48周未接受核苷（t）疗法的慢性HBV感染患者的REP 2139或REP 2165

StephenW

Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naïve to Nucleos(t)ide Therapy
Michel Bazinet1
, Victor Pântea2
, Gheorghe Placinta2
, Iurie Moscalu3
, Valentin Cebotarescu2
, Lilia Cojuhari2
, Pavlina Jimbei4
, Liviu Iarovoi2
, Valentina Smesnoi4
, Tatiana Musteata4
, Alina Jucov2,3
, Ulf Dittmer5
, Adalbert Krawczyk5,6
, Andrew Vaillant1,∗,'Correspondence information about the author Andrew VaillantEmail the author Andrew Vaillant
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DOI: https://doi.org/10.1053/j.gastro.2020.02.058 |
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Background & Aims

Nucleic acid polymers (NAPs) inhibit assembly and secretion of hepatitis B virus (HBV) subviral particles. We performed an open-label, phase 2 study of the safety and efficacy of the NAPs REP 2139 or REP 2165 combined with tenofovir disoproxil fumarate (TDF) and pegylated interferon alfa-2a (pegIFN) in patients with chronic HBV infection who were negative for hepatitis B e antigen.
Methods

Following 24 weeks TDF therapy, 40 patients were randomly assigned to groups that received 48 weeks of experimental therapy (TDF + pegIFN + REP 2139-Mg or REP 2165-Mg) or 24 weeks of control therapy (TDF + pegIFN) followed by 48 weeks of experimental therapy. Patients were then followed for a treatment-free period of 48 weeks. Primary outcomes were the safety and tolerability of REP 2139-Mg or REP 2165-Mg in combination with TDF + pegIFN compared with TDF + pegIFN alone through the first 48 weeks of therapy and subsequently throughout 48 weeks of NAP-based combination therapy (treatment weeks 24–72 in the experimental group and weeks 48–96 in the control group). Secondary outcomes were reductions in hepatitis B surface antigen (HBsAg) in control and experimental groups over the first 48 weeks of the study and throughout 48 weeks of combination therapy and virologic control (HBsAg positive, HBV DNA below 2000 IU/mL, normal level of alanine aminotransferase) or functional cure (HBsAg below 0.05 IU/mL, HBV DNA target not detected, normal level of alanine aminotransferase) after removal of all therapy.
Results

Levels of HBsAg, anti-HBs, and HBV DNA did not differ significantly between the groups given REP 2139 vs REP 2165. PegIFN-induced thrombocytopenia (P = .299 vs controls) and neutropenia (P = .112 vs controls) were unaffected by NAPs (REP 2139 vs REP 2165). Increases in levels of transaminases were significantly more frequent (P < .001 vs controls) and greater (P = .002 vs controls) in the NAP groups (but did not produce symptoms), correlated with initial decrease in HBsAg, and normalized during therapy and follow-up. During the first 24 weeks of TDF and pegIFN administration, significantly higher proportions of patients in NAP groups had decreases in HBsAg to below 1 IU/mL (P < .001 vs control) and HBsAg seroconversion (P = .046 vs control). At the time patients completed the TDF + pegIFN + NAP regimen, HBsAg levels were 0.05 IU/mL or lower in 24/40 participants (all with seroconversion up to 233,055 mIU/mL). During 48 weeks of treatment-free follow-up, virologic control persisted in 13 of 40 participants (2 lost to follow-up after 24 weeks), whereas functional cure persisted in 14 of 40 participants (all completing 48 weeks of follow-up) with persistent HBsAg seroconversion. One participant had a viral rebound during follow-up with hepatic decompensation and was placed on TDF therapy.
Conclusions

In a phase 2 randomized trial, we found that addition of NAPs to TDF + pegIFN did not alter tolerability and significantly increased rates of HBsAg loss and HBsAg seroconversion during therapy and functional cure after therapy. Clinicaltrials.gov no: NCT02565719.

StephenW

48周未接受核苷（t）疗法的慢性HBV感染患者的REP 2139或REP 2165，替诺福韦二甲酚，替诺福韦二钠，聚乙二醇干扰素Alfa-2a的安全性和有效性
米歇尔·巴赞特1
，维克多·潘泰2
，Gheorghe Placinta2
，Iurie Moscalu3
，Valentin Cebotarescu2
，莉莉亚·科朱哈里2
，帕夫利纳·金贝（Pavlina Jimbei）4
，Liviu Iarovoi2
瓦伦蒂娜（Valentina Smesnoi）4
，塔蒂亚娜·穆斯塔塔4
，阿丽娜·朱可夫2,3
乌尔夫·迪特默（Ulf Dittmer）5
，阿达伯特·克拉维奇5,6
，'Andrew Vaillant1，*，'有关作者Andrew Vaillant的通讯信息通过电子邮件发送给作者Andrew Vaillant
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DOI：https：//doi.org/10.1053/j.gastro.2020.02.058 |
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背景与目标

核酸聚合物（NAP）抑制乙肝病毒（HBV）亚病毒颗粒的组装和分泌。我们对NAP阴性的NAP REP 2139或REP 2165联合富马酸替诺福韦酯（TDF）和聚乙二醇化干扰素alfa-2a（pegIFN）的安全性和有效性进行了开放标签的2期研究乙型肝炎e抗原。
方法

在TDF治疗24周后，将40例患者随机分为接受48周实验治疗（TDF + pegIFN + REP 2139-Mg或REP 2165-Mg）或24周对照治疗（TDF + pegIFN）的组，然后进行48周实验疗法。然后，对患者进行48周的免费治疗。主要结果是，在治疗的前48周以及随后整个基于NAP的联合治疗（治疗周）中，REP 2139-Mg或REP 2165-Mg与TDF + pegIFN联合单独使用TDF + pegIFN的安全性和耐受性实验组为24-72周，对照组为48-96周）。次要结果是在研究的前48周以及组合治疗和病毒学控制的整个48周内，对照组和实验组的乙型肝炎表面抗原（HBsAg）降低（HBsAg阳性，HBV DNA低于2000 IU / mL，正常水平删除所有疗法后或恢复功能性治疗（HBsAg低于0.05 IU / mL，未检测到HBV DNA靶点，丙氨酸氨基转移酶水平正常）。
结果

给予REP 2139和REP 2165的组之间的HBsAg，抗HBs和HBV DNA的水平没有显着差异。PegIFN诱导的血小板减少症（P = .299与对照组）和中性粒细胞减少症（P = .112与对照组）不受这些影响NAP（REP 2139与REP 2165）。在NAP组中转氨酶水平的升高更为频繁（P <.001 vs对照），而更高（P = .002 vs对照）（但未产生症状），与HBsAg的初始降低相关，并在治疗期间恢复正常和跟进。在施用TDF和pegIFN的前24周内，NAP组中更高比例的患者的HBsAg降至1 IU / mL以下（与对照组相比，P <.001）和HBsAg血清转化（与对照组相比，P = .046）。在患者完成TDF + pegIFN + NAP方案时，24/40参与者的HBsAg水平为0.05 IU / mL或更低（所有患者的血清转化率最高为233,055 mIU / mL）。在无治疗随访的48周中，40名参与者中有13名坚持了病毒学控制（24周后失去了2名随访），而40名参与者中有14名坚持了功能性治愈（全部完成了48周的随访）持续存在HBsAg血清转化。一名参与者在进行肝代偿失调的随访过程中出现病毒反弹，并接受了TDF治疗。
结论

在一项2期随机试验中，我们发现在TDF + pegIFN中添加NAP不会改变耐受性，并且在治疗过程中和治疗后功能治愈的过程中HBsAg丢失和HBsAg血清转化的比率显着增加。 Clinicaltrials.gov编号：NCT02565719。

StephenW

https://www.gastrojournal.org/ar ... aven_jbs_etoc_email

乙肝人1949

感觉这个公司一直变着法儿夸reP，只听猪叫声，不见猪下楼。我就困惑了，再三年还要从哪些方面来夸，前几年，都是夸在三只鸭或四只鸭身上效果好的很，还夸在五只老鼠，6只老鼠效果好的很。那再过几年，估计是在

StephenW

回复 乙肝人1949 的帖子

我相信专家:

http://hbvhbv.info/forum/thread-1751566-1-1.html

sir

Replicor临床实验进度太慢了，做了这么多年还在2期，计划在美国做2期临床但现在一点动静没有。但现在出现了Replicor的竞争对手，Aligos开发了REP 2139的同类药物，对HBSAG的抑制效果是REP 2139的100倍，Aligos将在今年八月份正式开展临床试验，明年上半年会有治疗12周的结果，如果Aligos的临床试验成功，那Replicor就没什么竞争机会了，Aligos团队开发的STOP、CAMp、ASO抗病毒活性是所有公司里面最强的，临床试验顺利的话发展前景会非常好

StephenW

回复 sir 的帖子

"对HBSAG的抑制效果是REP 2139的100倍"  -  在体外HBV细胞模型

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