实对该项目充满了信心。这可能会在今年晚些时候报道,并且inarigivir的命运可以说取决于大型生物技术公司在看到数据后做出的任何决定。
Spring Bank EASL演示文稿
EASL 2019。

最后,Myr Pharma在共同感染的患者中显示出非常令人鼓舞的数据;先前感染hep B对于收缩肝D是必要的,其对抗病毒治疗很少有反应。除了在72周时使40%的患者无法检测到肝脏D病毒,27%的患者检测不到HBsAg,这表明该组合对这两种病毒起作用,这是一个非常意外和令人鼓舞的发现。
红旗包括试验在俄罗斯进行的事实,以及明显缺乏剂量反应,最低剂量显然具有不成比例的影响。然而,数据给会议上的医生留下了深刻印象。

“[干扰素]不是我们试图越来越多地纳入我们的治疗方案,但如果它被证明是一个必要的组成部分,那就更糟糕了,”奥地利Klinikum Klagenfurt的肝病学家Markus Peck-Radosavljevic教授,告诉Vantage。 “对于没有[肝炎D]的任何事情,这仍然是一个很大的进步。”

Heiner Wedemeyer博士在EASL上发表了Myrcludex数据,他认为该疗法也可以治疗单独的乙型肝炎,并表示Myr打算对此进行调查。然而,在这种情况下,对干扰素骨干的任何需求都可能使这成为一个非首发,鉴于其他地方的进展,尽管该项目至少表明它值得遵循。

涨潮

其他机制如RNAi也在EASL展出。强生公司/箭头公司JNJ-3989先前提供的数据更新显示,大部分患者的HBsAg降低非常深,尽管治疗撤销时出现的反弹突出表明需要做很多工作才能找到最佳治疗方案。

“你对乙型肝炎的了解越多,看起来就越难,”吉利德肝病治疗区副院长阿努伊加加尔告诉Vantage。 “我们在明年内部和外部都会有很多重要的数据集,他们将决定接下来会发生什么。我们希望在未来五年内,我们可以获得一些东西[开始提供治疗]。“

希望能够驾驭下一轮肝炎的投资者将更快地希望获得成功案例。然而,EASL的数据表明,乙型肝炎的进展看起来更像是一个缓慢上升的趋势。

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发表于 2019-4-15 16:27 |只看该作者
本帖最后由 newchinabok 于 2019-4-15 17:02 编辑

abi—h0731他预测表面抗原的下降应该随之而来。 “我们仍然需要降低RNA,然后接下来会发现cccDNA的衰变,然后我们会看到那些表面抗原消失,

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发表于 2019-4-15 16:28 |只看该作者
RNAi也在EASL展出。强生公司/箭头公司JNJ-3989先前提供的数据更新显示,大部分患者的HBsAg降低非常深,尽管治疗撤销时出现的反弹突出表明需要做很多工作才能找到最佳治疗方案
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