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标题: GSK将启动GSK3228836 phase 2b临床试验，入组440例，2022年出结果 [打印本页]
作者: sir    时间: 2020-7-17 00:39     标题: GSK将启动GSK3228836 phase 2b临床试验，入组440例，2022年出结果

本帖最后由 sir 于 2020-7-17 08:55 编辑

慢性乙型肝炎患者GSK3228836的研究：
phase 2a结果：GSK3228836治疗4周后，HBSAG 平均降低1.5log，2例（2/12=16%）HBSAG低于检测线，但安全性差一些，副作用是贫血，血小板减少，phase 2b入组440例患者，疗程24周，2022年临床试验结束。JNJ-73763989已经完成入组471人，明年三月出48周三联用药phase 2b结果。Man Fung Yuen在最近的一个会议上说，将来以RNAi为基础的组合方案可能实现30-40%的比例功能性治愈，低HBSAG的人群可能不需要再联合干扰素就可以实现功能性治愈，Man Fung Yuen负责了ARC520，JNJ-73763989，GSK3228836，ABI-H0731，SB9200 等项目的临床试验，他的一些看法应该是基于目前手里的临床数据，具有一定的参考价值。


慢性乙型肝炎病毒（HBV）感染是一个世界性的重大医学问题。GSK3228836在未接受治疗的慢性乙型肝炎患者和接受稳定核苷治疗的慢性乙型肝炎患者中显示靶向参与。本研究旨在评估GSK3228836治疗后是否能获得持续的病毒学应答（SVR），即乙肝病毒表面抗原（HBsAg）小于（<）定量下限（LLOQ）和HBV脱氧核糖核酸（DNA）<LLOQ持续24周。此外，本研究还将评估GSK3228836在4种给药方案中的安全性、耐受性、药代动力学和药效学特性。本研究将评估GSK328836对两组慢性乙型肝炎患者的疗效和安全性：接受稳定核仁（t）ide治疗的受试者（队列1）和目前未接受核仁（t）ide治疗的受试者（队列2）。对于每个人群，参与者将被随机分成4个不同的平行臂中的一个接受治疗。研究包括筛选和后续治疗阶段。大约有440名参与者将参加这项研究。



Study Type :

Interventional  (Clinical Trial)

Estimated Enrollment :

440 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Participants with CHB will be divided into two different cohorts; participants on stable nucleos(t)ide treatment and participants not currently on nucleos(t)ide therapy. For each cohort, participants will be randomized into one of the 4 different parallel arms to receive treatment.

Masking:

Single (Participant)

Masking Description:

Participants will be blinded to the study treatment.

Primary Purpose:

Treatment

Official Title:

Phase IIb Multi-Center, Randomised, Partial-Blind Parallel Cohort Study to Assess the Efficacy and Safety of Treatment With GSK3228836 in Participants With Chronic Hepatitis B Virus (B-Clear)

Estimated Study Start Date :

August 28, 2020

Estimated Primary Completion Date :

April 1, 2022

Estimated Study Completion Date :

October 3, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hepatitis Hepatitis A Hepatitis B
Genetic and Rare Diseases Information Center resources: Herpes Simiae (B Virus)
U.S. FDA Resources




Arms and Interventions

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[td]
ArmIntervention/treatment
Experimental: Cohort 1: GSK3228836 300 mg + LDEligible participants on stable nucleos(t)ide treatment will receive 300 milligrams (mg) GSK3228836 once weekly for 24 weeks along with loading dose (LD) of 300 mg GSK3228836 on Day 4 and Day 11.
Drug: GSK3228836GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Drug: Nucleos(t)ide therapyParticipants receiving nucleos(t)ide therapy upon entry in the study will continue to receive nucleotide therapy for the duration of the study.

Experimental: Cohort 1: GSK3228836 300 mg + LD/ GSK3228836 150 mg + PlaceboEligible participants on stable nucleos(t)ide treatment will receive 300 mg GSK3228836 once weekly for 12 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11 followed by step-down in dose of 150 mg GSK3228836 once weekly for 12 weeks along with placebo to match to maintain participant blinding.
Drug: GSK3228836GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Drug: PlaceboPlacebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly.

Drug: Nucleos(t)ide therapyParticipants receiving nucleos(t)ide therapy upon entry in the study will continue to receive nucleotide therapy for the duration of the study.

Experimental: Cohort 1: GSK3228836 300 mg + LD/ PlaceboEligible participants on stable nucleos(t)ide treatment will receive 300 mg GSK3228836 once weekly for 12 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11 followed by placebo once weekly for 12 weeks.
Drug: GSK3228836GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Drug: PlaceboPlacebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly.

Drug: Nucleos(t)ide therapyParticipants receiving nucleos(t)ide therapy upon entry in the study will continue to receive nucleotide therapy for the duration of the study.

Experimental: Cohort 1: Placebo/ GSK3228836 300 mg + Placebo LDEligible participants on stable nucleos(t)ide treatment will receive placebo once weekly for 12 weeks followed by 300 mg GSK3228836 once weekly for 12 weeks along with placebo LD to match on Day 4 and Day 11.
Drug: GSK3228836GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Drug: PlaceboPlacebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly.

Drug: Nucleos(t)ide therapyParticipants receiving nucleos(t)ide therapy upon entry in the study will continue to receive nucleotide therapy for the duration of the study.

Experimental: Cohort 2: GSK3228836 300 mg + LDEligible participants not currently on nucleos(t)ide therapy will receive 300 mg GSK3228836 once weekly for 24 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11.
Drug: GSK3228836GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Experimental: Cohort 2: GSK3228836 300 mg + LD/ GSK3228836 150 mg + PlaceboEligible participants not currently on nucleos(t)ide therapy will receive 300 mg GSK3228836 once weekly for 12 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11 followed by step-down in dose of 150 mg GSK3228836 once weekly for 12 weeks along with placebo to match to maintain participant blinding.
Drug: GSK3228836GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Drug: PlaceboPlacebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly.

Experimental: Cohort 2: GSK3228836 300 mg + LD/ PlaceboEligible participants not currently on nucleos(t)ide therapy will receive 300 mg GSK3228836 once weekly for 12 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11 followed by placebo once weekly for 12 weeks.
Drug: GSK3228836GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Drug: PlaceboPlacebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly.

Experimental: Cohort 2: Placebo/ GSK3228836 300 mg + Placebo LDEligible participants not currently on nucleos(t)ide therapy will receive placebo once weekly for 12 weeks followed by 300 mg GSK3228836 once weekly for 12 weeks along with placebo LD to match on Day 4 and Day 11.
Drug: GSK3228836GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Drug: PlaceboPlacebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly.




Outcome Measures

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Primary Outcome Measures :
  • Percentage of participants achieving SVR [ Time Frame: Up to Week 48 ]Sustained response is defined as a continuous 24 weeks from end of GSK3228836 treatment during which levels of HBsAg in serum remain <LLOQ and HBV DNA< LLOQ.


Secondary Outcome Measures :
  • Percentage of participants achieving HBsAg <LLOQ [ Time Frame: Up to Week 24 ]Participants achieving HBsAg <LLOQ at the end of treatment will be assessed.
  • Percentage of participants achieving HBV DNA <LLOQ [ Time Frame: Up to Week 24 ]Participants achieving HBV DNA <LLOQ at the end of treatment will be assessed.
  • Percentage of participants with alanine aminotransferase (ALT) normalization over time in absence of rescue medication [ Time Frame: Up to Week 48 ]Participants with Baseline ALT greater than (>) upper limit of normal (ULN) will be assessed for ALT normalization in absence of rescue medication over time.
  • HBsAg level at indicated time points [ Time Frame: Day 1 to Week 48 ]Blood samples will be collected from participants to assess HBsAg level at indicated time points.
  • Change from Baseline in HBsAg over time [ Time Frame: Baseline (Day 1) and up to Week 48 ]Blood samples will be collected from participants to assess HBsAg level at indicated time points.
  • HBV DNA level at indicated time points [ Time Frame: Day 1 to Week 48 ]Blood samples will be collected from participants to assess HBV DNA level at indicated time points.
  • Change from Baseline in HBV DNA over time [ Time Frame: Baseline (Day 1) and up to Week 48 ]Blood samples will be collected from participants to assess HBV DNA level at indicated time points.
  • Hepatitis B virus e-antigen (HBeAg) level at indicated time points [ Time Frame: Day 1 to Week 48 ]Blood samples will be collected to assess HBeAg level of each participant.
  • Change from Baseline in HBeAg level over time [ Time Frame: Baseline (Day 1) and up to Week 48 ]Blood samples will be collected to assess HBeAg level of each participant.
  • Hepatatis B surface antibody (HBsAb) level at indicated time points [ Time Frame: Day 1 to Week 48 ]Blood samples will be collected to assess HBsAb level of each participant.
  • Change from Baseline in HBsAb level over time [ Time Frame: Baseline (Day 1) and up to Week 48 ]Blood samples will be collected to assess HBsAb level of each participant.
  • HBeAb level at indicated time points [ Time Frame: Day 1 to Week 48 ]Blood samples will be collected to assess HBeAb level of each participant.
  • Change from Baseline in HBeAb level over time [ Time Frame: Baseline (Day 1) and up to Week 48 ]Blood samples will be collected to assess HBeAb level of each participant.
  • Time to ALT normalization in absence of rescue medication [ Time Frame: Day 1 to Week 48 ]Time to ALT normalization in absence of rescue medication will be measured in participants with Baseline ALT>ULN.
  • Percentage of participants achieving SVR over time [ Time Frame: Up to Week 24 ]Sustained response is defined as a continuous 24 weeks from end of GSK3228836 treatment during which levels of HBsAg in serum remain less than LLOQ and HBV DNA less than LLOQ.
  • Area under the concentration-time curve (AUC) following administration of GSK3228836- Intensive pharmacokinetics (PK) [ Time Frame: Any one week between Week 14 to Week 24 ]Blood samples will be collected for PK analysis of GSK3228836 at indicated time points.
  • AUC following administration of nucleos(t)ide therapy- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]Blood samples will be collected for PK analysis of nucleos(t)ide therapy at indicated time points.
  • Concentration at the end of the dosing interval (Ctau) following administration of GSK3228836- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]Blood samples will be collected for PK analysis of GSK3228836 at indicated time points.
  • Ctau following administration of nucleos(t)ide therapy- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]Blood samples will be collected for PK analysis of nucleos(t)ide therapy at indicated time points.
  • Maximum observed concentration (Cmax) following administration of GSK3228836- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]Blood samples will be collected for PK analysis of GSK3228836 at indicated time points.
  • Cmax following administration of nucleos(t)ide therapy- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]Blood samples will be collected for PK analysis of nucleos(t)ide therapy at indicated time points.
  • Time of maximum observed concentration (tmax) following administration of GSK3228836- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]Blood samples will be collected for PK analysis of GSK3228836 at indicated time points.
  • Tmax following administration of nucleos(t)ide therapy- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]Blood samples will be collected for PK analysis of nucleos(t)ide therapy at indicated time points.
  • Apparent subcutaneous plasma clearance for GSK3228836- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]Blood samples will be collected for PK analysis of GSK3228836 at indicated time points.
  • Apparent oral plasma clearance for nucleos(t)ide- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]Blood samples will be collected for PK analysis of nucleos(t)ide therapy at indicated time points.
  • Terminal half-life (T1/2) following administration of GSK3228836- All participants [ Time Frame: From Week 15 to Week 44 ]Blood samples will be collected for PK analysis of GSK3228836 at indicated time points.
  • T1/2 following administration of nucleos(t)ide therapy- All participants [ Time Frame: Any one week between Week 14 to Week 24 ]Blood samples will be collected for PK analysis of nucleos(t)ide therapy at indicated time points.
  • Ctau following administration of GSK3228836- All participants [ Time Frame: From Week 1 to Week 25 ]Blood samples will be collected for PK analysis of GSK3228836 at indicated time points.
  • Ctau following administration of nucleos(t)ide therapy- All participants [ Time Frame: From Week 1 to Week 25 ]Blood samples will be collected for PK analysis of nucleos(t)ide at indicated time points




作者: 平凡之路123    时间: 2020-7-17 05:56

我觉得有点乐观了，如果RNA干扰效果如此好，AROHBV就不用三联或者四联用药了，现在强生还在大力实验，说明RNA一方面有用，一方面效力还不是太强。
作者: sir    时间: 2020-7-17 09:33

回复 平凡之路123 的帖子

目前来说，强生的三联方案中部分患者应该已经有了24周-48周的结果，目前要启动的四联方案就是在原来的基础上加了干扰素，但纳入的不再是慢性乙型肝炎患者而是携带者，加了干扰素的联合方案针对的人群是e抗原阳性且肝功能正常的慢乙肝携带者，这部分人群的治疗难度应该是最大的，以前的指南根本不推荐携带者进行治疗，因为就算是TDF用上了依然可能达不到HBV DNA转阴，而现在的四联方案就是针对这部分人群设计的，强生的目的应该是用联合方案覆盖所有HBV人群（慢性乙型肝炎患者+乙肝携带者），对所有人群进行治疗是目前核苷或干扰素无法实现的，而要不要联合干扰素可能取决于基线HBSAG水平，比如低于1000的可能就不需要加干扰素，GSK3228836治疗4周后HBSAG转阴的2位患者就是HBSAG在1000左右的
作者: 乙肝人1949    时间: 2020-7-17 13:14

求证一下，9200sB，这个药啥进展?
作者: 傻狍子7号    时间: 2020-7-17 13:39

本帖最后由 傻狍子7号 于 2020-7-17 13:58 编辑

1.5log =97%
在肝脏时间那里找到这个2a的结果了，虽然只有12例，4周hbsag下降97%够猛。
440人的实验也是下本了，持续关注
作者: 傻狍子7号    时间: 2020-7-17 13:43

本帖最后由 傻狍子7号 于 2020-7-17 13:59 编辑

关注
作者: 傻狍子7号    时间: 2020-7-17 14:35

回复 平凡之路123 的帖子

其实正是有希望才大规模实验，如果觉得没戏就终止研究了。rnai药物应该是降低hbsag有很明显的效果，但最终functional cure估计仍需要结合免疫调节类药物。加入干扰素跟一些大V之前预测的类似。我看推特上的人讲不管jnj39897376最终能不能完全functional cure, 都很可能会上市，因为已经证明的降低hbsag的效果已经对患者很有利了。
作者: 平凡之路123    时间: 2020-7-17 16:30

回复 sir 的帖子

AROHBV效果如果这么好，但是阶段性的进度中没说实现多少功能治愈的，或者是入组患者用药时间不同，出结果的人比较少？
作者: 平凡之路123    时间: 2020-7-17 16:32

回复 傻狍子7号 的帖子

核蛋白抑制，加RNA干扰，加核苷，加干扰素，应该能治愈了，就是不知道组合起来副作用是否可控。
作者: 平凡之路123    时间: 2020-7-17 16:37

回复 sir 的帖子

希望强生和箭头一切顺利吧，AROHBV和0731是我最期待的两个药了，别的更遥远了。
作者: sir    时间: 2020-7-17 17:39

回复 平凡之路123 的帖子

AROHBV现在完全由强生负责开发了，不会再像arrowhead一样经常披露临床试验结果了，但现在强生已经开了三个phase2b的临床试验队列，总人数达到700例左右，FDA对于三期临床的要求也就1000例左右，说明已经开展了1年的联合用药试验还是比较顺利的，但我估计今年的EASL和AASLD强生不会披露更多的联合用药的结果，这些都是商业机密而且有很多竞争对手都在做联合用药的方案，明年结束了phase 2b有可能会公布部分结果，如果Phase 2b结果非常好，那直接就进入三期临床了，没有上市的把握的话强生不太可能轻易进入三期临床的，因为只要进入三期临床就需要向arrowhead支付非常高的里程碑付款，同时还有1000-2000例的临床试验的成本，失败了损失会比较大
作者: yangtze    时间: 2020-7-17 21:36

一竿子支到2年后。。。。。。。。
作者: 健康金牌    时间: 2020-7-18 23:25

四联药肯定有效果，就像治疗幽门螺杆菌一样也是四联
作者: 齐欢畅    时间: 2020-7-18 23:51





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