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标题: [AASLD2015](LB10)阶段1b疗效和NVR 3-778的安全,一个先入 类HBV核心 [打印本页]

作者: StephenW    时间: 2015-10-21 17:12     标题: [AASLD2015](LB10)阶段1b疗效和NVR 3-778的安全,一个先入 类HBV核心

LB-10
Phase 1b Efficacy and Safety of NVR 3-778, a First-In-
Class HBV Core Inhibitor, in HBeAg-Positive Patients
with Chronic HBV Infection
Man-Fung Yuen3, Dong Joon Kim4, Frank Weilert5, Henry lik-Yuen Chan6, Jacob P. Lalezari7, Seong Gyu Hwang8
, Tuan T. Nguyen9, Sandy Liaw1, Nathaniel Brown1, Klaus Klumpp
1, Lalo Flores1, George D. Hartman1, Edward J. Gane2;
1Novira Therapeutics,Inc., Doylestown, PA;
2Auckland Clinical Studies, Auckland, New Zealand;
3Queen Mary Hospital, University of Hong Kong, Hong Kong, Hong Kong;
4Chuncheon Sacred Heart Hospital, Hallym University, Gangwon-do, Korea (the Republic of);
5Waikato Hospital, Hamilton, New Zealand;
6Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, Hong Kong;
7Quest Clinical Research, San Francisco, CA;
8CHA Bundang Medical Center, Gyeonggi-do, Korea (the Republic of);
9Research and Education, Inc., San Diego, CA
Background: Current therapies for chronic hepatitis B (CHB)
can suppress HBV replication but long-term therapy is required
in most patients. HBV Core (capsid) protein plays multiple roles
in HBV persistence. NVR 3-778 is an HBV core inhibitor which
can potentially inhibit viral assembly, HBV genome replication,
cccDNA replenishment, and hepatic reinfection cycles. We
report clinical proof-of-concept data for NVR 3-778 from a
multicenter Phase 1b trial in patients with CHB.
Methods:
Safety and efficacy were assessed in 4 dosing cohorts of adults with chronic HBV infection. Patients were 18-65 yrs,, predominantly male, and HBeAg-positive with serum HBV DNA > 20,000 IU/mL . ALT levels could be normal or elevated to less than 7 times upper limit of normal. Patients were randomized to NVR
3-778 capsules (10 patients/cohort in first 2 cohorts, 8/cohort
in last 2 cohorts) or placebo (2 patients/cohort) for 28 days.
The first 3 cohorts received NVR 3-778 doses of 100, 200, or
400 mg QD, and the 4th cohort received 600 mg BD. Safety
evaluations included adverse events (AEs) and safety-related
clinical labs.
Results:
A total of 44 patients were enrolled in the 4 cohorts; 36 received active NVR 3-778 treatment. Safety and tolerability of NVR 3-778 were satisfactory for all cohorts, with no treatment-related discontinuations or serious adverse events (SAEs). AEs and lab abnormalities were generally mild and not related to study drug. A patient in the 100 mg cohort developed a rash involving the hands and feet that was considered to be serious. No other study patients developed a significant rash. Small HBV DNA reductions were apparent with 200 mg and 400 mg QD dose cohorts. With tripling of the daily dose to 1200 mg (600 mg BD) the mean 28-day reduction in serum HBV DNA levels increased substantially to 1.72 log10 (range 1.06-3.71 log10 IU/mL). PK results indicated multi-micromolar concentrations of NVR 3-778 supporting QD or BD dosing, with dose-related increases in drug levels. The study is advancing to evaluation of a combination of NVR 3-778 and peg-interferon. A higher dose will be tested to define a maximal-effect dose for NVR 3-778, and a nucleoside combination regimen will be tested later.
Conclusions:
NVR 3-778 was well-tolerated in patients with CHB. 600 mg BD dosing achieved significant reductions in HBV DNA. When used alone or in combination with current HBV antivirals, NVR 3-778 may contribute substantial efficacy by unique Core-related
mechanisms, toward a goal of increased durable response rates in HBV patients.
Disclosures:
Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, MSD, Bristol-Myers Squibb, Roche, Novartis Pharmaceutical, Abbvie; Speaking and Teaching: Echosens
Sandy Liaw - Employment: Novira Therapeutics
Nathaniel Brown - Consulting: Presidio Pharmaceuticals; Employment: Novira Therapeutics
Klaus Klumpp - Board Membership: Riboscience LLC; Employment: Novira Therapeutics Inc
Lalo Flores - Employment: Novira Therapeutics
George D. Hartman - Management Position: Novira Therapeutics
Edward J. Gane - Advisory Committees or Review Panels: Novira, AbbVie, Janssen, Gilead Sciences, Janssen Cilag, Achillion, Merck, Tekmira; Speaking and Teaching: AbbVie, Gilead Sciences, Merck
The following people have nothing to disclose: Man-Fung Yuen, Dong Joon Kim, Frank Weilert, Jacob P. Lalezari, Seong Gyu Hwang, Tuan T. Nguyen


作者: StephenW    时间: 2015-10-21 17:12

LB-10
阶段1b疗效和NVR 3-778的安全,一个先入
类HBV核心抑制剂,在HBeAg阳性患者
慢性HBV感染
满丰Yuen3,东俊Kim4,弗兰克Weilert5,亨利LIK-元Chan6,雅各布体育Lalezari7,洪城揆Hwang8
,抟T. Nguyen9,桑迪Liaw1,纳撒尼尔Brown1,克劳斯Klumpp的
1,拉罗Flores1,乔治D. Hartman1,爱德华J. Gane2;
1Novira治疗,公司,Doylestown的,PA。;
2Auckland临床研究,奥克兰,新西兰;
3Queen玛丽医院,香港,香港,香港大学;
4Chuncheon圣心医院,翰林大学,江原道,韩国(共和国);
5Waikato医院,汉密尔顿,新西兰;
6Prince威尔斯亲王医院,香港,香港,香港中国大学的;
7Quest临床研究,美国加州旧金山;
8CHA盆唐医疗中心,京畿道,韩国(共和国);
9Research和教育,公司,圣地亚哥,加利福尼亚
背景:目前治疗慢性乙型肝炎(CHB)
可以抑制乙肝病毒复制,但长期治疗是必需的
在大多数患者。 HBV核心(衣壳)蛋白扮演着多重角色
乙型肝炎病毒的持久性。 NVR 3-778是一个乙肝病毒核心抑制剂
可有效抑制病毒组装,HBV基因组的复制,
cccDNA的补充和肝再感染周期。我们
报告概念证明的临床数据NVR 3-778从
多阶段1b试验CHB患者。
方法:
安全性和有效性进行了评估4计量成人慢性HBV感染的同伙。患者年龄18-65岁,,以男性为主,而HBeAg阳性血清HBV DNA> 20000 IU /毫升。 ALT水平可能是正常或升高到正常小于7倍上限。患者被随机分配到NVR
3-778胶囊(10例/队列在第2同伙,8 /队列
在过去的2同伙)或安慰剂(2例/组)28天。
前3组群接收的NVR 3-778剂量的100,200,或
400毫克QD,而第四队列收到600毫克BD。安全
评估包括不良事件(AE)和安全相关的
临床实验室。
结果:
总共有44名患者参加的4个组; 36收到积极NVR 3-778处理。安全和NVR 3-778的耐受性是令人满意的所有队列,无治疗相关停药或严重不良事件(SAE)。 AES和实验室异常是一般轻微,不相关的研究药物。在100毫克队列一位患者制定涉及该被认为是严重的手脚出现皮疹。没有其他研究的患者制定了显著皮疹。小HBV DNA减少为200毫克和400毫克QD剂量同伙明显。与每日剂量三倍至1200毫克(600毫克,BD)的平均28天降低血清HBV DNA水平大幅增加至1.72日志10(范围1.06-3.71日志10国际单位/毫升)。 PK结果表明NVR 3-778多微摩尔浓度支持QD或BD剂量,与剂量相关增加药物水平。该研究推进到NVR 3-778和PEG-干扰素的组合的评价。较高的剂量将被测试以限定最大效应剂量为NVR 3-778,和核苷组合方案将在后面进行测试。
结论:
NVR 3-778耐受性良好的慢性乙肝患者。 600毫克BD剂量达到显著降低HBV DNA。当单独使用或与当前的HBV抗病毒药组合使用,NVR 3-778可通过独特的核心相关有助于实质性功效
机制,对在乙肝患者提高耐用的反应率的目标。
披露:
亨利沥,袁灿 - 咨询委员会或审查小组:G​​ilead公司,MSD,施贵宝,罗氏,诺华制药,艾伯维;口语和教学:Echosens
桑迪廖 - 就业:Novira治疗
纳撒尼尔·布朗 - 咨询:要塞药品;就业:Novira治疗
克劳斯Klumpp的 - 董事会成员:Riboscience有限责任公司;就业:Novira Therapeutics公司
拉罗弗洛雷斯 - 就业:Novira治疗
乔治D.哈特曼 -​​ 管理您的位置:Novira治疗
爱德华J.甘恩 - 咨询委员会或审查小组:Novira,艾伯维,扬森,Gilead Sciences公司,西安杨森Cilag公司,艾琪尔顿,默克,Tekmira;口语和教学领域:艾伯维,Gilead Sciences公司,默克公司
下面的人都没有透露:满凤园,东俊金,弗兰克Weilert,雅各布体育Lalezari,洪城揆黄某,抟T.阮
作者: zgct    时间: 2015-10-21 17:37

该药抑制剂是负责对负HBVDNA?所以类似核苷药大概原理
作者: StephenW    时间: 2015-10-21 17:46

zgct 发表于 2015-10-21 17:37
该药抑制剂是负责对负HBVDNA?所以类似核苷药大概原理

药抑制剂乙肝病毒衣壳形成 (类似甲磺酸莫非赛定胶囊(GLS4JHS)).
应减少HBVDNA.
作者: newchinabok    时间: 2015-10-21 17:52

回复 StephenW 的帖子

是不是说大剂量降hbvdna效果好?今后还要做加干扰素,加核苷试验?  今后能做肝穿查查病人cccdna变化更好。
作者: newchinabok    时间: 2015-10-21 17:54

试验病人是大三阳,不知dna转阴没有?
作者: newchinabok    时间: 2015-10-21 18:05

试验时间短,长期用药会不会减少cccdna?
作者: StephenW    时间: 2015-10-21 18:16

newchinabok 发表于 2015-10-21 17:52
回复 StephenW 的帖子

是不是说大剂量降hbvdna效果好?今后还要做加干扰素,加核苷试验?  今后能做肝穿查 ...

是, 是.
作者: StephenW    时间: 2015-10-21 18:19

newchinabok 发表于 2015-10-21 18:05
试验时间短,长期用药会不会减少cccdna?

理论上是 可能, 在实践中未知.
作者: newchinabok    时间: 2015-10-21 18:22

回复 StephenW 的帖子

二期,三期做肝穿就知道了,能核苷联用,防耐药,降肝癌也是大功一件,感谢sw总是给我们第一时间带来好消息
作者: zgct    时间: 2015-10-21 20:50

能停药吗?停药也可以持续护肝防止Ca?
作者: 咬牙硬挺    时间: 2015-10-21 20:57

感谢分享
作者: StephenW    时间: 2015-10-21 21:06

回复 zgct 的帖子


不能停药.
抑制剂乙肝病毒衣壳形成药与口服抗病毒药攻击不同的目标, 因此,结合使用能迅速降低血清HBVDNA达到“检测不到” - 治愈的第一步.
抑制剂乙肝病毒衣壳形成药也可能干扰cccDNA.
作者: newchinabok    时间: 2015-10-21 21:10

回复 StephenW 的帖子

肝穿,肝穿,就知道结果了
作者: zgct    时间: 2015-10-21 21:33

StephenW 发表于 2015-10-21 21:06
回复 zgct 的帖子

收到,感谢!




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