新药汇总

newchinabok

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069299/

newchinabok

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069299/table/T2/

StephenW

kite2002005

回复 StephenW 的帖子

看上去是那么多，但不知道有几个是真正有用的。这里面，只看到过 A5和Rep9ac这2个药，但后面那个貌似也很久没有消息了。。。

StephenW

Inhibitor of HBV DNA polymerase
抑制HBV DNA聚合酶
Clevudine: Clevudine [1-(2-deoxy-2-fluoro-β-L-arabinofuranosyl) thymine, L-FMAU], a thymidine nucleoside analogue, has potent antiviral activities against both HBV and Epstein-Barr virus but not human immunodeficiency virus (HIV). It acts as an inhibitor of the DNA-dependent DNA activity of HBV polymerase, as well as of reverse transcription and priming. Clevudine was approved for the treatment of CHB in South Korea and in the Philippines. However, the use of clevudine has not been endorsed by AASLD or EASL in their hepatitis B treatment guidelines[21,22] (Table ​(Table22).


Clevudine has demonstrated potent antiviral activity during therapy and induced a sustained post treatment antiviral effect for 6 mo after a 12-wk treatment period[23]. A clinical trial of 1-year of clevudine treatment demonstrated it to be effective in suppressing the serum HBV DNA level and in normalizing the ALT level. Viral breakthrough associated with the rtM204I mutation occurred in 1 patient after 9 mo of clevudine treatment[24]. The M204I mutant in HBV RT plays a major role in clevudine resistance and leads to viral breakthrough during long-term clevudine treatment. In vitro drug susceptibility assays have revealed clevudine-associated mutants to be all resistant to lamivudine and usually sensitive to adefovir, entecavir, and tenofovir[25].

In a double-blind study to evaluate the safety and antiviral activity of clevudine (30 mg daily) over a 48-wk period compared with lamivudine (100 mg daily) in 92 HBeAg-positive CHB patients, clevudine was shown to be superior to lamivudine by yielding a higher rate of HBV DNA suppression[26]. In contrast, in a 2-year observational study comparing the clinical efficacy and safety of clevudine and entecavir, clevudine not only was no more effective than entecavir but also was associated with the development of drug resistance and muscle-related problems[27,28].

Clinical trials of long-term therapy with clevudine in the United States were terminated due to safety issues, such as drug-induced myopathy[29-31]. Furthermore, clevudine is more potent than is lamivudine, but does not seem to be more potent than entecavir or tenofovir. It has no advantage over the more potent antiviral regimen in current use, and therefore, is unlikely to be more universally approved in most markets given the safety concerns and the availability of the more effective drugs entecavir and tenofovir.
克拉夫定：克拉夫定[1  - （2 - 脱氧-2 - 氟-β-L-阿拉伯呋喃糖基）胸腺嘧啶，L-FMAU]胸苷核苷类似物，具有抗HBV和Epstein-Barr病毒均有效的抗病毒活性，但尚未人类免疫缺陷病毒（HIV）。它作为HBV的DNA依赖性DNA聚合酶活性的抑制剂，以及逆转录和涂刷。克拉夫定被批准用于慢性乙肝的韩国和菲律宾的治疗。然而，使用克拉夫定处理不当在他们的乙肝治疗指南[21,22]（表（表22）已获AASLD，EASL或。
表2



克拉夫定表现出强效的抗病毒活性，在治疗期间和治疗后引起了持续的抗病毒效果持续6个月的12周治疗周期[23]之后。 1年克拉夫定治疗的临床试验证明它是有效的抑制血清HBV DNA水平和标准化的ALT水平。与rtM204I突变相关的病毒学突破发生1例术后9个月克拉夫定治疗[24]。该M204I突变的HBV逆转录起着克拉夫定阻了重要作用，并导致病毒突破在长期的克拉夫定治疗。体外药敏试验揭示了克拉夫定相关的突变体是所有耐拉米夫定，通常你敏感的阿德福韦，恩替卡韦和替诺福韦[25]。

在一项双盲研究，以评估在48周期间的安全性和克拉夫定的抗病毒活性（30毫克）与拉米夫定相比（每日100毫克）的92例HBeAg阳性CHB患者，克拉夫定被证明是优于拉米夫定通过高产率较高的HBV DNA抑制[26]。另一方面，在2年的观察研究，比较的临床疗效和克拉夫定和恩替卡韦的安全性，克拉夫定不仅不比卡韦也更有效，但与耐药性和肌肉相关的问题的发展[27,28]相关。

的长期治疗与克拉夫定在美国的临床试验被终止两到安全问题，：如药物引起的肌病[29-31]。此外，克拉夫定是更有效的比拉米夫定是，但似乎并没有成为黑莓强于恩替卡韦或替诺福韦。它拥有超过目前使用的黑莓强大的抗病毒治疗方案没有优势，因此，它是不可能被普遍认可的在考虑安全问题和黑莓有效的药物恩替卡韦和替诺福韦的可用性大多数市场的黑莓。

MIV-210 (Lagociclovir valactate): is a prodrug of the nucleoside analogue 3’-fluoro-2’, 3’-dideoxyguanosine (FLG) and has high oral bioavailability in humans and potent activity against HBV[32].

Preclinical in vitro and in vivo data reveal MIV-210 to be a good candidate for further testing as an agent against HIV and HBV. In Huh7 cells transiently transfected with different HBV constructs, FLG exhibits a broad spectrum of anti-HBV activity profiles against wild-type, lamivudine-resistant, adefovir-resistant, and lamivudine-plus-adefovir-resistant HBV mutants[33]. A study to determine the dose-related antiviral efficacy and safety of MIV-210 in chronically infected woodchucks showed that oral administration of MIV-210 at 20 or 60 mg/kg of body weight/day induced a rapid virological response[34]. The clinical development of this agent is ongoing. Following favorable plasma levels of MIV-210 and good oral bioavailability in phase I studies, a phase IIa clinical trial has been initiated in South Korea.
MIV-210（Lagociclovir valactate）是核苷类似物，3'-氟-2'，3'-双脱氧（FLG）的前体药物，具有很高的口服生物利用度在人类和有效的活性抗HBV[32]。

临床前的体外和体内数据显示MIV-210是一个很好的候选人进一步顶级测试，抗HIV和HBV的代理。在Huh7细胞中瞬时转染用不同的HBV结构，FLG表现出对野生型，拉米夫定耐药，阿德福韦耐药和拉米夫定加阿德福韦耐药HBV突变体[33]抗HBV活性谱的广谱。的研究，以决定簇MIV-210的在慢性感染的土拨鼠的剂量相关的抗病毒疗效和安全性表明，MIV-210，在20或60毫克口服给药/公斤体重/天诱导的快速病毒学应答[34]。本剂的临床开发正在进行中。以下MIV-210的良好血浆水平和良好的口服生物利用度I期研究中的一个IIa期临床试验已经开始在韩国。

Besifovir (LB80380): is an acyclic nucleotide phosphonate with chemical similarity to adefovir and tenofovir. LB80380 is the prodrug of LB80331, which in turn is metabolized to LB80317, the active metabolite with antiviral effects against HBV after further intracellular phosphorylation to the triphosphate form[35].

In a phase Ib dose-finding study of LB80380 in treatment-naïve HBeAg-positive CHB patients, the safety, antiviral activity and pharmacokinetics were assessed[36]. A 3- to 4.2-log reduction of HBV DNA was observed with doses ranging from 30 to 240 mg daily, and viral suppression reached the optimal level when besifovir was administered at dose above 60 mg/d. In a phase IIa clinical study, LB80380 was found to be effective in reducing the viral load in lamivudine-resistant HBeAg-positive CHB patients for a period of 12 wk[37]. In both studies, LB80380 was safe and well tolerated up to a dose of 240 mg daily. In a phase IIb study that compared the safety and antiviral activity of besifovir with entecavir in Asian CHB patients for 48 wk, the proportions of patients who achieved undetectable HBV DNA, HBeAg loss, and HBeAg seroconversion were similar in all 3 groups of patients (besifovir 90 mg daily, besifovir 150 mg daily or entecavir 0.5 mg daily). Two doses of besifovir (90 mg and 150 mg) were non-inferior to entecavir 0.5 mg daily in treatment-naive CHB patients[38]. No antiviral drug resistance was observed in this study. A phase III study (ClinicalTrials.gov identifier NCT01937806) to assess the antiviral activity and safety of besifovir 150 mg compared with tenofovir 300 mg in CHB patients for 48 wk is not yet open for participant recruitment.
Besifovir（LB80380）与化学相似性阿德福韦和替诺福韦的无环核苷膦酸盐。 LB80380是LB80331，而这又是代谢为LB80317，活性代谢物与后进一步顶胞内磷酸化的三磷酸形式[35]抗HBV抗病毒效果的前药。

在LB80380在治疗初治的HBeAg阳性CHB患者Ib期剂量探索研究，安全，抗病毒活性和药代动力学进行了评估[36]。乙型肝炎病毒DNA的3至4.2-log减少观察到的剂量每日30至240毫克，以及抑制病毒时达到最佳水平besifovir施用剂量高于60毫克/天。在IIa期临床研究，LB80380被认为是有效减少病毒载量在拉米夫定耐药HBeAg阳性CHB患者，为期12周[37]。在两项研究中，LB80380是安全的，耐受性好高达240毫克的剂量（每日）。在IIb期研究比较的安全性和恩替卡韦与besifovir亚洲CHB患者48周的抗病毒活性，谁取得检测不到HBV DNA，HBeAg转阴，HBeAg血清学转换，并在所有3组患者的类似患者的比例（besifovir 90毫克，每日150毫克，每日besifovir或恩替卡韦0.5 mg，每日）。两种剂量besifovir（90毫克和150毫克）不劣于日常恩替卡韦在治疗初治慢性乙肝患者[38]0.5毫克。没有抗病毒耐药性中观察到本研究中。一项III期研究（ClinicalTrials.gov标识符NCT01937806），以评估抗病毒活性和150毫克的安全besifovir300毫克替诺福韦慢性乙型肝炎患者48周相比，尚未开放的受试者招募。

Tenofovir Alafenamide (GS-7340): associated with acyclic nucleotide phosphonates is currently under clinical development, with the goal of increasing oral availability, improving antiviral activity, and decreasing the potential for nephrotoxicity. Tenofovir alafenamide (TAF; formerly GS-7340) is a prodrug of TDF, achieving higher active metabolite concentrations in peripheral blood mononuclear lymphocytes and lymphatic tissues[39].

Inside cells, TAF is initially hydrolyzed to the intermediate tenofovir-alanine conjugate (TFV-Ala). TFV-Ala is converted to the parent tenofovir, which then undergoes subsequent phosphorylations to yield the active tenofovir diphosphate (TFV-DP) metabolite[40]. TFV-DP inhibits the activity of HIV reverse transcriptase by competing with natural substrates and causing DNA chain termination after incorporation into viral DNA[41]. TAF is being studied for the treatment of HIV infection, and is a potent inhibitor of hepatitis B virus. A phase I study to evaluate the safety and efficacy of TAF compared with that of TDF in treatment-naive and experienced adult subjects with chronic hepatitis B virus infection is currently recruiting participants (ClinicalTrials.gov Identifier: NCT01940341).
替诺福韦Alafenamide（GS-7340）：伴有无环核苷酸膦酸盐是目前在临床开发，以提高口服利用度，提高了抗病毒活性，并降低肾毒性的潜在的目标。替诺福韦alafenamide（TAF;以前GS-7340）是前体药物TDF，并实现在外周血单核细胞和淋巴组织[39]高活性代谢产物浓度。

在细胞内，TAF最初被水解成中间丙氨酸共轭替诺福韦（TFV-丙氨酸）。 TFV-丙氨酸转化为母体替诺福韦，其中然后进行后续的磷酸化物，得到活性替诺福韦二磷酸（TFV-DP）的代谢产物[40]。 TFV-DP通过与天然底物竞争，引起DNA链终止后掺入到病毒DNA[41]抑制HIV逆转录酶的活性。 TAF正在研究艾滋病毒感染的治疗，是乙肝病毒的强效抑制剂。 I期研究，以评估TAF的安全性和有效性比较了在治疗过的和经验丰富的成年人患有慢性B型肝炎病毒的感染，华盈目前正在招募参与者（ClinicalTrials.gov标识符：NCT01940341​​）。

CMX157: is another investigational prodrug of tenofovir that is currently undergoing a phase I clinical study. CMX157 is a hexadecyloxypropyl conjugate of tenofovir with antiviral activity against HIV and HBV. In vitro, CMX157 is 267-fold more active than tenofovir against HIV-1 and 4.5-fold more active against HBV. CMX157 is orally bioavailable and has no toxicity in rats treated for 7 d at doses ranging from 10 to 100 mg/kg per day[42].

A phase I study to evaluate the safety, tolerability, and pharmacokinetics of a single dose of CMX157 in healthy volunteers has been completed (ClinicalTrials.gov Identifier: NCT01080820). Both TAF and CMX157 represent second-generation tenofovir analogues which may have an improved clinical profile.
CMX157：替诺福韦是另一种研究性药物前体，目前正在进行I期临床研究。 CMX157是替诺福韦的十六烷结合物与抗HIV和HBV抗病毒活性。在体外，CMX157是267倍，比黑莓替诺福韦抗HIV-1活性和抗HBV4.5倍黑莓活跃。 CMX157是口服生物利用度和对大鼠没有毒性的剂量范围为10至100毫克/千克每天[42]治疗7天。

I期研究，以评估安全性，耐受性和单剂量CMX157在健康志愿者的药代动力学已经完成（ClinicalTrials.gov标识符：NCT01080820）了。既TAF和CMX157代表第二代类似物替诺福韦可具有改善的临床信息。

AGX-1009: is a novel patented prodrug of tenofovir but is activated by a different molecular side-chain. Ongoing preclinical studies demonstrate good efficacy in inhibiting viral replication, and phase I trials are planned for 2013 in China.
AGX-1009：替诺福韦是一种获得专利的新型药物前体，而是由不同的分子侧链激活。正在进行临床前研究表明在抑制病毒复制的疗效好，并计划I期临床试验于2013年在中国。

StephenW

Inhibitor of viral entry

Myrcludex-B: Specific inhibition of virus entry represents a rather new and attractive therapeutic concept for controlling acute and chronic infections. The establishment of the HBV-susceptible cell line HepaRG[43] and systems based on primary human hepatocytes and primary Tupaia belangeri hepatocytes have facilitated investigations of the cellular and viral determinants involved in HBV entry and resulted in the discovery of envelope protein-derived entry inhibitors. Both genetic and functional examination identified one domain in the N-terminusof HBV preS1 (amino acids 1-47) that is essential for HBV and hepatitis delta virus (HDV) infectivity.

Myrcludex-B, a synthetic lipopeptide consisting of the authentically myristoylated N-terminal 47 amino acids of the preS1 domain of the large viral envelope protein (L protein), specifically targets hepatocytes and efficiently blocks de novo HBV infection both in vitro[9,44-46], and in vivo[47]. Humanized chimeric uPA mice were first injected with HBV to permit an initial infection establishment, followed by administration of Myrcludex-B for either 3 d, 3 wk or 8 wk post-HBV inoculation. Myrcludex-B not only prevented the spread of HBV from infected human hepatocytes in vivo; but also hindered amplification of the cccDNA pool in initially infected hepatocytes[48]. A phase 0/1 clinical study to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of single ascending doses of Myrcludex-B in healthy volunteers is ongoing[49]. The data to date have shown Myrcludex-B to be very well tolerated in healthy volunteers for all investigated doses of up to 5 mg intravenous (iv) injection and 0.8 mg subcutaneous (sc) injection.

The entry inhibitor Myrcludex-B has been shown to prevent de novo establishment of HDV infection in vitro[50]. Furthermore, in a successfully established uPA/SCID mice model of HBV/HDV coinfection and superinfection, preclinical antiviral evaluations of the efficacy of Myrcludex-B in inhibiting the establishment of de novo HDV infection in vivo were performed[51].

Currently, the potential role of viral peptide-derived lipoproteins is primarily preventative and limited to post-exposure prophylaxis, the prevention of vertical transmission, and graft reinfection after liver transplant

抑制病毒进入的

Myrcludex-B：病毒进入的特异性抑制代表一个相当新的，有吸引力的治疗理念，为控制急性和慢性感染。乙型肝炎病毒易感的HepaRG细胞系[43]和系统的基础上的原代人肝细胞和初级树鼩肝建立了便利涉及式HBV条目的细胞和病毒决定簇的调查结果中的包膜蛋白衍生的侵入抑制剂的发现。遗传和功能检查中的N terminusof乙肝病毒前S1（氨基酸1-47），这是必不可少的乙肝病毒和丁型肝炎病毒（HDV）感染确定了一个域名。

Myrcludex-B，合成的脂肽真实肉豆蔻组成的大的病毒包膜蛋白（L蛋白）的前S1结构域的N-末端47个氨基酸，特别是针对肝细胞和有效块的从头HBV感染在体外[9,44 -46]和体内[47]。人性化的uPA嵌合体小鼠先注射乙肝病毒感染允许的初步建立，后跟Myrcludex-B3天，3周或8周后接种乙肝管理。 Myrcludex-B不仅阻止乙肝病毒的传播从体内被感染的人类肝细胞;但也阻碍了最初感染的肝细胞[48]中的cccDNA池的扩增。 A相0/1的临床研究，以评估在健康志愿者单剂量递增Myrcludex-B的安全性，耐受性，药代动力学和免疫原性正在进行中。[49]数据以日期显示Myrcludex-B被很好的耐受性在健康志愿者中对所有研究的剂量达到5毫克静脉内（IV）注射和0.8毫克皮下（SC）注射。

在进入抑制剂Myrcludex-B已被证明有助于预防从头建立HDV感染体外[50]。此外，在成功建立的uPA/ SCID小鼠的HBV/ HDV同时感染和重叠，抗病毒药Myrcludex-B的功效的抑制建立从头HDV感染的体内临床前评价模型，进行[51]。

目前，病毒肽衍生的脂蛋白中的潜在作用主要限于预防性和暴露后预防，防止垂直传播和接枝再感染肝移植后

StephenW

Inhibitor of nucleocapsid formation
抑制剂形成核衣壳
Heteroaryldihydropyrimidines: The HBV capsid plays an indispensable role in the virus life cycle, participating in genome packaging, reverse transcription, intracellular trafficking, and maintenance of a stable infection. HBcAg serves as the structural unit in the assembly of the viral nucleocapsid, leading to nucleocapsid formation through a process of self-assembly. Perturbing HBV assembly, and thereby altering either the timing or the geometry of capsid formation, has great potential as an antiviral strategy. Recently, heteroaryldihydropyrimidines (HAPs), a family of assembly effectors, have been identified as highly potent non-nucleosidic inhibitors of HBV replication in vitro and in vivo[52-55]. HAPs act as allosteric effectors to increase the kinetics of assembly and strengthen dimer-dimer association to prevent the proper formation of viral capsids. Additionally, at high concentrations, HAPs misdirect viral assembly[56].

Bay 41-4109, a member of the HAP family, inhibits HBV replication by inducing inappropriate assembly and an aberrant transition to yield virus particles no longer competent for reverse transcription, budding, and/or nuclear transport[57]. In a humanized uPA/SCID HBV mouse model, a decrease in the HBV viral load of approximately 1 log (10) copies/mL was observed after treatment with Bay41-4109 for 5 d. Viral rebound was observed within 5 d of treatment cessation. A phase I study is ongoing, but no clinical results have been reported to date.
Heteroaryldihydropyrimidines：在乙肝病毒衣壳起在病毒生命周期中不可或缺的角色，参与基因组包装，逆转录稳定感染，细胞内运输和维护。核心抗原作为在病毒衣壳的组装的结构单元，从而通过自组装的一个过程，以核衣壳的形成。扰动乙肝病毒装配和从而改变无论是时间或衣壳形成的几何形状，具有很大的潜力作为一种抗病毒策略。近日，heteroaryldihydropyrimidines（HAPS），家庭组装的效应，已被确定为HBV复制的体外高度有效的非核苷抑制剂和体内的[52-55]。有害空气污染物作为变构效应来提高装配的动力学和加强二聚体二聚体的关联，以防止正常形成病毒衣壳的。此外，在高浓度，有害空气污染物误导病毒组装[56]。

托架41-4109中，HAP家族的一员，通过诱导不适当的装配和一个异常的过渡，以产生病毒粒子不再主管用于逆转录，萌芽和/或核运输[57]抑制病毒复制。在人性化的uPA/ SCID小鼠模型乙肝，乙肝病毒的病毒载量下降约1日志（10）拷贝/ mL的治疗后观察Bay41-4109为5天。病毒反弹，观察在5天的治疗停止。我研究了阶段正在进行，但无临床结果已经报告的日期。


GLS4, a small molecular compound that inhibits HBV replication, is also a member of the HAP family. It is a potent inhibitor of the replication of both wild-type and ADV-resistant HBV mutant strains in vitro[58]. GLS4 is currently undergoing a phase I study in China to evaluate its safety, tolerability, and pharmacokinetics, and it exhibits good pharmacological behavior and tolerance. These inhibitors have a potential role as part of future therapeutic regimens against chronic HBV due to their specific mechanisms of action.
GLS4，抑制乙肝病毒复制的小分子化合物，也是HAP家族的一员。它是野生型和阿德福韦耐药HBV突变株的复制的体外[58]的强效抑制剂。 GLS4目前正在进行I期研究在中国，以评估其安全性，耐受性和药代动力学阶段，并表现出良好的行为和药物耐受性。这些抑制剂有作为对慢性HBV未来的治疗方案组成部分的潜在作用，以行动两项具体他们的机制。


Phenylpropenamides: Molecules of the phenylpropenamide family of compounds, AT-61 and AT-130, have been shown to inhibit HBV replication in vitro[59,60]. These compounds are specific to HBV and have no activity against related viruses such as duck HBV, woodchuck HBV, and human immunodeficiency virus type 1 (HIV-1). Both AT-61 and AT-130 were found to be active against LMV-resistant HBV mutants. Studies with these compounds have shown that the phenylpropenamides appears to effectively inhibit HBV replication by interfering with the encapsidation process at the level of pregenomic RNA encapsidation, producing apparently normal capsids that lacked genetic material[61]. Subsequent studies revealed an assembly effector mechanism underlying the apparent blocking of RNA packaging[62]. Unlike HAPs, the effects of the phenylpropenamides are almost entirely kinetic, affecting only assembly reaction rate and timing while still producing normal capsids, with very little thermodynamic effects on capsid stability. Although this class of compounds has a favorable toxicity profile, clinical trials are still required.
Phenylpropenamides：化合物的phenylpropenamide家族的分子，AT-61和AT-130，已被证明能抑制乙型肝炎病毒复制的影响[59,60]。这些化合物所特有的具有抗乙肝病毒及相关病毒没有活性：如鸭乙肝病毒，乙肝病毒土拨鼠，与人类免疫缺陷病毒1型（HIV-1）。两个AT-61和AT-130被认为是有效对抗LMV耐药HBV突变体。有研究，这些化合物显示，似乎与在前基因组RNA的衣壳化水平的壳体化过程中的干扰，从而产生明显正常的衣壳有效抑制乙肝病毒复制的phenylpropenamides缺乏这种基因材料[61]。随后的研究发现组装的效应机制的RNA包装[62]的明显阻塞基础。不像有害空气污染物的phenylpropenamides的效果几乎完全是动能，影响只装配反应速率和定时，同时仍然产生正常的衣壳，与衣壳的稳定性非常小的热力学效果。虽然这类化合物具有良好的毒性特征，临床试验仍然需要。

StephenW

Inhibitor of HBsAg release

REP 9 AC: Phosphorothioated oligonucleotides (PS-ONs), a novel class of compounds, constitute a promising microbicide approach. Early studies indicated the antiviral activity of PS-ONs to be independent of antisense activity but specifically dependent on their amphipathic characteristic[63]. Thus, PS-ONs with sequence-independent antiviral activity were describedas amphipathic DNA polymers (APs). APs possess broad spectrum antiviral activity, via multiple mechanisms, against a range of viruses, including human HIV-1[64], herpes simplex virus[65-67], arenavirus lymphocytic choriomeningitis virus[68], and hepatitis C virus (HCV)[69].

REP 9 AC is a 40-nucleotide polycytidine (alternating adenosine) amphipathic DNA polymer that inhibits the release of HBsAg from infected hepatocytes in HBV infected patients and allows patients to regain durable immunity by eliminating HBsAg-mediated immunosuppression. This agent is currently in a phase I/II clinical trial. The safety and efficacy of REP 9 AC in 8 HBsAg+ patients with HBV DNA levels of 6-12 log10 copies/ml were evaluated[70]. Interim clinical data demonstrated that REP 9AC led to rapid clearance of HBsAg from the serum and development of anti-HBs in as early as 7 d and in no more than 32 wk. Seven of the 8 treated patients exhibited residual to no levels of serum HBsAg and developed anti-HBs. Three of these 7 patients demonstrated durable immunological control over their infections, as evidenced by substantial reductions in serum HBV DNA within 20-27 wk of treatment. REP 9 AC, a modification of REP 9 AC to reduce pro-inflammatory activity and improve compound stability, shows similar efficacy with respect to HBsAg clearance and HBV DNA suppression with no pro-inflammatory side effects[71]. These results suggest that APs may become an important new tool in the treatment of CHB

抑制乙肝表面抗原的释放

REP9交流：硫化磷酸酯寡核苷酸（PS-ONS），一类新的化合物，构成了一个充满希望的杀微生物剂的方法。早期的研究表明PS-寡核苷酸的抗病毒活性是独立的反义活性的，但依赖具体地在它们的两亲特性[63]。因此，PS项与顺序无关的抗病毒活性是describedas两亲性聚合物的DNA（APS）。接入点具有广谱抗病毒活性，通过多种机制，针对各种病毒，包括人类HIV-1[64]，疱疹病毒[65-67]，沙粒病毒淋巴细胞性脉络丛脑膜炎病毒[68]，和丙型肝炎病毒（HCV） [69]。

REP9的AC为40个核苷酸的polycytidine（交替腺苷）两亲性聚合物的DNA抑制乙肝表面抗原的释放，从受感染的肝细胞中的乙肝病毒感染者和病人允许通过消除乙肝表面抗原介导的免疫抑制重拾持久免疫力。目前这个代理是在I / II期临床试验。众议员9 AC在8乙肝表面抗原阳性患者以6.12 log10拷贝/ ml的HBV DNA水平的安全性和有效性进行了评估[70]。中期临床数据表明，REP9AC导致快速清除HBsAg的血清和抗-HBs抗体的发展中，早在第7天，并在不超过32周。 8例患者处理过七证物血清HBsAg无残留水平和开发抗HBs。这三个7例患者中表现出持久的免疫控制他们的感染，就证明了在血清HBV DNA大幅削减在20-27周的治疗。 REP9交流，REP9交流的变型，以减少促炎活性和稳定性提高的化合物，示出了相对于HBsAg和HBV DNA的抑制的间隙，没有促炎副作用[71]相似的功效。这些结果表明，受影响可能成为慢性乙型肝炎的治疗的一个重要的新工具

StephenW

Small molecules

Nitazoxanide (alinia): Nitazoxanide, a thiazolide anti-infective agent, is active against anaerobic bacteria, protozoa, and a range of viruses in cell culture models, and it is currently in phase II clinical development for the treatment of chronic hepatitis C. Nitazoxanide was approved by the United States Food and Drug Administration in 2002 for treating diarrhea caused by Cryptosporidium spp. or Giardia lamblia in adults and children as young as 12 mo[72].

The antiviral activity of nitazoxanide was discovered by serendipity when patients with AIDS and HBV or HCV co-infection were treated for diarrhea. Nitazoxanide is potent inhibitor of HBV and displays synergistic interactions with LMV or ADV against HBV in vitro. Nitazoxanide is also effective against HBV mutants that are resistant to lamivudine and adefovir[73]. In preliminary open-label studies, nitazoxanide alone has shown evidence of efficacy in the treatment of CHB over 1-year course of therapy[74]. Nitazoxanide 500 mg twice daily resulted in a decrease in serum HBV DNA in all 4 HBeAg-positive patients, with undetectable HBV DNA in 2 of the 4 patients, loss of HBeAg in 3 patients, and loss of HBsAg in 1 patient. Nitazoxanide and related agents represent a class of small molecules that modulate host antiviral pathways via protein kinase activation, thereby acting as interferon immune enhancers[75].

Phase II clinical trials have demonstrated the efficacy and safety of nitazoxanide added to peginterferon with or without ribavirin in treating patients with chronic hepatitis C. Multiple clinical trials of nitazoxanide for treating chronic hepatitis C are underway or have been completed; however, no trials of this drug for treating CHB are currently registered with ClinicalTrials.gov.

小分子

硝唑尼特（alinia）：硝唑尼特一个thiazolide抗感染剂，有效防止厌氧菌，原虫，以及一系列的细胞培养模型的病毒，它是目前在II期临床开发用于治疗慢性丙型肝炎硝唑尼特治疗在2002年批准了美国食品和药物管理局用于治疗腹泻由隐孢子虫引起的。和贾第鞭毛虫在成人和儿童年仅12个月[72]。

硝唑尼特的抗病毒活性是通过偶然发现当艾滋病患者和HBV或HCV合并感染患者治疗腹泻。硝唑尼特是HBV和显示器用LMV或ADV体外协同作用对HBV有效的抑制剂。此外硝唑尼特是有效的抗HBV突变株耐拉米夫定是和阿德福韦酯[73]。在初步的开放标签研究中，单独硝唑尼特已经表明疗效的证据，慢性乙型肝炎的治疗超过10年，当然治疗[74]。硝唑尼特500毫克，每天两次导致了血清HBV DNA下降在所有4个HBeAg阳性患者中，有1例患者检测不到HBV DNA的24例，HBeAg阳性3例损耗，损耗的HBsAg。硝唑尼特和相关代理商代表了一类能调节主机通过蛋白激酶活化的抗病毒途径的小分子，干扰素从而作为免疫促进剂[75]。

II期临床试验已经证明的有效性和硝唑尼特的安全添加聚乙二醇干扰素有或无利巴韦林治疗的患者硝唑尼特的慢性丙型肝炎的多个临床试验，用于治疗慢性丙型肝炎正在进行或已完成已;然而，用于治疗慢性乙型肝炎没有试验这种药物目前正与ClinicalTrials.gov注册。

StephenW

Immune-based therapies

Zadaxin: Zadaxin (thymosin alpha 1), a synthetic peptide of 28 amino acids, is a substance found naturally in the circulation and produced in the body’s thymus gland. Zadaxin has been evaluated for its immunomodulatory activities and related therapeutic potential in several conditions and diseases, including cancer (such as HCC, lung cancer, and melanoma) and infectious disease (sepsis, infections after bone marrow transplant, lung infections including chronic obstructive pulmonary disorder (COPD), SARS, hepatitis B or C, and HIV). Investigation of Zadaxin’s mechanism of action at the cellular level has revealed both immune-modulating and direct-acting effects.

Interest in using Zadaxin for treating CHB has been based on the drug’s immunomodulating effects, which can trigger lymphocyte maturation, augment T-cell function, and reconstitute immune defects.

A study revealed that Zadaxin added to lamivudine was not superior to lamivudine alone and did not prevent resistance to lamivudine despite increased HBeAg seroconversion[82]. The data from a meta-analysis showed that, compared with IFN-α, the benefit of thymosin alpha-1 was not immediately significant at the end of therapy but that the virological, biochemical, and complete response had a tendency to increase or accumulate gradually after the therapy[83]. No persuasive data have yet emerged to suggest a great potential for Zadaxin.

NOV-205 (BAM 205): NOV-205 acts as a hepatoprotective agent with immunomodulating and anti-inflammatory properties and, thus, likely requires treatment periods longer than 14 d to affect a clinical response. Its regulatory approval in the Russian Federation under the trade name Molixan® in 2001 was based on clinical studies in 178 Russian hepatitis B and C patients. When used as mono-therapy for 1 mo in hepatitis B and for 2 mo in hepatitis C patients, NOV-205 has been shown to greatly reduce/eliminate viral loads and to significantly improve liver function. NOV-205 was also well-tolerated in those studies.

GS 9620: Toll-like receptors (TLRs) are components of the innate immune system and serve as a first line of defense against invading pathogens. TLR activation could represent a powerful and novel therapeutic strategy for the treatment of chronic HBV infection[84]. GS-9620, a potent selective TLR-7 agonist, was designed to have rapid clearance and low systemic levels after oral administration. In chimpanzees chronically infected with HBV, the effects of immune activation have been investigated using GS-9620 administered 3 times each week for 4 wk at 1 mg/kg and a 1-wk rest period, for a second cycle of 4 wk at 2 mg/kg[85]. A detailed evaluation was performed that included an assessment of the pharmacokinetics of GS-9620, viral load, IFN-stimulated gene (ISG) expression, cytokine and chemokine levels, and lymphocyte and NK cell activation, as well as safety and tolerability parameters. Short term administration of GS-9620 provided long-term suppression of serum and liver HBV DNA. Serum levels of HBsAg and HBeAg, as well as numbers of HBV antigen-positive hepatocytes, were reduced as hepatocyte apoptosis increased. In parallel, GS-9620 administration induced the production of IFN-α and other cytokines and chemokines, up-regulated ISGs expression, and activated NK-cell and lymphocyte subsets, confirming the activation of TLR-7 signaling.

The safety, tolerability, pharmacokinetics and pharmacodynamics of GS-9620 in 75 healthy volunteers were evaluated with a single ascending-dose up to 12 mg. GS-9620 demonstrated safety and pharmacodynamic activity at doses up to 12 mg and induced an antiviral response before systemic adverse events were observed[86].

The novel approach inhibiting HBV replication and inducing infected cell clearance represents a step toward the development of a true combination therapy for CHB.

GI-13020: HBV-specific T cell responses have been shown to have a positive association with infectious status in patients with chronic HBV, with the weakest T cell responses observed in patients with untreated chronic active infection and the strongest T cell responses observed in patients who have achieved seroconversion or cure. GI-13020 is a recombinant yeast-based biological product engineered to express a chimera of HBV X, S, and C antigens. GI-13020 is immunogenic in murine models and has also been used to stimulate human immune cell samples ex vivo to elicit HBV specific T cell responses, which could predict the immune responses in patients dosed with GI-13020.

A phase Ia trial assessing the safety, tolerability, and ability to elicit HBV-specific T cell responses of GI-13020 at various doses and with various regimens in healthy adults is ongoing but is not recruiting participants (ClinicalTrials.gov Identifier: NCT01779505). In the future, GI-13020 could be used in combination with HBV antivirals in an attempt to improve HBsAg seroconversion rates in patients with chronic HBV infection.

DV-601: Therapeutic vaccines may promote the resolution of chronic HBV infection through the stimulation of specific cytotoxic T-lymphocyte and B-cell antibody responses against dominant HBV-antigens. DV-601, which comprises recombinant HBsAg and HBcAg, is an investigational therapeutic vaccine. A phase Ib dose-escalation study has been completed to determine whether DV-601 would be well-tolerated and induce HBV-specific virological and immunological responses in CHB patients undergoing concurrent treatment with a nucleoside analogue (ClinicalTrials.gov, Identifier: NCT01023230).

In this initial dose-escalation study of DV-601, 6 injections of DV-601 were administered over a period of 12 wk. The primary objective was to assess the safety and tolerability of DV-601 by evaluating local and systemic adverse events on Day 99, including changes in laboratory analyses. Secondary objectives were to evaluate the virological response and immunogenicity of DV-601 based on viral load, and humoral and T cell immunological responses. DV-601 appears to be a safe and well-tolerated therapeutic vaccine for the treatment of CHB, and virological response is evident[87].