Replicor发布NAP对乙型肝炎病毒感染的治疗效应的临床前数据

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专注于治愈慢性乙型肝炎病毒(HBV)以及慢性HBV与丁型肝炎病毒(HDV)联合感染患者的私营生物制药公司Replicor Inc.在PLOS ONE杂志上发布的临床前数据显示，核酸聚合物(NAP)对HBV感染具有治疗效应。

该研究与澳大利亚阿德莱德大学Allison Jilbert博士合作开展，在既往确诊感染鸭HBV (DHBV)的北京鸭中评估Replicor的首个临床候选药物NAP (REP 2055)每天治疗的抗病毒效应，疗程28天。北京鸭的DHBV感染是公认的人类HBV感染的替代模型。该研究是Replicor在亚洲开展的概念验证临床试验中支持NAP应用（以REP 2055作为起始用药）的主要临床前有效性数据。

在确诊感染DHBV 的鸭子中，REP 2055治疗显示能在治疗一周内降低所有鸭子的血清DHBV表面抗原(DHBsAg)至接近或低于可检出水平，同时DHBsAg抗体的滴度升高。研究显示，DHBsAg的这种清除对治疗停止后确立感染控制具有关键作用：治疗结束时及治疗停止后16周时，55% (6/11)的受治鸭子血液内未测出DHBsAg和DHBV DNA，肝脏内未见病毒抗原（DHBsAg和DHBV核心抗原）的证据，同时，作为病毒转录模板的共价闭合环状DNA (cccDNA)，其转录也停止，其拷贝数/在肝细胞内的数量比生理盐水处理的对照动物肝细胞中的cccDNA 拷贝数低200多倍(~2.3 log)。

尽管另外几个已获批的治疗HBV的抗病毒药物（拉米夫定、阿德福韦酯和恩替卡韦）在DHBV 模型中已显示具有抗病毒活性，但REP 2055是首个显示在绝大多数受治鸭子中快速清除DHBsAg 并持久控制DHBV 感染的抗病毒药物。

关于 Replicor

Replicor是一家私营生物制药公司，在HBV和HDV根治药物的开发领域拥有最先进的动物和人体临床数据。公司致力于加快开发HBV和HBV/HDV联合感染患者的有效治疗药物。有关Replicor 的进一步信息，请访问我们的网站 www.replicor.com并在Twitter @replicorinc上关注我们。

来源：生物谷

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Therapeutic Antiviral Effect of the Nucleic Acid Polymer REP 2055 against Persistent Duck Hepatitis B Virus Infection

Faseeha Noordeen, Catherine A. Scougall, Arend Grosse, Qiao Qiao, Behzad B. Ajilian, Georget Reaiche-Miller, John Finnie, Melanie Werner, Ruth Broering, Joerg F. Schlaak, Andrew Vaillant , Allison R. Jilbert

Previous studies have demonstrated that nucleic acid polymers (NAPs) have both entry and post-entry inhibitory activity against duck hepatitis B virus (DHBV) infection. The inhibitory activity exhibited by NAPs prevented DHBV infection of primary duck hepatocytes in vitro and protected ducks from DHBV infection in vivo and did not result from direct activation of the immune response. In the current study treatment of primary human hepatocytes with NAP REP 2055 did not induce expression of the TNF, IL6, IL10, IFNA4 or IFNB1 genes, confirming the lack of direct immunostimulation by REP 2055. Ducks with persistent DHBV infection were treated with NAP 2055 to determine if the post-entry inhibitory activity exhibited by NAPs could provide a therapeutic effect against established DHBV infection in vivo. In all REP 2055-treated ducks, 28 days of treatment lead to initial rapid reductions in serum DHBsAg and DHBV DNA and increases in anti-DHBs antibodies. After treatment, 6/11 ducks experienced a sustained virologic response: DHBsAg and DHBV DNA remained at low or undetectable levels in the serum and no DHBsAg or DHBV core antigen positive hepatocytes and only trace amounts of DHBV total and covalently closed circular DNA (cccDNA) were detected in the liver at 9 or 16 weeks of follow-up. In the remaining 5/11 REP 2055-treated ducks, all markers of DHBV infection rapidly rebounded after treatment withdrawal: At 9 and 16 weeks of follow-up, levels of DHBsAg and DHBcAg and DHBV total and cccDNA in the liver had rebounded and matched levels observed in the control ducks treated with normal saline which remained persistently infected with DHBV. These data demonstrate that treatment with the NAP REP 2055 can lead to sustained control of persistent DHBV infection. These effects may be related to the unique ability of REP 2055 to block release of DHBsAg from infected hepatocytes.

http://journals.plos.org/plosone ... ournal.pone.0140909