A Phase 2a Randomized, Double-blinded, Placebo-controlled, Multi Center, Dose Ranging Study of the Safety and Efficacy of ATI-2173 and Vebicorvir in Combination With Tenofovir Disoproxil Fumarate in Subjects With Chronic Hepatitis B Virus Infection

This is a randomized, double-blinded, placebo-controlled, multi center, dose ranging study of safety and efficacy in volunteers with chronic hepatitis B virus infection. Volunteers will be administered multiple oral doses of ATI-2173 vebicorvir in combination with tenofovir disoproxil fumarate and assessed for safety and efficacy including blood tests to show how the body metabolizes and eliminates the investigational drug as well as how the drug effects the virus infection.

开始日期2022-04-11

申办/合作机构

Antios Therapeutics, Inc.初创企业

EUCTR2020-005766-34-BG / Unknown status临床2期

A Randomized Phase 2a, Multicenter, Open-Label, Multiple-Cohort Study Evaluating Regimens Containing Vebicorvir in Subjects with Chronic Hepatitis B Virus Infection

开始日期2021-07-22

申办/合作机构

Assembly Biosciences, Inc.

NCT04820686 / Terminated临床2期

A Randomized Phase 2a, Multicenter, Open-Label, Multiple-Cohort Study Evaluating Regimens Containing Vebicorvir in Subjects With Chronic Hepatitis B Virus Infection

The purpose of this study is to determine if vebicorvir (VBR, ABI-H0731) in combination with AB-729 is safe and effective in participants with chronic hepatitis B infection (cHBV) receiving a standard of care nucleos(t)ide/reverse transcriptase inhibitor (SOC NrtI).

开始日期2021-05-07

申办/合作机构

Assembly Biosciences, Inc.

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100 项与 Vebicorvir 相关的临床结果

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100 项与 Vebicorvir 相关的转化医学

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100 项与 Vebicorvir 相关的专利（医药）

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项与 Vebicorvir 相关的文献（医药）

2024-04-01·JHEP reports : innovation in hepatology

Long-term open-label vebicorvir for chronic HBV infection: Safety and off-treatment responses

Article

作者: Weilert, Frank ; Bonacini, Maurizio ; Schiff, Eugene R ; Nguyen, Tuan T ; Han, Steven-Huy ; Agarwal, Kosh ; Gane, Edward J ; Kwo, Paul Yien ; Bennett, Michael ; Stamm, Luisa M ; Hassanein, Tarek ; Fung, Scott ; Hann, Hie-Won ; Ayoub, Walid S ; Yuen, Man-Fung ; Ma, Julie ; Ramji, Alnoor ; Zomorodi, Katie ; Ravendhran, Natarajan ; Sulkowski, Mark S ; Park, James S ; Chan, Sing ; Ma, Xiaoli ; Jacobson, Ira M ; Dieterich, Douglas T ; Nahass, Ronald G ; Bae, Ho S ; Lalezari, Jacob ; Knox, Steven J ; Elkhashab, Magdy ; Yan, Ran

Background & Aims:

The investigational first-generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open-label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs).

Methods:

Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171). After receiving VBR + NrtI for ≥52 weeks, stopping criteria (based on the treatment history and hepatitis B e antigen status in the parent studies) were applied, and patients either discontinued both VBR + NrtI, discontinued VBR only, or continued both VBR + NrtI. The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at 24 weeks off treatment.

Results:

Ninety-two patients entered the extension study and received VBR + NrtI. Long-term VBR + NrtI treatment led to continued suppression of HBV nucleic acids and, to a lesser extent, HBV antigens. Forty-three patients met criteria to discontinue VBR + NrtI, with no patients achieving the primary endpoint; the majority of virologic rebound occurred ≥4 weeks off treatment. Treatment was generally well tolerated, with few discontinuations due to adverse events (AEs). There were no deaths. Most AEs and laboratory abnormalities were related to elevations in alanine aminotransferase and occurred during the off-treatment or NrtI-restart phases. No drug-drug interactions between VBR + NrtI and no cases of treatment-emergent resistance among patients who adhered to treatment were observed.

Conclusions:

Long-term VBR + NrtI was safe and resulted in continued reductions in HBV nucleic acids following completion of the 24-week parent studies. Following treatment discontinuation, virologic relapse was observed in all patients. This first-generation core inhibitor administered with NrtI for at least 52 weeks was not sufficient for HBV cure.

Clinical trial number:

NCT03780543.

Impact and implications:

Approved treatments for chronic hepatitis B virus infection (cHBV) suppress viral replication, but viral rebound is almost always observed after treatment discontinuation, highlighting an unmet need for improved therapies with finite treatment duration producing greater therapeutic responses that can be sustained off treatment. First-generation core inhibitors, such as vebicorvir, have mechanisms of action orthogonal to standard-of-care therapies that deeply suppress HBV viral replication during treatment; however, to date, durable virologic responses have not been observed after treatment discontinuation. The results reported here will help researchers with the design and interpretation of future studies investigating core inhibitors as possible components of finite treatment regimens for patients with cHBV. It is possible that next-generation core inhibitors with enhanced potency may produce deeper and more durable antiviral activity than first-generation agents, including vebicorvir.

2023-04-06·Antibiotics (Basel, Switzerland)

Fast and Sensitive Method for Simultaneous Quantification of Meropenem and Vaborbactam in Human Plasma Microsamples by Liquid Chromatography-Tandem Mass Spectrometry for Therapeutic Drug Monitoring.

Article

作者: Conti, Matteo ; Giorgi, Beatrice ; Barone, Rossella ; Cojutti, Pier Giorgio ; Viale, Pierluigi ; Pea, Federico ; Gatti, Milo

Meropenem (MRP)-Vaborbactam (VBR) is a novel beta-lactam/beta-lactamase inhibitor used for the management of difficult-to-treat Gram-negative infections. Among critically ill patients, MRP-VBR shows remarkable inter-individual variability in pharmacokinetic behavior, thus justifying the implementation of therapeutic drug monitoring (TDM) for improving real-time management in different challenging scenarios. In this study, we developed and validated a fast and sensitive Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) method for the simultaneous quantification of MRP and VBR in human plasma microsamples of 3 microliters. The analysis required only a single-step sample preparation and was performed by means of a fast chromatographic run of 4 min, followed by positive electrospray ionization and detection on a high-sensitivity triple quadrupole tandem mass spectrometer operated in multiple reaction monitoring modes. The straightforward analytical procedure was successfully validated, based on the EMA guidelines, in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, the limit of quantification, and stability. The novel method was successfully applied for simultaneously measuring MRP and VBR concentrations in more than 42 plasma samples collected from critically ill patients affected by carbapenem-resistant Gram-negative bacteria infections.

2022-11-01·Journal of hepatology

Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection

Article

作者: Ayoub, Walid S ; Hann, Hie-Won L ; Nguyen, Tuan T ; Hassanein, Tarek ; Evanchik, Marc ; Weilert, Frank ; Alves, Katia ; Ma, Julie ; Chan, Sing ; Lalezari, Jacob P ; Ramji, Alnoor ; Knox, Steven J ; Yuen, Man-Fung ; Gane, Edward J ; Schiff, Eugene R ; Agarwal, Kosh ; Bae, Ho S ; Bonacini, Maurizio ; Lopatin, Uri ; Han, Steven-Huy B ; Park, James S ; Elkhashab, Magdy ; Kwo, Paul Yien ; Ma, Xiaoli ; Huang, Qi ; Ravendhran, Natarajan ; Stamm, Luisa M ; Jacobson, Ira M ; Nahass, Ronald G ; Fung, Scott K ; Colonno, Richard ; Bennett, Michael ; Sulkowski, Mark S ; Yan, Ran ; Dieterich, Douglas T

BACKGROUND & AIMS:

Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV.

METHODS:

HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log₁₀ HBV DNA from Baseline to Week 12 and 24.

RESULTS:

All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log₁₀ IU/ml HBV DNA (-4.45 [1.03]) vs. PBO+ETV (-3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log₁₀ IU/ml HBV DNA (-5.33 [1.59]) vs. PBO+ETV (-4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury.

CONCLUSIONS:

In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile.

CLINICAL TRIAL NUMBER:

NCT03577171 LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.

项与 Vebicorvir 相关的新闻（医药）

2024-08-14

·药渡

国产First in class横空出世

8月12日早，广生堂发布公告：公司宣布完成乙肝治疗创新药GST-HG141慢性乙型肝炎低病毒血症二期临床试验并取得积极临床结果，将支持GST-HG141进一步开展三期确证性临床试验。据公司公告称，GST-HG141具有与在市一线乙肝抗病毒药物不同的作用机制，属于全球领先的潜在First-in-class项目，有望成为全球口服乙肝抗病毒治疗里程碑式的创新药。受该消息影响，广生堂当日收涨20%，不过随后在第二交易日迅速回落，并未延续“类香雪制药”的走势。尽管广生堂未能给部分投资者带来短期持续的赚钱效应，但GST-HG141这类创新机制的药物潜力以及乙肝药物市场，仍然值得深度探讨与分析的价值。 01 乙肝治愈的难题无论是国内还是全球范围内，治愈乙肝的需求存在巨大缺口。数据显示，全球受乙肝和丙肝影响的有3.25亿人，每年导致140万人死亡。据估算，中国乙肝病毒感染者约8600万人，每年约33万人死于乙肝或丙肝感染导致的肝硬化和原发性肝癌，中国乙肝表面抗原携带者人数是全球最多。慢性乙型肝炎患者如果不积极治疗发生肝硬化、肝癌的风险较高。长期抗乙肝病毒治疗可以阻止肝脏炎症，减轻甚至逆转慢性乙型肝炎引起的肝纤维化。而抗乙肝病毒治疗在临床上有三个治疗里程碑：部分治愈、功能性治愈、彻底治愈（区别如下）。功能性治愈和完全彻底治愈区别在于，功能性治愈未能清除肝内共价闭合环状的DNA和整合基因组的HBV DNA，功能性治愈是经过一段时间的治疗后患者的免疫系统足以压制乙肝病毒，也能安全停药，肝损伤恢复，肝癌风险降到最低。而功能性治愈，不同于彻底治愈的完全清除掉乙肝病毒，由于乙肝病毒仍然存在，随着患者免疫力下降，仍有复发的可能，所以实现乙肝功能性治愈的药物不存在像吉利德推出的丙肝特效药Sovaldi把大部分病人都彻底治愈且治疗市场萎缩的情况，另一方面现有的技术也无法短时间实现乙肝的彻底治愈。目前国内一线抗乙肝病毒治疗药物有两大类，分别为干扰素和核苷（酸）类似物，这两类药物优缺点都比较明显：干扰素是较强的免疫调节剂，既具有抗病毒作用，又具有抗纤维化作用，其优点在于疗程相对固定、疗效相对持久、耐药变异较少；缺点是需要注射给药，不良反应较明显，不适于肝功能失代偿者。高效的一线核苷药物够将病毒载量抑制到无法检测的水平。然而一旦治疗停止，绝大多数患者会出现病毒反弹，因此需要接受终身治疗。最核心的痛点是，这两类药物均无法在短期内清除乙肝病毒，并且治愈率较低（3%-7%），多数患者需终身服药抑制HBV的复制，防止病毒对肝脏造成损害。市场急需一款能够实现HBV功能性治愈的新型药物，患者余生中可免于服用HBV药物，并显著降低罹患肝硬化及肝癌风险，这无论是社会价值还是经济价值，都十分巨大。 02 广生堂的GST-HG141 乙肝之所以难治，核心在于HBV病毒会通过肝细胞膜上NTCP作为受体进入并感染肝细胞，在其中建立其基因组，即具有染色体特征的共价闭合环状DNA（cccDNA），同时HBV病毒还可能将编码表面抗原的部分基因片段至宿主肝细胞基因组中，这两个部分很难被靶向和清除。现有药物多针对HBV病毒生命周期的其中一环，比如控制病毒复制，但大多不足以根除cccDNA。不同于现有的干扰素、核苷酸药物，广生堂的GST-HG141是一种乙肝核心蛋白（HBcAg）抑制剂（也可称I类MOA核衣壳抑制剂）。这里就不得不提乙肝病毒的特点，HBV是一种有包膜的病毒，包膜由乙肝病毒核衣壳的3种病毒表面蛋白LHBs、MHBs和SHBs组成；而核衣壳则是由HBV核心蛋白控制形成，HBV核心蛋白是一种对HBV生命周期至关重要的多功能蛋白，如果核衣壳的组装和功能受到干扰，可能影响HBV DNA的复制，严重削弱子代病毒的毒性和再次侵染能力，因此具有抗病毒作用。显而易见，GST-HG141是一种病毒核衣壳组装抑制剂（CpAM）。这类CpAM又细分为两类抑制剂，一类是诱导异常核心结构的形成的II类MOA，另一类是诱导形成形态完整但病毒核酸缺失的衣壳的I类MOA。 GST-HG141是典型的I类MOA核衣壳抑制剂，从发挥作用机理便能看出： 1）当HBV在肝细胞核孔进行脱壳时，该分子可以附着在HBV表面来稳定病毒衣壳结构抑制HBV脱壳，阻止HBV DNA进入肝细胞核产生出cccDNA并削减cccDNA储备池，阻止cccDNA转录出多种mRNA并续贯复制出三种主要抗原； 2）该分子具备强于核酸的亲合力，在子代HBV组装时诱导病毒衣壳蛋白不依赖于子代HBV-DNA发生自发组装，大量形成不包含子代HBV-DNA的空泡病毒，从而隔绝子代病毒复制能力。从已有的疗效数据看，GST-HG141的疗效和安全性遵循其作为I类MOA核衣壳抑制剂的作用机理： EASL 2022公布的GST-HG141多递增剂量治疗慢性乙肝的1b期临床研究数据显示：25、50和100mg队列均（BID给药）观察到了血清HBV DNA迅速而强劲地下降，血清pgRNA也有显著下降，未观察到病毒学突破；PK方面，血浆GST-HG141暴露几乎与剂量成正比增加。安全性方面，三个队列的患者耐受性良好，未见剂量相关性不良反应，未发生3级以上不良反应，未发生SAE。据广生堂公告的GST-HG141最新公布的慢性乙型肝炎低病毒血症二期临床数据（90 例患者）显示：不同剂量GST-HG141均表现出明显的HBV DNA抑制效果，GST-HG141联合核苷类似物连续治疗24周，高低剂量组HBV DNA低于检测下限的比例达到81.5%和84.0%（意味着药物疗效显著，控制乙肝病毒在正常范围内），远超核苷类似物单药治疗（32.1%），而且疗效稳定无波动。更值得注意的是，患者HBV DNA和pgRNA下降幅度均超过1 log10，进一步验证了GST-HG141阻断HBV病毒复制和耗竭cccDNA的作用。从单个管线到全局，广生堂在治愈乙肝的路上做出了很多努力，除了GST-HG141之外，公司还布局了一、二代HBsAg抑制剂GST-HG131和GST-HG121，其中GST-HG131的临床进度推进与GST-HG141保持一定同步，旨在实施先使用GST-HG141对乙肝患者cccDNA进行耗竭，再序贯使用GST-HG131实现HBsAg血清学清除或血清学转换（其中还可能出现两者联用进行过渡），最终达到以停药为目的的临床治愈目标。（来源：2023年广生堂年报） 03 海外价值对标对于GST-HG141的临床进度而言，广生堂将其称之为全球潜在FIC口服乙肝抗病毒药物其实“有理有据”。早在GST-HG141进入临床之初，全球同属I类MOA核衣壳抑制剂的还有Assembly Bioscience的ABI-H0731、ABI-H2158及ABI-H3733。早在2020年，百济神州曾经以“4000万美元首付+最高不超过5亿美元+分成”获得Assembly Bioscience上述三款分子的中国权益（含港澳台地区）。如今三个分子均因不同原因被终止开发，如Vebicorvir （ABI-H0731）是在与核苷酸、干扰素的三联用药三期临床中的数据不支持对慢性乙肝患者实现有意义的功能性治愈而被放弃，ABI-H2158是由于二期临床中患者出现严重肝毒性而被迫终止开发。上述两个项目终止后，ABI-H3733和ABI-4334这个新一代病毒核衣壳组装抑制剂被Assembly给予厚望，临床前数据显示两者抑制新cccDNA形成方面的效力比ABI-H0731分别高35倍和900倍。后ABI-H3733也因为优先级被Assembly公司终止，转而专注在ABI-4334的临床推进上。 ABI-4334在2023年公布的最新一期数据也比较优良，每天给药一次，单次口服最高剂量达400mg，患者具有良好耐受性（避免了之前公司老一代管线的毒性，临床中没有出现三级TARE和相关SAE），仅中间剂量便能实现高效的HBV DNA抑制和cccDNA生成抑制。尽管如此，在经历了诸多波折后，Assembly Bioscience调低了乙肝管线的优先级，且市值也跌落谷底，公司市值仅为8294万美元。除了病毒核衣壳组装抑制剂，全球也出现了一些致力于治愈乙肝的新型药物，其中比较火热的是小核酸药物，包括反义寡核苷酸（ASO）和小干扰RNA（siRNA），前者如GSK的3228836和Aligos的ALG-020572，后者如VIR-2218。 GSK的3228836的二期慢性乙肝临床结果显示：使用每周300mg治疗24周可使26%的核苷类似物经治和29%的乙肝初治患者获得乙肝表面抗原清除、HBV DNA阴转，随访24周后上述比例分别降至9%和10%，保持效果差且复发率高（同时肝毒性也值得注意），需要续贯长效干扰素治疗。 VIR-2218呈现出与GSK的3228836类似的表现，其二期临床结果显示：在接受VIR-2218与长效干扰素组合疗法的31名受试者中，8名患者（25.8%）在治疗结束时出现乙肝表面抗原清除，5名患者（16%）在治疗结束后的24周实现了持续的乙肝表面抗原水平清除。值得注意的是，非头对头数据对比如VIR-2218单药治疗，那么患者HBV DNA复阳概率则比GSK3228836更高。结语：广生堂的回落，与公司未公布完整数据有关，无论是病毒核衣壳组装抑制剂还是小核酸药物在24周治疗结束全球均已有管线表现出不错的疗效，但更重要的是随后24周随访中患者的乙肝表面抗原水平和HBV DNA转阳率，这代表了药物的持久程度和中期疗效，让我们期待GST-HG141的完整数据。药渡媒体商务合作媒体公关 | 新闻&会议发稿张经理：18600036371（微信同号）点击下方“药渡“，关注更多精彩内容免责声明 “药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！👇👇👇

临床2期寡核苷酸

2024-08-08

·同写意

一家抗病毒明星Biotech的溃逃

本次以“突破瓶颈打造健康产业新引擎”为主题，设一场主论坛和八场主题论坛，从前沿创新突破、临床应用拓展、工艺技术优化、商业化开发等多个全新视角推动CGT技术开发与应用，成就健康产业未来。差不多十年前，著名风投公司ARCH Venture Partners联合创始人Robert Nelsen，萌生了想要创办一家药企，以应对世界上最为严重的病原体。 “这是一个疯狂的想法。”曾在渤健和Vertex从事艾滋病毒和丙肝药物开发工作的Vicki Sato，在接到Nelsen的电话时评价道。虽然传染病一直存在，但在彼时，越来越多的药企正撤出传染病领域。然而，对于以疯狂的想法发家致富的Nelsen，这没有什么值得大惊小怪的。毕竟，有时科学听起来也很疯狂：通过改造细胞来治疗癌症，找到延缓衰老的药物。凭借“用免疫系统解决病原体”的独特想法，Nelsen收获了肯定，2016年成功组建Vir Biotechnology。戏剧性的是，信誓旦旦，言犹在耳，这家Biotech却在前不久宣布停止肝炎之外的传染病项目研究，引入抗癌产品。 Vir并不孤单，曾经因抗病毒药物而声名鹊起的吉利德和Vertex，也已将不少精力转向癌症、神经学、罕见疾病和自身免疫。传染病药企发展的宿命注定如此吗？相较于行业，这更是准备重组的Vir需要回答的问题。 1 创造没有传染病的世界多年来，生物技术公司一直想要攻克传染病。但由于技术、投入产出不成比例等原因，这个领域的进展缓慢。 Nelsen获得信赖的想法是，与其试图为每种病原体想出解药，不如像研究癌症的科学家那样，利用免疫系统做这项工作。成立之初，Vir的目标是“创造一个没有传染病的世界”，并请来渤健前首席执行官George Scangos，担任Vir CEO。在一年的时间里，Vir收购了Humabs，获得5亿美元融资，并和斯坦福大学、哈佛大学等知名科研机构达成合作。 Vir开局顺利，但当时的大环境对传染病领域并不友好。 2014年，诺华几乎用整个传染病部门交换了GSK的相关癌症项目；Achaogen在2018年成功在美国推出自研的新型抗生素普拉佐米星（Zemdri），却因销售惨淡而在次年宣布破产。因而，在2019年10月IPO时，Vir股价以低于发行价18％的16.50美元开盘，并以14.02美元收盘（下跌29.9%）的表现，就并没有太让人感到意外。这种困扰并未持续多久。因为很快，COVID-19就来了。在此前，Vir就从埃博拉幸存者体内分离出了高效的中和抗体MAb114，疗效媲美再生元的REGN-EB3（三种抗体鸡尾酒），且明显优于美国另一家公司Mapp研发的ZMapp。2020年下旬，REGN-EB3、MAb114先后获得FDA批准。 COVID-19期间，在传染病领域已经有了一些积淀的Vir，从SARS康复患者体内分离出可以交叉识别COVID-19病毒的中和抗体，在此基础上开发了VIR-7831和VIR-7832两款中和抗体。 Vir抓住了风口，而MNC选择抓住了Vir。2020年4月，GSK宣布对Vir进行2.5亿美元的股权投资，共同开发上述两款产品。 2021年1月，Vir与礼来、GSK达成合作，在低风险的轻中度COVID-19患者中评估两种中和抗体疗法的组合。彼时，礼来已扩展其正在进行的BLAZE-4试验，以评估bamlanivimab与VIR-7831构成的组合疗法的效果。这次联盟，让Vir的股价飙升，一度达到141美元。 VIR-7831没有辜负期待。2021年5月，它获得FDA的紧急使用授权（EUA），通用名为sotrovimab，商品名为Xevudy，成为礼来、再生元之后第3款获得EUA的中和抗体，半年时间里取得了超10亿美元的销售额。即使面对“神兵”mRNA疫苗，中和抗体也有一战之力。数据显示，2021年COVID-19中和抗体试产规模达到110亿美元。在2022年，由于sotrovimab的贡献，Vir的营收超过16亿美元，在COVID-19期间的营收增长率一度达到1334%。Sotrovimab在40多个国家获得上市批准、临时授权或紧急使用授权，Vir市值水涨船高，一度接近200亿美元。 2 Biotech，起落落落随着COVID-19消退，相关红利也逐渐消失。据GSK年报，在2022年，sotrovimab销售额为23亿英镑，增长100%。到了2023年，销量下滑幅度直逼去年涨幅，达到98%，仅有4400万英镑。而在此前，由于病毒不断变异，sotrovimab的效力已经逐渐减弱。2021年3月，Vir宣布sotrovimab一项针对住院患者的III期临床ACTIV-3停止入组，原因是独立数据和安全监察委员会经分析认为对获益可能较小。 2022年4月，卫生保健提供者情况说明书中包含的数据显示，sotrovimab的授权剂量不太可能对BA.2亚型有效，sotrovimab在美国任何州或地区授权均被撤销。时来天地皆同力，运去英雄不自由。随后，REGEN-COV（再生元）、Evusheld（阿斯利康）等COVID-19中和抗体也相继撤出美国市场。2023年2月，GSK宣布不再与Vir就COVID-19相关项目进行继续合作。 COVID-19像是Vir发展的一个分界线，一边是泛着金光的光明未来，一边是迷雾笼罩的原始丛林。在剔除COVID-19项目后，当时Vir管线中走在前面的只有两个处在临床II期的肝炎项目，分别是单抗VIR-3434（Tobevibart）和siRNA药物VIR-2218（Elebsiran），均引进自Alynlam。 Tobevibart旨在抑制乙肝病毒和丁肝病毒进入肝细胞，中和乙肝病毒和丁肝病毒病毒体，并降低血液中的病毒体和亚病毒颗粒水平；Elebsiran可降解乙肝病毒RNA转录本并限制乙肝表面抗原的产生，可能对乙肝病毒和丁肝病毒具有直接的抗病毒活性。数据显示，2022年约有130万⼈死于病毒性肝炎，与结核病并列成为当年传染病中第二大死亡原因，仅次于COVID-19。但需要指出的是，乙肝市场并不是一个容易吃上的“饼”。就目前来说，乙肝病毒形成的cccDNA（共价闭合环状DNA）难以被清除，导致乙肝很难被彻底治愈，即使现在追求的功能性治愈也存在诸多问题，停药后容易复阳，中途放弃探索的药企也不在少数。比如，同样获得快速通道资格的在研乙肝新药ABI-H0731、ABI-H2158（Assembly Biosciences）均已折戟沙场。本身的技术难度之外，如何追赶并超越“前辈”，甚至抢占已上市产品的市场份额，也是颇不容易。 GSK、吉利德等巨头都有处在中后期的肝炎在研药物。GSK用于慢性乙肝治疗的Bepirovirsen在今年2月获得FDA“快速通道”资格；3月，吉利德Vemlidy扩充适应症，获得FDA批准治疗六岁及以上乙肝患者。尴尬的是，Vir能否在肝炎领域杀出一片天尚有待观察，该公司关注的另一重点领域流感也出了岔子。 2023年7月，Vir用于预防症状性甲型流感的VIR-2482在II期研究中未达到主要或次要疗效终点，股价大跌近45%。到年底，Vir宣布进行重组，裁员12%，并关闭位于密苏里州圣路易斯和俄勒冈州波特兰的研发设施。 3 选择更具性价比的路 8月1日，Vir宣布了一项战略性改革，透露将不再继续COVID-19和流感方面的工作，叫停基于T细胞的病毒载体平台，并把病毒学业务限制在其乙型和丁型肝炎项目中，专注于“近期的高价值机会”。具体来看，管线中的下一代COVID单克隆抗体VIR-7229、针对流感A和B的神经氨酸酶靶向单克隆抗体VIR-2981、临床前治疗性癌症疫苗VIR-1949，以及进入I期试验的HIV疫苗VIR-1388，都将不复存在。同时，Vir还披露了一项与赛诺菲达成的许可协议，获得后者三个临床阶段的条件激活CD3双抗，以及可切割蛋白酶掩蔽平台的独家使用权。 3款产品分别为： • SAR446309，一种双掩蔽HER2xCD3分子，目前正在I期开发中，用于治疗转移性、治疗抵抗性HER2阳性肿瘤，如乳腺癌和结直肠癌。 • SAR446329，一种双掩蔽PSMAxCD3候选物，处于I期临床试验阶段，针对患有转移性、去势抵抗性前列腺癌的患者。 • SAR446368，针对EGFR的双重掩蔽CD3 TCE，其IND已获得批准。预计1期临床试验将在2025年第一季度或更早启动，用于各种EGFR阳性癌症。不难看出，Vir新的重点锚定了癌症。 Vir的选择也许对标了赛诺菲、礼来、辉瑞等起初也是“传染病”起家的巨头，在某款产品中获得巨额利润后转向更大的疾病领域。需要指出的是，这些巨头已经拥有了巨大的资本积累。与Vir基本退出传染病领域形成对比的是，今年6月，吉利德预防HIV的III期试验取得积极结果，一年两针，100%有效。欢呼声掩盖了失意者的落寞，但现实困境确实横亘在前。囿于传染病的患者群体、地区、患病率、付费能力等现实因素，产品市场并不稳定，在大多数拥有支付能力的国家，癌症、自身免疫性疾病、神经退化才是“主要矛盾”。此外，药企公共沟通的不足可能也进一步加深传染病药物研发的困境。根据Endpoints数据，从2010年到2020年，风险资本向癌症投入的现金是传染病的5倍多。回望Vir的来时路，很遗憾一个为传染病而生的公司还是走向了更“稳妥”的选择。丁肝成了“最后的倔强”。6月初，Vir更新了在研项目的利好进展。 II期试验SOLSTICE的初步数据显示，tobevibart单药或与elebsiran联用治疗丁型肝炎病毒感染中耐受性良好，受试者在第12周和第24周实现了高病毒学应答率，且病毒学应答持久至48周，患者丙氨酸转氨酶（ALT）水平正常化的比率高。完整的24周治疗数据有望在2024年第四季度报告。FDA已授予tobevibart和elebsiran组合药物快速通道资格，用于治疗慢性丁型肝炎病毒感染。接受tobevibart与elebsiran联合疗法的HDV患者快速达到病毒学抑制和ALT水平正常化，图源：药明康德 2024年第二季度，Vir的收入为310万美元，低于去年同期的380万美元。截至2024年6月30日，Vir拥有14.3亿美元的现金、现金等价物和投资。在战略重组的工作中，Vir将裁员25%，在其运营中取消大约140个职位。年底时，员工人数将降至约435人，比去年的峰值减少了约200人。而作为与赛诺菲协议的一部分，Vir将从后者引进一些“具有丰富的T细胞接合剂科学和开发专业知识的关键员工”。这些调整预计将节省5000万美元，直至2025年底，Vir计划将这些资金重新投资于从赛诺菲获得的候选药物。未来，这家Biotech计划利用PRO-XTEN技术在多个领域进行创新开发，加强在癌症治疗领域的产品线，也将拓展至抗感染领域。不可否认，传染病仍是一个巨大的潜在市场。GlobalData预计，传染病市场将以每年5.7%的速度增长，2029年达到年销售额1500亿美元。问题是，这条赛道上，对于“脱胎换骨”的Vir能跑到什么位置，或许就不是那么乐观了。参考文献： 1、Vir Lays Off 25% of Staff, Abandons Most Virus Work and Pivots to Cancer in Sanofi Deal；biospace 2、Can investing in infectious disease pay off? Vir Biotechnology’s tightrope walk shows it’s a struggle；statnews 3、Vir Biotechnology官网 4、100%肝炎患者病毒持久抑制近1年！创新疗法亮眼结果公布；药明康德 5、After Big Pharma abandoned infectious diseases, 5 biotech contrarians decided to go all in. Then Covid-19 changed everything；endpoints 同写意媒体矩阵，欢迎关注↓↓↓

IPO并购

2024-05-08

·GlobeNewswire-Health Care

Assembly Biosciences Reports First Quarter 2024 Financial Results and Recent Highlights

Clinical trial application clearances received for a Phase 1a/1b trial for ABI-5366 targeting recurrent genital herpes, and a Phase 1b trial for ABI-4334 in chronic HBV infection; both studies on track to initiate by mid-2024 ABI-5366 interim Phase 1a first-in-human data expected in Q3 2024 and ABI-4334 interim Phase 1b data expected by end of year SOUTH SAN FRANCISCO, Calif., May 08, 2024 (GLOBE NEWSWIRE) -- Assembly Biosciences, Inc. (Nasdaq: ASMB), a biotechnology company developing innovative therapeutics targeting serious viral diseases, today reported financial results and recent highlights for the first quarter ended March 31, 2024. “We are pleased that we now have regulatory clearance to initiate trials evaluating our promising investigational therapies ABI-5366 and ABI-4334 and look forward to sharing interim data from these studies later this year,” said Jason Okazaki, chief executive officer and president of Assembly Bio. “These clearances are a significant step toward our goal of reaching key clinical inflection points for multiple programs in our antiviral pipeline by year end. Our continued clinical progress reflects the strength and agility of our highly experienced team and our singular focus of improving treatment options for those living with serious viral diseases.” First Quarter 2024 and Recent Highlights Two clinical trial applications received clearance to proceed: ABI-5366, a long-acting herpes simplex virus (HSV) helicase-primase inhibitor candidate, for initiation of Phase 1a/1b clinical studies in both healthy volunteers and in individuals with recurrent genital herpesABI-4334, a next-generation, highly potent capsid assembly modulator candidate, for initiation of a Phase 1b study in individuals with chronic hepatitis B virus (HBV) infection An abstract highlighting preclinical data for ABI-6250, an oral, small molecule HBV/hepatitis delta virus (HDV) entry inhibitor candidate, has been accepted for poster presentation at the European Association for the Study of the Liver (EASL) CongressTM 2024, June 5-8, 2024 Anticipated 2024 Milestones ABI-5366 and ABI-4334 studies expected to initiate by mid-2024: ABI-5366 Phase 1a interim clinical data expected in Q3 2024 and interim Phase 1b data expected in the first half of 2025ABI-4334 Phase 1b interim clinical data expected by the end of 2024 Two additional candidates are anticipated to enter the clinic by the end of 2024: ABI-1179, a long-acting HSV helicase-primase inhibitor contributed by Gilead Sciences, Inc. (Gilead) under the collaboration between Assembly Bio and GileadABI-6250, a small molecule orally-bioavailable HDV entry inhibitor First Quarter 2024 Financial Results Cash, cash equivalents and marketable securities were $113.0 million as of March 31, 2024, compared to $130.2 million as of December 31, 2023. Assembly Bio’s cash position is projected to fund operations into the second half of 2025.Revenues from collaborative research were $5.8 million for the three months ended March 31, 2024. There was no revenue recognized for the same period in 2023. Revenue for the three months ended March 31, 2024 consists of amounts recognized under the collaboration with Gilead.Research and development expenses were $11.9 million for the three months ended March 31, 2024, compared to $14.5 million for the same period in 2023. Increased expenses related to the development of ABI-1179 and ABI-6250 were more than offset by savings from the discontinuation of ABI-H3733 and vebicorvir as well as reduced employee and contractor-related expenses.General and administrative expenses were $4.6 million for the three months ended March 31, 2024, compared to $5.0 million for the same period in 2023. The decrease is primarily due to a decrease in non-cash stock-based compensation expense.Net loss attributable to common stockholders was $9.1 million, or $1.66 per basic and diluted share, for the three months ended March 31, 2024, compared to $19.0 million, or $4.46 per basic and diluted share, for the same period in 2023. The investigational products and investigational product candidates referenced here have not been approved anywhere globally, and their safety and efficacy have not been established. About Assembly BiosciencesAssembly Biosciences is a biotechnology company dedicated to the development of innovative small-molecule therapeutics designed to change the path of serious viral diseases and improve the lives of patients worldwide. Led by an accomplished team of leaders in virologic drug development, Assembly Bio is committed to improving outcomes for patients struggling with the serious, chronic impacts of herpesvirus, hepatitis B virus (HBV) and hepatitis delta virus (HDV) infections. For more information, visit assemblybio.com. Forward-Looking StatementsThe information in this press release contains forward-looking statements that are subject to certain risks and uncertainties that could cause actual results to materially differ. These risks and uncertainties include: Assembly Bio’s ability to realize the potential benefits of its collaboration with Gilead Sciences, Inc., including all financial aspects of the collaboration and equity investments; Assembly Bio’s ability to initiate and complete clinical studies involving its therapeutic product candidates, including studies contemplated by Assembly Bio’s collaboration with Gilead, in the currently anticipated timeframes or at all; safety and efficacy data from clinical or nonclinical studies may not warrant further development of Assembly Bio’s product candidates; clinical and nonclinical data presented at conferences may not differentiate Assembly Bio’s product candidates from other companies’ candidates; results of nonclinical studies may not be representative of disease behavior in a clinical setting and may not be predictive of the outcomes of clinical studies; and other risks identified from time to time in Assembly Bio’s reports filed with the U.S. Securities and Exchange Commission (the SEC). You are urged to consider statements that include the words may, will, would, could, should, might, believes, hopes, estimates, projects, potential, expects, plans, anticipates, intends, continues, forecast, designed, goal or the negative of those words or other comparable words to be uncertain and forward-looking. Assembly Bio intends such forward-looking statements to be covered by the safe harbor provisions contained in Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. More information about Assembly Bio’s risks and uncertainties are more fully detailed under the heading “Risk Factors” in Assembly Bio’s filings with the SEC, including its most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q and Current Reports on Form 8-K. Except as required by law, Assembly Bio assumes no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. Contacts Investor and Corporate: Shannon Ryan SVP, Investor Relations, Corporate Affairs and Alliance Management (415) 738-2992 investor_relations@assemblybio.com Media: Sam Brown Inc.  Hannah Hurdle  (805) 338-4752  ASMBMedia@sambrown.com ASSEMBLY BIOSCIENCES, INC. CONDENSED CONSOLIDATED BALANCE SHEETS (In thousands except for share amounts and par value) March 31, December 31, 2024 2023 (Unaudited) ASSETS Current assets Cash and cash equivalents $18,749 $19,841 Marketable securities 94,227 110,406 Accounts receivable from collaboration 43 43 Prepaid expenses and other current assets 4,149 3,497 Total current assets 117,168 133,787 Property and equipment, net 367 385 Operating lease right-of-use assets 2,036 2,339 Other assets 312 312 Total assets $ 119,883 $ 136,823 LIABILITIES AND STOCKHOLDERS' EQUITY Current liabilities Accounts payable $727 $461 Accrued research and development expenses 2,059 885 Other accrued expenses 2,051 5,744 Deferred revenue from a related party - short-term 32,771 30,915 Operating lease liabilities - short-term 1,145 1,220 Total current liabilities 38,753 39,225 Deferred revenue from a related party - long-term 47,738 55,379 Operating lease liabilities - long-term 791 1,122 Total liabilities 87,282 95,726 Commitments and contingencies Stockholders' equity Preferred stock, $0.001 par value; 5,000,000 shares authorized; no shares issued or outstanding — — Common stock, $0.001 par value; 150,000,000 shares authorized as of March 31, 2024 and December 31, 2023; 5,482,752 shares issued and outstanding as of March 31, 2024 and December 31, 2023 5 5 Additional paid-in capital 827,660 826,921 Accumulated other comprehensive loss (239) (81) Accumulated deficit (794,825) (785,748) Total stockholders' equity 32,601 41,097 Total liabilities and stockholders' equity $ 119,883 $ 136,823 ASSEMBLY BIOSCIENCES, INC. CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS (In thousands except for share and per share amounts) (Unaudited) Three Months Ended March 31, 2024 2023 Collaboration revenue from a related party $5,785 $— Operating expenses Research and development 11,879 14,547 General and administrative 4,635 5,012 Total operating expenses 16,514 19,559 Loss from operations (10,729) (19,559) Other income Interest and other income, net 1,652 609 Total other income 1,652 609 Net loss $ (9,077) $ (18,950) Other comprehensive loss Unrealized (loss) gain on marketable securities (158) 290 Comprehensive loss $ (9,235) $ (18,660) Net loss per share, basic and diluted $(1.66) $(4.46) Weighted average common shares outstanding, basic and diluted 5,483,313 4,251,037

财报临床1期临床申请临床2期

100 项与 Vebicorvir 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D12054	-	-	-

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
慢性乙型肝炎	临床2期	澳大利亚	Assembly Biosciences, Inc.	2017-06-15
慢性乙型肝炎	临床2期	韩国	Assembly Biosciences, Inc.	2017-06-15
乙型肝炎	临床2期	-	Indiana University	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04781647 (CTgov)	临床2期	慢性乙型肝炎	54	ETV+ABI-H0731 (ABI-H0731 + ETV)	築膚餘蓋廠積窪積築夢(壓網構齋壓選選遞膚獵) = 齋膚願醖憲鑰繭鏇願夢選憲鑰製獵憲範簾範窪 (鬱夢壓淵鏇醖餘顧築構, 餘糧繭衊築遞糧網鹹鹽 ~ 網醖製鏇憲壓遞簾選鹽) 更多	-	2023-10-06
				Peg-IFNα+ETV+ABI-H0731 (ABI-H0731 + ETV + Peg-IFNα)	築膚餘蓋廠積窪積築夢(壓網構齋壓選選遞膚獵) = 蓋積糧範餘製鹹構糧鹽選憲鑰製獵憲範簾範窪 (鬱夢壓淵鏇醖餘顧築構, 鏇蓋選鹽壓膚廠觸範選 ~ 淵衊艱顧鬱鹽顧製艱網) 更多
NCT04454567 (CTgov)	临床2期	慢性乙型肝炎	2	NrtI+ABI-H0731 (ABI-H0731 + SOC NrtI)	艱顧鑰糧壓製築觸構蓋(艱鏇廠範衊簾鏇膚築觸) = 襯憲艱蓋積廠築窪積願膚窪製鹽顧積鹽範範廠 (鑰餘襯範夢繭選鏇糧範, 積願積齋網蓋齋獵積範 ~ 範築積壓憲醖遞觸範齋) 更多	-	2022-10-20
				NrtI+ABI-H0731 (Placebo + SOC NrtI)	艱顧鑰糧壓製築觸構蓋(艱鏇廠範衊簾鏇膚築觸) = 壓構廠壓遞築鏇遞膚衊膚窪製鹽顧積鹽範範廠 (鑰餘襯範夢繭選鏇糧範, 艱夢衊壓簾繭膚膚簾糧 ~ 壓夢淵顧鹹簾壓鑰觸齋) 更多
NCT03577171 (Study 202, EASL2022)	临床2期	慢性乙型肝炎	25	Vebicorvir 300 mg + Entecavir 0.5 mg	壓夢廠繭膚構遞醖壓襯(範醖醖壓夢餘廠構築範) = 顧艱構淵鬱獵憲積鬱製顧襯廠鏇範蓋膚簾鏇範 (糧醖淵醖選艱繭壓衊鏇 )	-	2022-06-25
				Placebo + Entecavir 0.5 mg	襯顧鬱獵範鏇夢窪膚鏇(遞鑰選獵廠蓋觸積範願) = 醖膚簾糧觸網鹹顧鹽餘鏇憲窪壓鑰壓淵願壓醖 (網簾顧製願鏇積簾蓋簾 ) 更多
NCT03577171 (Study 202, EASL2022)	临床2期	乙型肝炎 HBeAg positive \| HBcrAg \| HBV DNA ... 更多	-	Vebicorvir+Entecavir	網鏇蓋鹽壓積網顧餘鹽(構鏇鑰糧築網鏇製積簾) = 積壓餘鹽構簾蓋鬱選遞積壓憲構製鹹遞願窪襯 (夢淵觸網淵蓋淵製夢壓 )	-	2022-06-23
NCT03577171 (Pubmed)	临床2期	慢性乙型肝炎	25	Vebicorvir 300 mg+Entecavir 0.5 mg	(餘鏇膚積構廠窪鬱簾鏇) = 齋築憲鹽鏇鹽夢繭膚積夢窪鹽網廠繭窪觸夢鏇 (網製膚壓窪觸餘選醖選 ) 更多	-	2022-06-10
				Placebo+Entecavir 0.5 mg	(餘鏇膚積構廠窪鬱簾鏇) = 壓夢鑰膚醖鬱鹽築繭糧夢窪鹽網廠繭窪觸夢鏇 (網製膚壓窪觸餘選醖選 ) 更多
Study 211 (EASL2021)	N/A	慢性乙型肝炎 eAg positive \| sAg \| crAg	41	Vebicorvir	齋糧鏇獵鹹範繭構選夢(遞遞遞衊齋襯壓窪製夢) = ALT elevation in 4/41 (10%) pts 鹹壓簾齋鑰鹽壓製構襯 (鹹廠襯製願淵繭範襯壓 ) 更多	-	2021-06-23
				Placebo+NrtI
NCT03577171 (ABI-H0731-202 \| Study 202, CTgov)	临床2期	慢性乙型肝炎	25	SOC ETV+ABI-H0731 (ABI-H0731 + SOC ETV)	廠鏇鏇夢壓積鑰鹽製積(願壓鑰齋淵獵齋蓋餘膚) = 繭鹹鏇觸夢衊蓋蓋鬱繭製獵簾衊獵選願構範壓 (糧遞網積壓襯築餘觸積, 繭齋艱鹽構構廠鹹選齋 ~ 醖艱範醖廠網蓋構範齋) 更多	-	2021-01-28
				Placebo Oral Tablet+SOC ETV (Placebo + SOC ETV)	廠鏇鏇夢壓積鑰鹽製積(願壓鑰齋淵獵齋蓋餘膚) = 選蓋鏇願襯艱鬱壓淵構製獵簾衊獵選願構範壓 (糧遞網積壓襯築餘觸積, 築範鬱積壓範願選鏇鬱 ~ 廠衊鬱蓋獵廠齋鹽醖獵) 更多
NCT03576066 (ABI-H0731-201, CTgov)	临床2期	慢性乙型肝炎	73	SOC NUC+ABI-H0731 (ABI-H0731 + SOC NUC)	膚膚蓋襯築觸夢遞鹹憲(廠廠夢積夢顧窪範鬱網) = 鹽膚憲選顧淵夢襯窪膚範醖齋齋構範糧壓鹽鏇 (鏇壓壓夢顧襯淵觸選襯, 襯範窪醖襯廠糧醖構鏇 ~ 衊鏇蓋醖積築築獵鹹齋) 更多	-	2021-01-28
				Placebo Oral Tablet (Placebo + SOC NUC)	膚膚蓋襯築觸夢遞鹹憲(廠廠夢積夢顧窪範鬱網) = 顧構鏇艱繭衊遞製願鏇範醖齋齋構範糧壓鹽鏇 (鏇壓壓夢顧襯淵觸選襯, 壓構窪窪鑰鬱糧廠簾築 ~ 壓廠餘糧淵觸鏇構範廠) 更多
ABI-H0731-211 (EASL2020)	临床2期	慢性乙型肝炎	-	ABI-H0731	獵鹽膚築願選顧顧窪遞(獵廠廠糧願窪遞鹹憲構) = 壓夢鏇蓋蓋觸齋壓製願淵鏇艱簾願醖醖醖遞鏇 (壓製餘顧觸構壓衊顧簾 ) 更多	-	2020-08-27