核心蛋白抑制剂nuc组合在HBV中显示出前景

StephenW

Core protein inhibitor, nuc combination shows promise in HBV
April 13, 2019

VIENNA — A combination of a core protein inhibitor and nucleos(t) ide analogues brought hepatitis B virus RNA and DNA following levels of quantification, pointing toward the possibility of a cure, according to a presenter at the International Liver Congress.

"In both study 201 and 202, we are seeing the same story - very significant declines in viral nucleic acids," Jacob Lalezari, MD, from Quest Clinical Research in San Francisco, said during his presentation. "The end game in all of this It's cure for hepatitis B. elimination of the cccDNA and elimination of the viral proteins. We expect the elimination of viral proteins to follow elimination of viral nucleic acids."

Lalezari presented the interim results of two phase 2a studies where ABI-H0731 (Assembly Biosciences) was given in combination with nucleos(t)ide analogue (nuc) therapy. In the 201 cohort, Lalezari and colleauges looked at patients who were already suppressed on Nucs (n = 73) and then received ABI-HO731 300 mg as a daily add-on therapy or placebo. In the 202 study, the same dosage of ABI-HO731 was delivered to patients (n = 25) who were treatment-naive But HBeAg-positive; in combination with ABI-HO731 or placebo, patients started entecavir.

The interim analysis of cohort 201 included 64 participants who completed 12 weeks of the study and nine who reached week 24. The interim analysis of cohort 202 included 24 participants who completed week 12 and 12 who completed week 24.

In discussing safety of the novel treatment, Lalezari showed a "smattering" of abnormal lab results but no signals and mentioned rash in two patients.

"Bottom line, the drug was safe and well tolerated and I don’t see a safety issue," he said.

In the 202 cohort of treatment-naive, but high viral load participants, Lalezari said the combination arm showed quick impact.

"What we see is superior DNA reductions with the combination vs. the nuc alone starting at week 2. ... Faster and deeper declines with DNA that persist out to week 12 and to week 24," he said. "With the DNA, So with the RNA. ... There were faster and deeper declines in RNA that again were manifest at week 2 and persisted out to week 12 and 24."

At week 12, HBV DNA declines in the combination arm were 4.54 log10 IU/mL compared with 3.29 log10 IU/mL in the placebo plus encetevir group (P < .011). HBV RNA declined 2.27 log10 IU/mL in the combination arm and 0.44 log10 IU/mL in the placebo group (P < .005). Week 24 saw DNA declines of 5.94 log10 IU/mL vs. 3.99 log10 IU/mL (P < .005) and RNA declines of 2.54 log10 IU/mL vs 0.61 log10 IU/mL (P < .005).
Lalezari explained that the nuc-suppressed group in the 201 cohort lend themselves to thinking more about a cure for HBV.

“There is a persistence of PCR positive virus below the 20 IU threshold,” he said. “That virus is infectious virus. That virus can infect hepatocytes.”

What he showed was the new combination therapy gets lower than previously seen.

“If you add the core inhibitor to the nuc therapy, you see resolution and elimination of the virus in five of six subjects over 8 to 16 weeks,” Lalezari said. “This is not elimination of virus but elimination down to the level of sensitivity of this assay.”

At week 12, participants receiving the combination therapy had reductions in HBV RNA levels of 2.34 log10 IU/mL compared with 0.05 log10 IU/mL in the group receiving nuc and placebo (P < .001). At week 24, combination therapy reduced 2.20 log 10 IU/mL vs. 0.15 log 10 IU/mL with placebo (P = .012).

“On the nuc for the 24 weeks, none of the subjects go undetectable, but then in contrast on the combination arm, 50% 60% of subjects are going below the level of quantification,” Lalezari said.

DNA persisted in the nuc plus placebo.

“You only see this elimination below the current threshold in the combination arm,” he said. “It’s giving us a sense of the time frame involved of what cure might look like in that subjects who are coming in fully suppressed are Still taking 2 to 6 months to get this virus closer to a true 0, at least in DNA.” – by Katrina Altersitz

Reference:

Lalezari J. LB-06. Presented at: International Liver Congress; April 10-14, 2019; Vienna, Austria.

Disclosures: Lalezari reports serving as a consultant to Assembly Biosciences.

StephenW

核心蛋白抑制剂nuc组合在HBV中显示出前景
2019年4月13日

维也纳 - 根据国际肝病大会的一位主持人的说法，核心蛋白抑制剂和核苷（酸）类似物的组合使乙型肝炎病毒RNA和DNA达到了定量水平，指出了治愈的可能性。

“在201和202研究中，我们看到同样的故事 - 病毒核酸的显着下降，”来自旧金山Quest Clinical Research的医学博士Jacob Lalezari在他的演讲中说。 “所有这一切的最终结果都是治愈乙型肝炎的方法。消除cccDNA和消除病毒蛋白。我们期望消除病毒蛋白以消除病毒核酸。”

Lalezari介绍了两项2a期研究的中期结果，其中ABI-H0731（Assembly Biosciences）与核苷（t）ide类似物（nuc）联合给予。在201名队列中，Lalezari和colleauges研究了已经被Nucs抑制的患者（n = 73），然后接受ABI-HO731 300 mg作为每日附加疗法或安慰剂。在202研究中，相同剂量的ABI-HO731被递送给接受治疗的患者（n = 25）但HBeAg阳性;患者与ABI-HO731或安慰剂联合开始使用恩替卡韦。

队列201的中期分析包括完成研究12周的64名参与者和达到第24周的9名参与者。队列202的中期分析包括完成第12周和第12周完成第24周的24名参与者。

在讨论新型治疗的安全性时，Lalezari显示出“少量”的实验室异常结果，但没有信号，并提到两名患者出现皮疹。

“最重要的是，该药物安全且耐受性良好，我没有看到安全问题，”他说。

Lalezari表示，在202名接受治疗的队列中，天真但高病毒载量的参与者表示组合臂显示出快速的影响。

“我们看到的是，与第二周开始的单独使用组合相比，DNA的减少效果更好。... DNA持续到第12周和第24周的速度越来越快，”他说。 “使用DNA，使用RNA。... RNA的下降速度越来越快，在第2周再次显现，并持续到第12周和第24周。”

在第12周，联合组中HBV DNA下降为4.54 log10 IU / mL，而安慰剂加encetevir组为3.29 log10 IU / mL（P <.011）。联合组HBV RNA下降2.27 log10 IU / mL，安慰剂组下降0.44 log10 IU / mL（P <.005）。第24周DNA下降为5.94 log10 IU / mL对3.99 log10 IU / mL（P <.005），RNA下降为2.54 log10 IU / mL对比0.61 log10 IU / mL（P <.005）。
Lalezari解释说，201队列中的nuc抑制组有助于更多地考虑治疗HBV。

“PCR阳性病毒持续存在于20 IU阈值以下，”他说。 “那种病毒是传染性病毒。那种病毒可以感染肝细胞。“

他所展示的是新的联合疗法比以前看到的要低。

“如果你将核心抑制剂添加到nuc疗法中，你可以在8到16周内看到6个受试者中的5个解决并消除病毒，”Lalezari说。 “这不是消除病毒，而是消除到这种分析的灵敏度水平。”

在第12周，接受联合治疗的参与者的HBV RNA水平降低了2.34 log10 IU / mL，而接受nuc和安慰剂的组则降低了0.05 log10 IU / mL（P <.001）。在第24周，联合治疗用安慰剂降低2.20 log 10 IU / mL对0.15 log 10 IU / mL（P = .012）。

“对于24周的nuc，没有一个受试者检测不到，但在组合臂上相反，50％60％的受试者正在低于量化水平，”Lalezari说。

DNA持续存在于nuc加安慰剂中。

“你只能看到这种消除低于组合臂的当前阈值，”他说。 “这让我们了解了治疗可能会出现什么样的时间框架，那些受到完全抑制的受试者仍需要2至6个月才能使这种病毒接近真正的0，至少在DNA中。” - 卡特里娜·阿尔特西茨

参考：

Lalezari J. LB-06。发表于：国际肝脏大会; 2019年4月10日至14日;维也纳，奥地利。

披露：Lalezari报告担任Assembly Biosciences的顾问。

newchinabok

耗尽cccdna，治愈hbv，很多战友认为6个月试验就可以耗尽，这是情怀

newchinabok

You only see this elimination below the current threshold in the combination arm,” he said. “It’s giving us a sense of the time frame involved of what cure might look like in that subjects who are coming in fully suppressed are Still taking 2 to 6 months to get this virus closer to a true 0, at least in DNA.” – by Katrina Altersitz

yyjj777

这个肝脏内阻断HBVDNA 和RNA到一个空前低的水平，听起来不错。希望随时间的推移，表抗也可以随之下降。

newchinabok

yyjj777 发表于 2019-4-14 14:22
这个肝脏内阻断HBVDNA 和RNA到一个空前低的水平，听起来不错。希望随时间的推移，表抗也可以随之下降。 ...

很难做到，肝脏总有残余cccdna和人体基因整合hbv，必须靠免疫药组合。研发人员认为cccdna，基因整合hbv，靠人体肝脏新陈代谢丟失

newchinabok

RNAi，核衣壳，sb9200如果单用药，我哪个药都不看好