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

NCT05298332 / Terminated临床1期

A Phase 1, Open-Label, 3-Cohort, Parallel, Single Dose Study of the Safety, Tolerability, and Pharmacokinetics of a Single Oral Dose ATI-2173 50 mg in Healthy Japanese, Chinese, and Non-Asian Subjects

This is a single center, open-label, 3-Cohort, parallel, single-dose, study to evaluate the PK, safety, and tolerability of ATI-2173 50 mg administered orally in Japanese, Chinese, and Non-Asian healthy subjects incorporating a food effect analysis in Non-Asian healthy subjects.

开始日期2022-03-29

申办/合作机构

Antios Therapeutics, Inc.初创企业

NCT05137600 / Completed临床1期

A Phase 1, Open-label, 2-cohort, Fixed-sequence, Drug-drug Interaction Study to Investigate the Potential Interaction Between ATI-2173 When Coadministered With Midazolam or Clarithromycin in Healthy Subjects

This study is a single-center, open-label, 2-cohort, fixed-sequence, DDI study in healthy adult subjects. Healthy volunteers will be administered multiple oral doses of ATI-2173 in combination with midazolam or clarithromycin and assessed for safety and tolerability including blood tests to show how the body metabolizes and eliminates the investigational drug as well as how the investigational drug interacts with midazolam or clarithromycin.

开始日期2021-10-28

申办/合作机构

Antios Therapeutics, Inc.初创企业

100 项与 ATI-2173 相关的临床结果

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100 项与 ATI-2173 相关的转化医学

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100 项与 ATI-2173 相关的专利（医药）

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项与 ATI-2173 相关的文献（医药）

2023-01-01·Journal of viral hepatitis

A randomized phase 1b trial of the active site polymerase inhibitor nucleotide ATI‐2173 in patients with chronic hepatitis B virus infection

Article

作者: Anastasiy, Igor ; Squires, Katherine E. ; Huguet, Jade ; Melara, Rebeca ; De La Rosa, Abel ; Ghicavii, Nelli ; Jucov, Alina ; Constantineau, Martin ; Ogilvie, Lauren ; Mayers, Douglas L.

Abstract:

ATI‐2173 is an active site polymerase inhibitor nucleotide in development as part of a potentially curative regimen for chronic hepatitis B virus (HBV) infection. This study evaluated the safety, tolerability, pharmacokinetics (PK) and antiviral activity of ATI‐2173. This was a phase 1b, randomized, double‐blind, placebo‐controlled trial in treatment‐naive adults with chronic HBV infection conducted in the Republic of Moldova and Ukraine (ClinicalTrials.gov: NCT04248426). Patients positive for hepatitis B surface antigen were randomized 6:2 to receive once‐daily oral doses of ATI‐2173 10, 25, or 50 mg (n = 6 per dose) or placebo (n = 7) for 28 days, with off‐treatment monitoring for 24 weeks. Endpoints included PK parameters of ATI‐2173 and its metabolite clevudine, maximum reduction from baseline in HBV DNA, and safety and tolerability. Treatment‐emergent adverse events occurred in eight patients (47%) receiving ATI‐2173 and five (71%) receiving placebo; headache was the most common (n = 4). ATI‐2173 PK was generally dose proportional. Systemic clevudine exposure with ATI‐2173 dosing was substantially reduced compared with historical values observed with clevudine administration. On Day 28, mean changes from baseline in HBV DNA were −2.72 to −2.78 log10 IU/ml with ATI‐2173 and +0.17 log10 IU/ml with placebo. Off‐treatment sustained viral suppression and decreases in covalently closed circular DNA biomarkers were observed in most patients; one maintained undetectable HBV DNA at 24 weeks off treatment. In this 28‐day monotherapy study, ATI‐2173 demonstrated safety and antiviral activity, with sustained off‐treatment effects and substantially reduced systemic clevudine exposure. These results support evaluation of ATI‐2173 with tenofovir disoproxil fumarate in phase 2 studies.

2022-01-01·Antiviral chemistry & chemotherapy

Active site polymerase inhibitor nucleotides (ASPINs): Potential agents for chronic HBV cure regimens

Review

作者: Squires, Katherine ; Gish, Robert G ; Asselah, Tarik ; Mayers, Douglas

Chronic hepatitis B virus (HBV) infection affects 240 to 300 million people worldwide. In the nucleus of infected hepatocytes, the HBV genome is converted to covalently closed circular DNA (cccDNA), which persists and serves as a transcriptional template for viral progeny. Therefore, a long-term cure for chronic HBV infection will require elimination of cccDNA. Although currently available nucleos(t)ide analogues (eg, tenofovir disoproxil fumarate, tenofovir alafenamide, entecavir) effectively control HBV replication, they are seldom curative (functional cure rate ∼10%) and require lifelong treatment for most patients. As such, antiviral agents with novel mechanisms of action are needed. Active site polymerase inhibitor nucleotides (ASPINs) noncompetitively distort the HBV polymerase active site to completely inhibit all polymerase functions, unlike traditional chain-terminating nucleos(t)ide analogues, which only target select polymerase functions and are consumed in the process. Clevudine, a first-generation ASPIN, demonstrated potent and prolonged HBV suppression in phase 2 and 3 clinical studies, but long-term treatment was associated with reversible myopathy in a small number of patients. ATI-2173, a novel next-generation ASPIN, is structurally similar to clevudine but targets the liver and demonstrates potent anti-HBV activity on and off treatment, and may ultimately demonstrate an improved pharmacokinetic and safety profile by significantly reducing systemic clevudine exposure. Thus, ATI-2173 is currently in clinical development as an agent for HBV cure. Here, we review the mechanism of action and preclinical and clinical profiles of clevudine and ATI-2173 to support the role of ASPINs as part of curative regimens for chronic HBV infection.

2020-08-20·Antimicrobial agents and chemotherapy

ATI-2173, a Novel Liver-Targeted Non-Chain-Terminating Nucleotide for Hepatitis B Virus Cure Regimens

Article

作者: Mayers, Douglas L. ; Squires, Katherine E. ; Kolykhalov, Alexander A. ; De La Rosa, Abel ; Guthrie, David B. ; Edpuganti, Vindhya ; Bluemling, Gregory R. ; Sticher, Zachary M. ; Reddy, Prabhakar ; Mitchell, Debbie G. ; Saindane, Manohar T.

ATI-2173 is a novel liver-targeted molecule designed to deliver the 5′-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5′-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of treatment. However, long-term clevudine treatment was found to exhibit reversible skeletal myopathy in a small subset of patients and was subsequently discontinued from development.

项与 ATI-2173 相关的新闻（医药）

2023-09-22

·FierceBiotech

Hep B biotech Antios closed after FDA hold proved insurmountable

ATI-2173 was previously advanced into phase 3 study a decade ago, only to be sidelined due to cases of muscle weakness in long-term users. Viral disease biotech Antios Therapeutics shut down earlier this year after an FDA hold on its lead hepatitis B therapy due to a serious adverse event proved insurmountable. Former Chief Medical Officer and co-founder Douglas Mayers, M.D., confirmed to Fierce Biotech Friday morning that the company shut down as of February. Antios had planned to develop a curative hepatitis B therapy but progress was halted in May 2022 when the FDA placed a clinical hold over a safety report for the med, ATI-2173. The hold prompted Assembly Biosciences to terminate its clinical trial collaboration agreement as well. The company later showcased results showing that ATI-2173 slowed rebound of the virus and allowed patients to continue treatment without having to go back on Gilead Sciences' Viread medicine during a phase 2a clinical trial. But ultimately, the FDA hold proved too difficult to overcome. “The FDA hold was written in a way that there was no viable response,” Mayers told Fierce Biotech. The company wound down and returned money to investors, with the doors closing officially in February. Two other individuals formerly involved with Antios also confirmed the news, with a former scientific advisor saying that the FDA’s response to efforts to clear the hold was not favorable. The small, Atlanta-based biotech was founded in 2018 and employed between 11 and 50 people, according to its LinkedIn page. Antios received $171 million in financing in 2021 to move ATI-2173 into the clinic. The safety event was flagged in a trial that was being conducted in Moldova when a patient experienced “a serious, unexpected, suspected adverse reaction of bradycardia and hypotension.” ATI-2173 was being combined with Assembly Biosciences' vebicorvir and a nucleotide reverse transcriptase inhibitor. ATI-2173 was previously advanced into phase 3 study a decade ago, only to be sidelined due to cases of muscle weakness in long-term users. Assembly also ended its quest for a functional cure of hepatitis B with vebicorvir in July 2022 after lackluster data showed the core inhibitor was unlikely to succeed. The company pivoted to earlier-stage candidates and laid off staff. “The hepatitis B space has contracted dramatically over the past year. Hopefully, things will turn around soon,” Mayers said. Max Bayer contributed to this article.

临床2期临床结果临床3期siRNA寡核苷酸

2023-03-24

·药时代

全球首创肝靶向恩替卡韦Ib期临床试验启动

春分之日，昼夜共长；人间向暖，万物向阳。在这特别的日子，北京君科华元医药科技有限公司研发的全球首创肝靶向恩替卡韦—MBT-1316的Ib期临床试验启动会顺利召开，君科华元在征服乙肝的征途上迈出新的一步。MBT-1316是君科华元利用ProTide技术打造的恩替卡韦肝靶向新药，曾经获得北京市科委“G20工程医药产业创新研发”项目资助，在刚刚结束的第二届“未来之星”生物医药创新成果转化项目大赛中荣获“生物医药组”二等奖。ProTide技术是迄今为止最成功的核苷类药物的靶向给药技术。这是一项产出了包括索磷布韦、瑞德西韦和丙酚替诺福韦在内的多个抗病毒重磅新药的技术。其中，全球首个丙肝治愈药物索磷布韦实现了人类治愈丙肝的革命性突破，上市第一年其全球销售额便超过100亿美元，成为名副其实的“超级重磅炸弹”；全球首个小分子新冠治疗药物瑞德西韦，在新冠肺炎爆发后的第5个月，即获得美国食品药品监督管理局（FDA）的紧急使用授权（EUA），用于治疗疑似或确诊新冠肺炎的重症患者，包括成年人和儿童，当年实现销售收入28亿美元，2021年增至56亿美元。全球首个肝靶向替诺福韦-丙酚替诺福韦(TAF)治疗乙肝的有效剂量仅有一代替诺福韦（TDF）的1/10，其降低骨密度和肾功的副作用显著低于TDF。恩替卡韦是我国临床应用最多的抗乙肝药物，年销售额最高达50亿元。临床前研究结果显示，在国际公认的土拨鼠乙肝模型中，恩替卡韦是已知（包括已上市和在研品种）最强的功能性治愈药物之一；临床研究结果表明，恩替卡韦是停药后病毒反弹率最低的抗乙肝药物，停药后6个月的反弹率只有13%，而TDF反弹率高达 74%。作为核苷类似物，恩替卡韦需要经过三次磷酸化，才能转化为三磷酸恩替卡韦的活性形式，单磷酸化是其中的限速步骤。由于临床剂量小，磷酸化效率低，恩替卡韦的功能性治愈作用在临床上未能达到充分发挥。肝靶向给药是乙肝创新药物研发的重要方向，在小分子核苷类药物和核酸类药物的研发中均取得了重大突破。研发进展最快的核酸类药物JNJ-3989和GSK-836均为偶联了GalNAc的肝靶向偶合物，GSK-836是首个进入III期临床的核酸类药物。GS-9620、GS-9688及APR002均为肝靶向TLR激动剂，可以选择性地在肝脏靶组织中激活免疫反应，诱导干扰素、促炎细胞因子和趋化因子的产生，发挥抗乙肝作用。已经成功上市的TAF、艾米替诺福韦，进入注册阶段的帕拉德福韦，以及进入临床研究阶段的海普诺韦、PA1010、NCO-048等均为替诺福韦类的肝靶向药物，其肝靶向的效果主要是为了降低骨密度降低和肾功能损伤的副作用。为了最大限度地发挥恩替卡韦的功能性治愈作用，北京君科华元医药科技有限公司利用ProTide技术对恩替卡韦进行改造，研发了单磷酸恩替卡韦的肝靶向前药MBT-1316，突破了单磷酸化的限速步骤；通过肝脏的靶向吸收、靶向活化、靶向蓄积，在不增加恩替卡韦系统暴露、以保证安全性的前提下，极大提高肝脏靶器官中三磷酸恩替卡韦活性分子的浓度，从而提高疗效。由北京首都医科大学附属友谊医院完成的MBT-1316片健康受试者3个剂量组的临床试验结果显示，MBT-1316吸收良好，转化完全，Cmax和AUC具有较好的剂量相关性，未见与药物相关的副作用。1mg剂量（约与0.5mg恩替卡韦等摩尔）的MBT-1316片给药后，MBT-1316原型的Cmax和AUC分别只有主要代谢产物的4.8%和1.44%, 转化效率远远高于利用相同技术研发的索磷布韦、TAF和ATI-2173，极大限度地避免了前药原型转化不完全所致的安全性风险。MBT-1316片 Ib期临床试验为一项多中心、随机、开放、阳性药对照、剂量递增的临床研究，将评价MBT-1316片在慢性乙型肝炎患者中单次及多次给药的安全性、耐受性、药效学及药代动力学特征。试验由首都医科大学附属北京友谊医院牵头，主要研究者是我国乙肝领域知名专家贾继东教授和乙肝新药临床药理学专家董瑞华教授。贾继东教授，首都医科大学附属北京友谊医院肝病中心教授、主任医师；首都医科大学肝硬化与门脉高压诊疗及研究中心主任。贾教授是中国医师协会消化医师分会肝病专业委员会主任委员，中华医学会肝病学分会主任委员（2006－2012），亚太地区肝病学会主席（APASL 2009－2010），国际肝病学会主席（IASL 2013-2016），中国肝炎防治基金会副理事长（2010-2020），先后担任Hepatol Int、Liver Int、 JGH、 JCTH、《中华肝脏病杂志》、《临床肝胆病杂志》及《肝脏》等国内外杂志的副主编及共同主编。董瑞华教授，药理学博士，研究员，硕导，北京友谊医院研究型病房主任。董博士主要从事药物临床试验和临床药理学方向研究。中华医学会肝病学分会临床流行病学与循证医学协作组委员，中国药理学会临床药理学专业委员会委员，中国药理学会药物临床试验专业委员会委员，中国毒理学会临床毒理专业委员会委员，中国药师协会临床试验用药品管理工作委员会委员，北京药理学会药物代谢专委会委员，北京药理学会精准药学专业委员会委员。公司创始人和MBT-1316发明人仲伯华教授坚持肝靶向创新药物的研发30余年，历任国家药典委员会第八、九、十届委员，江苏康缘药业股份有限公司独立董事；作为主要完成人研发的肝靶向治疗药物“乳糖化白蛋白－单磷酸阿糖腺苷偶合物”被列入《国家级化学药品开发指南》，并获得军队科技进步二等奖；作为第一发明人研发的PD创新药物左旋盐酸去甲基苯环壬酯为全球首个进入临床的M4选择性拮抗剂。关于肝病新药联盟肝病新药联盟，作为一个聚焦脂肪肝、乙型肝炎、肝硬化和肝癌四大疾病领域新药研发的行业组织，汇聚了研发、医疗、服务、投资、监管、咨询等相关行业的机构和专业人士，通过分享信息、举办会议、培训等活动促进会员、行业同仁之间的交流、合作以及联盟与海内外监管机构、药企、研究机构、同类组织之间的互动、合作，提升中国肝病新药研发的整体水平，最终推动、加快更多肝病新药的研发、上市，惠及中国及全球的患者。欢迎欣赏肝病新药联盟前沿论坛！点击在看，共济新药研发浪潮

临床3期临床1期引进/卖出临床2期申请上市

2022-11-25

·Business Wire

Global Chronic Hepatitis Delta Virus (HDV) Infection Drug Pipeline Insight Report 2022: Comprehensive Insights About 10+ Companies and 10+ Pipeline Drugs - ResearchAndMarkets.com

DUBLIN--( BUSINESS WIRE )--The "Chronic Hepatitis Delta Virus (HDV) Infection - Pipeline Insight, 2022" clinical trials has been added to ResearchAndMarkets.com's offering. This report provides comprehensive insights about 10+ companies and 10+ pipeline drugs in Chronic Hepatitis Delta Virus (HDV) Infection pipeline landscape. It covers the pipeline drug profiles, including clinical and nonclinical stage products. It also covers the therapeutics assessment by product type, stage, route of administration, and molecule type. It further highlights the inactive pipeline products in this space. The assessment part of the report embraces, in depth Chronic Hepatitis Delta Virus (HDV) Infection commercial assessment and clinical assessment of the pipeline products under development. In the report, detailed description of the drug is given which includes mechanism of action of the drug, clinical studies, NDA approvals (if any), and product development activities comprising the technology, Chronic Hepatitis Delta Virus (HDV) Infection collaborations, licensing, mergers and acquisition, funding, designations and other product related details. Report Highlights The companies and academics are working to assess challenges and seek opportunities that could influence Chronic Hepatitis Delta Virus (HDV) Infection R&D. The therapies under development are focused on novel approaches to treat/improve Chronic Hepatitis Delta Virus (HDV) Infection. Chronic Hepatitis Delta Virus (HDV) Infection Emerging Drugs Chapters This segment of the Chronic Hepatitis Delta Virus (HDV) Infection report encloses its detailed analysis of various drugs in different stages of clinical development, including phase II, I, preclinical and Discovery. It also helps to understand clinical trial details, expressive pharmacological action, agreements and collaborations, and the latest news and press releases. Chronic Hepatitis Delta Virus (HDV) Infection Emerging Drugs Lonafarnib: Eiger Biopharmaceuticals Eiger's lead drug candidate, Lonafarnib is an orally administered small molecule in development for the treatment of chronic HDV infection. The Phase I and II clinical trials have demonstrated good safety and efficacy. The drug acts by blocking the key enzyme required by HDV virus to replicate which is anticipated to cure the HDV infection.Currently, the drug is in Phase III stage of Clinical trial evaluation for the treatment of Chronic Hepatitis D Virus Infection. JNJ-73763989: Janssen Pharmaceuticals Janssen "breakthrough" drug JNJ-73763989 is currently being evaluated for the treatment of chronic hepatitis delta virus infection. The drug is a liver-targeted antiviral class molecule designed to treat HVB and HVD infection via RNA interference mechanism. Currently, the drug is in Phase II stage of Clinical trial evaluation for the treatment of Chronic Hepatitis D Virus Infection. Chronic Hepatitis Delta Virus (HDV) Infection: Therapeutic Assessment This segment of the report provides insights about the different Chronic Hepatitis Delta Virus (HDV) Infection drugs segregated based on following parameters that define the scope of the report, such as: Major Players in Chronic Hepatitis Delta Virus (HDV) Infection There are approx. 10+ key companies which are developing the therapies for Chronic Hepatitis Delta Virus (HDV) Infection. The companies which have their Chronic Hepatitis Delta Virus (HDV) Infection drug candidates in the mid to advanced stage, i.e. phase III include, Eiger Biopharmaceuticals. Phases This report covers around 10+ products under different phases of clinical development like Late-stage products (Phase III) Mid-stage products (Phase II and Phase I/II) Early-stage products (Phase I/II and Phase I) along with the details of Pre-clinical and Discovery stage candidates Discontinued & Inactive candidates Route of Administration Chronic Hepatitis Delta Virus (HDV) Infection pipeline report provides the therapeutic assessment of the pipeline drugs by the Route of Administration. Products have been categorized under various ROAs such as Subcutaneous Intravenous Oral Intramuscular Molecule Type Products have been categorized under various Molecule types such as Small molecules Natural metabolites Monoclonal antibodies Product Type Drugs have been categorized under various product types like Mono, Combination and Mono/Combination. Chronic Hepatitis Delta Virus (HDV) Infection: Pipeline Development Activities The report provides insights into different therapeutic candidates in phase II, I, preclinical and discovery stage. It also analyses Chronic Hepatitis Delta Virus (HDV) Infection therapeutic drugs key players involved in developing key drugs. Pipeline Development Activities The report covers the detailed information of collaborations, acquisition and merger, licensing along with a thorough therapeutic assessment of emerging Chronic Hepatitis Delta Virus (HDV) Infection drugs. Chronic Hepatitis Delta Virus (HDV) Infection Report Insights Chronic Hepatitis Delta Virus (HDV) Infection Pipeline Analysis Therapeutic Assessment Unmet Needs Impact of Drugs Chronic Hepatitis Delta Virus (HDV) Infection Report Assessment Pipeline Product Profiles Therapeutic Assessment Pipeline Assessment Inactive drugs assessment Unmet Needs Key Players Janssen Pharmaceuticals Eiger Biopharmaceutical Pharma Essentia Vir Biotechnology, Inc. Huahui Health Antios Therapeutics Key Products JNJ-73763989 Lonafarinib P1101 VIR 2218 VIR 3434 Nivolumab HH 003 ATI 2173 For more information about this clinical trials report visit https://www.researchandmarkets.com/r/wr0q5q

临床2期临床3期临床结果临床1期

100 项与 ATI-2173 相关的药物交易

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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	摩尔多瓦	Antios Therapeutics, Inc.初创企业	2021-03-30
慢性乙型肝炎	临床2期	乌克兰	Antios Therapeutics, Inc.初创企业	2021-03-30
丁型肝炎	临床2期	摩尔多瓦	Antios Therapeutics, Inc.初创企业	2021-03-30
丁型肝炎	临床2期	乌克兰	Antios Therapeutics, Inc.初创企业	2021-03-30
乙型肝炎	临床2期	美国	Antios Therapeutics, Inc.初创企业	2021-03-29

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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


NCT04248426 (Pubmed) 人工标引	临床1期	慢性乙型肝炎	25	ATI 2173	顧鬱簾繭顧夢鏇膚獵膚(窪淵製壓鏇蓋壓醖鏇鹽) = 構廠蓋淵製選淵糧獵選製窪憲願餘網願繭鑰選 (積艱獵繭淵廠糧願淵窪 ) 更多	积极	2022-10-06
				Placebo	顧鬱簾繭顧夢鏇膚獵膚(窪淵製壓鏇蓋壓醖鏇鹽) = 願網糧餘窪獵構構構憲製窪憲願餘網願繭鑰選 (積艱獵繭淵廠糧願淵窪 ) 更多
NCT04248426 (ANTT101, EASL2021)	临床1期	乙型肝炎 HBeAg-negative \| HBsAg-positive	25	ATI-2173 10 mg	網遞獵獵糧範醖艱願壓(蓋蓋淵築構齋憲積願構) = The most common AE was headache 簾積餘製窪廠鏇衊鏇窪 (襯獵夢醖製蓋簾襯艱獵 ) 更多	-	2021-06-23
				ATI-2173 25 mg
NCT04248426 (ANTT101, EASL2021)	临床1期	慢性乙型肝炎	17	ATI-2173 10 mg	醖繭壓築鑰繭淵觸顧糧(蓋膚製襯膚壓窪夢鏇鹽) = 願餘淵窪糧蓋襯淵餘網蓋鑰鹽膚膚簾願網鏇範 (壓鹽夢鹹鬱夢範鹹繭廠 )	-	2021-06-23
				ATI-2173 25 mg	醖繭壓築鑰繭淵觸顧糧(蓋膚製襯膚壓窪夢鏇鹽) = 壓壓築鹹鑰鏇範遞繭窪蓋鑰鹽膚膚簾願網鏇範 (壓鹽夢鹹鬱夢範鹹繭廠 )
not available (EASL2020)	N/A	乙型肝炎	-	ATI-2173	憲製窪衊選築襯鹽襯淵(淵構醖觸鹹簾築壓壓餘) = 鬱廠網鬱願淵餘獵襯積糧襯簾鑰構夢鑰繭願簾 (蓋鬱窪獵憲膚艱廠膚鬱 ) 更多	积极	2020-08-27