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标题: 衣壳装配调节剂NVR 3-778在慢性HBV感染患者中的抗病毒活性， [打印本页]
作者: StephenW    时间: 2019-3-29 19:51     标题: 衣壳装配调节剂NVR 3-778在慢性HBV感染患者中的抗病毒活性，

Antiviral Activity, Safety, and Pharmacokinetics of Capsid Assembly Modulator NVR 3-778 in Patients with Chronic HBV Infection [url=]Man Fung Yuen[/url]1,∗,[url=]Correspondence information about the author Man Fung Yuen[/url]Email the author Man Fung Yuen
, [url=]Edward J. Gane[/url]2
, [url=]Dong Joon Kim[/url]3
, [url=]Frank Weilert[/url]4
, [url=]Henry Lik Yuen Chan[/url]5
, [url=]Jacob Lalezari[/url]6
, [url=]Seong Gyu Hwang[/url]7
, [url=]Tuan Nguyen[/url]8
, [url=]Osvaldo Flores[/url]9
, [url=]George Hartman[/url]10
, [url=]Sandy Liaw[/url]11
, [url=]Oliver Lenz[/url]12
, [url=]Thomas N. Kakuda[/url]13
, [url=]Willem Talloen[/url]14
, [url=]Christian Schwabe[/url]15
, [url=]Klaus Klumpp[/url]16
, [url=]Nathaniel Brown[/url]9

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DOI: https://doi.org/10.1053/j.gastro.2018.12.023 |

Article Info







Background & AimsNVR 3-778 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator that can inhibit HBV replication. We performed a proof-of-concept study to examine the safety, pharmacokinetics, and antiviral activity of NVR 3-778 in patients with chronic HBV infection.


MethodsWe performed a phase 1 study in 73 hepatitis B envelope antigen (HBeAg)-positive patients with chronic HBV infection without cirrhosis. In a 2-part study (part 1 in New Zealand and part 2 in Hong Kong, Singapore, Taiwan, Korea, and the United States), patients were randomly assigned to groups that were given oral NVR 3-778 (100 mg, 200 mg, or 400 mg daily or 600 mg or 1000 mg twice daily) or placebo for 4 weeks. Additional groups received combination treatment with pegylated interferon (pegIFN) and NVR 3-778 (600 mg twice daily) or pegIFN with placebo.


ResultsReductions in serum levels of HBV DNA and HBV RNA were observed in patients receiving ≥1200 mg/d NVR 3-778. The largest mean reduction in HBV DNA was observed in the group given NVR 3-778 plus pegIFN (1.97 log10 IU/mL), compared with the groups given NVR 3-778 or pegIFN alone (1.43 log10 IU/mL and 1.06 log10 IU/mL, respectively). The mean reduction in HBV RNA was also greatest in the group given NVR 3-778 plus pegIFN (2.09 log10 copies/mL), compared with the groups given NVR 3-778 or pegIFN alone (1.42 log10 copies/mL and 0.89 log10 copies/mL, respectively). There was no significant mean reduction in HBsAg during the 4-week treatment period. There were no discontinuations and no pattern of dose-related adverse effects with NVR 3-778.


ConclusionsIn a phase 1 study of HBeAg-positive patients with chronic HBV infection without cirrhosis, NVR 3-778 was well tolerated and demonstrated antiviral activity. The agent reduced serum levels of HBV DNA and HBV RNA, to the greatest extent in combination with pegIFN. The observed reductions in HBV RNA confirmed the novel mechanism of NVR 3-778. Clinicaltrials.gov no. NCT02112799 (single-center) and NCT02401737 (multicenter).



Keywords:Encapsidation, [url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=Capsid Inhibitor&code=ygast-site]Capsid Inhibitor[/url], [url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=Hepatitis B Treatment&code=ygast-site]Hepatitis B Treatment[/url], [url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=Clinical Trial&code=ygast-site]Clinical Trial[/url]
Abbreviations used in this paper:AE ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=adverse event&code=ygast-site]adverse event[/url]), ALT ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=alanine aminotransferase&code=ygast-site]alanine aminotransferase[/url]), BD ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=twice daily&code=ygast-site]twice daily[/url]), CAM ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=capsid assembly modulators&code=ygast-site]capsid assembly modulators[/url]), cccDNA ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=covalently closed circular DNA&code=ygast-site]covalently closed circular DNA[/url]), EC50 ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=median effective concentration&code=ygast-site]median effective concentration[/url]), HBc ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=HBV core protein&code=ygast-site]HBV core protein[/url]), HBcrAg ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=hepatitis B core-related antigen&code=ygast-site]hepatitis B core-related antigen[/url]), HBeAg ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=hepatitis B envelope antigen&code=ygast-site]hepatitis B envelope antigen[/url]), HBsAg ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=hepatitis B surface antigen&code=ygast-site]hepatitis B surface antigen[/url]), HBV ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=hepatitis B virus&code=ygast-site]hepatitis B virus[/url]), pegIFN ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=pegylated interferon&code=ygast-site]pegylated interferon[/url]), pgRNA ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=pregenomic RNA&code=ygast-site]pregenomic RNA[/url]), QD ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=once daily&code=ygast-site]once daily[/url]), SAE ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=serious adverse event&code=ygast-site]serious adverse event[/url]), TDF ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=tenofovir disoproxil fumarate&code=ygast-site]tenofovir disoproxil fumarate[/url]), ULN ([url=https://www.gastrojournal.org/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=upper limit of normal&code=ygast-site]upper limit of normal[/url])


Conflicts of interest These authors disclose the following: Man Fung Yuen is an advisor for AbbVie, Arbutus, Arrowhead, Biocartis, Gilead Sciences, GlaxoSmithKline, Ionis, Roche, and Vir Biotechnology; and received speaker and grant supports from AbbVie, Arrowhead, Bristol Myers Squibb, Fujirebio, Gilead Sciences, Merck Sharp & Dohme, Novartis Pharmaceuticals, Sysmex. Henry Lik Yuen Chan is an advisor for AbbVie, Aptorum, Arbutus, Altimmune, Gilead, GRAIL, Intellia, Janssen, MedImmune, Roche, and Vir Biotechnology; and a speaker for AbbVie, Gilead, and Roche. George Hartman, Sandy Liaw, Klaus Klumpp, and Nathaniel Brown were employees of Novira Therapeutics Inc, part of the Janssen Pharmaceutical Companies. Osvaldo Flores was an employee of Novira Therapeutics Inc, part of the Janssen Pharmaceutical Companies, at the time that this study was undertaken, but is no longer employed by this company. Oliver Lenz and Willem Talloen are employees of Janssen Pharmaceutica NV. Thomas N. Kakuda is an employee of Janssen Biopharma, a Janssen Pharmaceutical Company, and holds stocks in Johnson & Johnson. The remaining authors disclose no conflicts.
Funding The multicenter phase 1b clinical trial reported here was supported by grants from Novira Therapeutics, the discoverer and developer of the investigational agent NVR 3-778.

作者: StephenW    时间: 2019-3-29 19:52

衣壳装配调节剂NVR 3-778在慢性HBV感染患者中的抗病毒活性，安全性和药代动力学
Man Fung Yuen1，*，'关于作者的通讯信息Man Fung YuenEmail作者Man Fung Yuen
，Edward J. Gane2
，Dong Joon Kim3
，Frank Weilert4
，Henry Lik Yuen Chan5
，Jacob Lalezari6
，Seong Gyu Hwang7
，Tuan Nguyen8
，Osvaldo Flores9
，乔治哈特曼10
，Sandy Liaw11
，Oliver Lenz12
，Thomas N. Kakuda13
，Willem Talloen14
，Christian Schwabe15
，Klaus Klumpp16
，纳撒尼尔布朗9
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DOI：https：//doi.org/10.1053/j.gastro.2018.12.023 |
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背景与目的

NVR 3-778是一种能够抑制HBV复制的一流乙型肝炎病毒（HBV）衣壳装配调节剂。我们进行了概念验证研究，以检查NVR 3-778在慢性HBV感染患者中的安全性，药代动力学和抗病毒活性。
方法

我们对73例乙型肝炎包膜抗原（HBeAg）阳性患者进行了1期研究，该患者患有无肝硬化的慢性HBV感染。在一项由两部分组成的研究中（新西兰的第1部分和香港，新加坡，台湾，韩国和美国的第2部分），患者被随机分配到口服NVR 3-778（100 mg，200 mg或400 mg每日或600 mg或1000 mg每日两次）或安慰剂，持续4周。另外的组接受聚乙二醇化干扰素（pegIFN）和NVR 3-778（600mg，每天两次）或pegIFN与安慰剂的组合治疗。
结果

在接受≥1200mg/ d NVR 3-778的患者中观察到血清HBV DNA和HBV RNA水平的降低。在给予NVR 3-778加pegIFN（1.97 log10 IU / mL）的组中观察到HBV DNA的最大平均减少，与仅给予NVR 3-778或pegIFN的组相比（1.43 log10 IU / mL和1.06 log10 IU /分别为mL）。与给予NVR 3-778或pegIFN单独组（1.42 log10拷贝/ mL和0.89 log10拷贝/组）相比，给予NVR 3-778加pegIFN（2.09 log10拷贝/ mL）的组中HBV RNA的平均降低也最大。分别为mL）。在4周治疗期间，HBsAg没有显着的平均降低。 NVR 3-778没有中断并且没有剂量相关副作用的模式。
结论

在一项针对无肝硬化慢性HBV感染的HBeAg阳性患者的1期研究中，NVR 3-778耐受性良好且具有抗病毒活性。该药物与pegIFN联合使用可最大程度地降低HBV DNA和HBV RNA的血清水平。观察到的HBV RNA减少证实了NVR 3-778的新机制。 Clinicaltrials.gov没有。 NCT02112799（单中心）和NCT02401737（多中心）。
关键词：
包封，衣壳抑制剂，乙型肝炎治疗，临床试验
本文中使用的缩写：
AE（不良事件），ALT（丙氨酸氨基转移酶），BD（每日两次），CAM（衣壳组装调节剂），cccDNA（共价闭合环状DNA），EC50（中位有效浓度），HBc（HBV核心蛋白），HBcrAg（肝炎） B核心相关抗原），HBeAg（乙型肝炎包膜抗原），HBsAg（乙型肝炎表面抗原），HBV（乙型肝炎病毒），pegIFN（聚乙二醇化干扰素），pgRNA（前基因组RNA），QD（每日一次），SAE（严重不良事件），TDF（替诺福韦地索普西富马酸盐），ULN（正常上限）

利益冲突这些作者披露了以下内容：Man Fung Yuen是AbbVie，Arbutus，Arrowhead，Biocartis，Gilead Sciences，GlaxoSmithKline，Ionis，Roche和Vir Biotechnology的顾问;并获得了AbbVie，Arrowhead，Bristol Myers Squibb，Fujirebio，Gilead Sciences，Merck Sharp＆Dohme，Novartis Pharmaceuticals，Sysmex的发言人和资助。 Henry Lik Yuen Chan是AbbVie，Aptorum，Arbutus，Altimmune，Gilead，GRAIL，Intellia，Janssen，MedImmune，Roche和Vir Biotechnology的顾问;并为AbbVie，Gilead和Roche发表演讲。 George Hartman，Sandy Liaw，Klaus Klumpp和Nathaniel Brown是Janssen制药公司的一部分Novira Therapeutics Inc的员工。 Osvaldo Flores是该研究开始时Janssen制药公司的一部分Novira Therapeutics Inc的员工，但该公司已不再雇用该公司。 Oliver Lenz和Willem Talloen是Janssen Pharmaceutica NV的员工。 Thomas N. Kakuda是Janssen制药公司Janssen Biopharma的员工，持有Johnson＆Johnson的股票。其余作者未披露任何冲突。

资助这里报告的多中心1b期临床试验得到了Novira Therapeutics的支持，Novira Therapeutics是研究药剂NVR 3-778的发现者和开发者
作者: StephenW    时间: 2019-3-29 19:52

https://www.gastrojournal.org/ar ... 18)35438-6/fulltext
作者: newchinabok    时间: 2019-3-29 20:38

这个药不强效，没前途
作者: fuke    时间: 2019-3-29 20:47

。在4周治疗期间，HBsAg没有显着的平均降低。 NVR 3-778没有中断并且没有剂量相关副作用的模式
作者: fuke    时间: 2019-3-29 20:47

联合干扰素，没有表抗降低
作者: StephenW    时间: 2019-3-29 21:41

fuke 发表于 2019-3-29 20:47
。在4周治疗期间，HBsAg没有显着的平均降低。 NVR 3-778没有中断并且没有剂量相关副作用的模式 ...

The principal activity of HBc inhibitors does not necessarily involve direct inhibition of cccDNA formation, although inhibition of nucleocapsid formation might result in reduced cccDNA in HBV-infected cells over time. Studies with longer treatment durations will be needed to assess the ability of NVR 3-778 treatment to reduce the number of HBV-infected cells in the liver via antiviral or secondary immunomodulatory activities, leading to HBsAg reductions over time.
HBc抑制剂的主要活性不一定涉及直接抑制cccDNA形成，尽管抑制核衣壳形成可能导致HBV感染细胞中cccDNA随时间减少。 需要更长治疗时间的研究来评估NVR 3-778治疗通过抗病毒或继发免疫调节活性减少肝脏中HBV感染细胞数量的能力，导致HBsAg随时间减少。
作者: 齐欢畅    时间: 2019-3-29 21:44





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