Impact of HCV Eradication on Neurocognitive Functions and CNS Metabolism: a Trial of Daclatasvir, Asunaprevir and Beclabuvir for Patients With HCV Genotype 1 Infection

The purpose of this study is to examine whether neurocognitive impairments experienced by patients with chronic hepatitis C virus (HCV) infection can be reversed by treating HCV, with a new combination of direct acting antiviral drugs (daclatasvir (DCV), asunaprevir (ASV) and beclabuvir (BCV)). The study will assess the effect of HCV on the central nervous system (CNS) by assessing neurocognitive function and brain injury prior to treatment, and comparing it to the end of treatment, and 4, 12 and 24 weeks after treatment.

开始日期2015-07-01

申办/合作机构

Kirby Institute

[+1]

NCT02309450

/ Withdrawn临床2期IIT

Pilot Study to Assess Efficacy and Safety of a Triple Therapy With Asunaprevir, Daclatasvir and BMS-791325 in HCV Genotype 4-infected Patients After Failure of Pegylated Interferon-Ribavirin Regimen

ANRS HC 33 is a pilot study to assess efficacy and safety of a DCV 3DAA therapy with Asunaprevir, Daclatasvir and BMS-791325 in HCV genotype 4-infected patients after failure of pegylated Interferon-Ribavirin regimen.
Proportion of patients with cirrhosis will be limited to 50% of all patients included, cirrhosis being defined as a METAVIR score of F4 on the liver biopsy or an hepatic impulse elastometry ≥ 14 kPa or a Fibrotest® result > 0,75.

开始日期2014-12-01

申办/合作机构

France Recherche Nord & Sud SIDA HIV-Hepatites

[+1]

NCT02175966

/ Completed临床2期

Short Duration Combination Therapy With Daclatasvir, Asunaprevir, BMS-791325 and Sofosbuvir in Subjects Infected With Chronic Hepatitis C (FOURward Study)

The purpose of the study is to determine whether the combination of Daclatasvir (DCV), Asunaprevir (ASV), BMS-791325 and Sofosbuvir is effective and safe in treating Hepatitis-C virus.

开始日期2014-07-28

申办/合作机构

Bristol Myers Squibb Co.

100 项与 Daclatasvir dihydrochloride/Asunaprevir/Beclabuvir hydrochloride 相关的临床结果

登录后查看更多信息

100 项与 Daclatasvir dihydrochloride/Asunaprevir/Beclabuvir hydrochloride 相关的转化医学

登录后查看更多信息

100 项与 Daclatasvir dihydrochloride/Asunaprevir/Beclabuvir hydrochloride 相关的专利（医药）

登录后查看更多信息

项与 Daclatasvir dihydrochloride/Asunaprevir/Beclabuvir hydrochloride 相关的文献（医药）

2020-02-11·EXPERT OPINION ON PHARMACOTHERAPY

Efficacy and safety of a fixed dose combination tablet of asunaprevir + beclabuvir + daclatasvir for the treatment of Hepatitis C

Review

作者: Gentile, Ivan ; Zappulo, Emanuela ; Maraolo, Alberto Enrico ; Scotto, Riccardo ; Pinchera, Biagio ; Buonomo, Antonio Riccardo

Introduction: Hepatitis C virus (HCV) is estimated to infect approximately 70 million people worldwide. If left untreated, chronic infection can progress to cirrhosis, liver failure or hepatocellular carcinoma. The advent of new direct-acting antivirals (DAA) has revolutionized patients' chances of treatment and viral elimination. Currently, several DAA options are available on the market.Areas covered: This review focuses on the pharmacokinetics, efficacy, tolerability and safety profile of DCV-TRIO, a twice-daily fixed-dose combination of daclatasvir, asunaprevir and beclabuvir approved in Japan for the treatment of genotype 1 HCV infection.Expert opinion: The DCV-TRIO combination achieved good response rates in genotype 1 patients (SVR12 ≥ 95% in naïve subtype 1b), independently from IL28B genotype, cirrhotic status and prior interferon exposure. On the other hand, unsatisfying response rates were reported in DAA-experienced patients and the risk of RAS selection should not be underestimated. Moreover, DCV-TRIO lacks differentiation from its earlier-launched DAA rivals, presents an inconvenient twice-daily dosing schedule and is not recommended in patients with advanced liver and kidney disease. All these drawbacks considerably limit its effective commercial potential. However, it can be a therapeutic option against HCV in tailored approaches according to the needs of different markets across the world.Abbreviations AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ASV: asunaprevir; AUC: area under the curve; BCRP: Breast Cancer Resistance Protein; BCV: boceprevir; BID: bis in die; CI: confidence intervals; CLcr: creatinine clearance; DAA: direct acting antivirals; DCV: daclatasvir; EC50: Half maximal effective concentration; GT: genotype; HCV: Hepatitis C virus; IFN: Interferon; NHL: non-Hodgkin lymphoma; OATP: Organic anion transporting polypeptides; OR: odds ratio; P-gp: P-glycoprotein; PK: pharmacokinetics; QD: quo die; RAS: resistance-associated substitutions; SVR: sustained virological response; USD: Unites States dollar.

2018-09-01·Journal of gastroenterology1区 · 医学

Potent viral suppression and improvements in alpha-fetoprotein and measures of fibrosis in Japanese patients receiving a daclatasvir/asunaprevir/beclabuvir fixed-dose combination for the treatment of HCV genotype-1 infection

1区 · 医学

Article

作者: Akuta, Norio ; Toyota, Joji ; Inada, Yukiko ; Fujiyama, Shigetoshi ; McPhee, Fiona ; Chayama, Kazuaki ; Kumada, Hiromitsu ; Naganuma, Atsushi ; Takaguchi, Koichi ; Watanabe, Hideaki ; Ishikawa, Hiroki ; Ikeda, Fusao ; Tomita, Eiichi ; Tanaka, Katsuaki ; Karino, Yoshiyasu ; Yoshiji, Hitoshi ; Noviello, Stephanie ; Ido, Akio

BACKGROUND:

In the UNITY-3 study, 96% sustained virologic response (SVR12) rate was observed in Japanese patients with hepatitis C virus (HCV) genotype (GT)-1 infection treated for 12 weeks with fixed-dose daclatasvir, asunaprevir, and beclabuvir (DCV-TRIO). As HCV clearance may improve liver outcomes, we assessed hepatic fibrosis and alpha-fetoprotein (AFP), a hepatocellular carcinoma risk marker, pre- and post-treatment in UNITY-3.

METHODS:

Treatment-naive or interferon-experienced UNITY-3 patients with HCV GT-1 who received twice-daily DCV-TRIO were assessed for fibrosis [FibroTest; FibroScan; fibrosis-4 index (FIB-4), aspartate-aminotransferase-to-platelet-ratio index] and AFP at baseline and Weeks 4 (FIB-4 only), 12 or 24 post-treatment.

RESULTS:

Of 217 patients, 99% had GT-1b infection, 46% were aged > 65 years, 21% had compensated cirrhosis, and 26% baseline HCV-RNA > 10⁷ IU/mL. All GT-1b patients treated ≥ 4 weeks achieved SVR12 with (n = 54) or without (n = 144) baseline NS5A polymorphisms associated with DCV resistance (positions 28/30/31/93). Statistically significant post-treatment reductions from baseline were observed for all fibrosis measures and AFP, with numerically greater reductions in cirrhotic patients. FibroTest category improved in 44%, remained stable in 50%, and worsened in 6% of patients; 98% with baseline AFP < 6 μg/L remained < 6 μg/L and 51% with baseline AFP ≥ 6 μg/L were < 6 μg/L post-treatment.

CONCLUSIONS:

DCV-TRIO administered for 12 weeks to Japanese patients with primarily GT-1b infection achieved a high SVR12 rate and resulted in improved measures of hepatic fibrosis and serum AFP that may reduce the risk of future liver disease progression and hepatocellular carcinoma, particularly in those with compensated cirrhosis.

2018-06-03·Expert opinion on drug metabolism & toxicology2区 · 医学

Pharmacokinetic and pharmacodynamic evaluation of daclatasvir, asunaprevir plus beclabuvir as a fixed-dose co-formulation for the treatment of hepatitis C

2区 · 医学

Review

作者: Marciano, Sebastián ; Trinks, Julieta ; Esposito, Isabella

INTRODUCTION:

Many reports have evaluated the clinical efficacy and safety of the fixed-dose all-oral combination of daclatasvir, asunaprevir, and beclabuvir (DCV-TRIO), which was approved in Japan in December 2016 for the treatment of hepatitis C genotype (GT)-1 infection. Areas covered: This article reviews the pharmacodynamic and pharmacokinetic properties of the DCV-TRIO combination. The topics covered include data regarding the drug's absorption, distribution, metabolism, excretion, and antiviral activity strategies. Its therapeutic efficacy and safety in GT-1 infection from phase 2/3 clinical trials are also discussed. Expert opinion: The ideal regimen for the treatment of Hepatitis C virus infection should be potent, pangenotypic, Ribavirin-free, safe, co-formulated, and affordable. Considering these characteristics, DCV-TRIO is neither pangenotypic nor potent enough against GT-1a, regardless of the presence or absence of cirrhosis. Other potential limitations of this regimen are its dosification (twice-daily), and the fact that since it includes a protease inhibitor, it is contraindicated in decompensated cirrhosis. For these reasons, it has only been approved in Japan, where more than 70% of the patients are infected with GT-1b. However, this co-formulation might still have a place in the treatment of non-cirrhotic patients infected with GT-1b provided that massive access to treatment is facilitated.

项与 Daclatasvir dihydrochloride/Asunaprevir/Beclabuvir hydrochloride 相关的新闻（医药）

2025-02-11

·CPHI制药在线

东阳光新药获批上市，盘点丙肝治愈的重要时刻

关注并星标CPHI制药在线近日，东阳光药业1类创新药磷酸萘坦司韦胶囊获NMPA批准上市，用于与艾考磷布韦片联用，治疗初治或干扰素经治的基因1、2、3、6型成人慢性丙型肝炎病毒（HCV）感染，可合并或不合并代偿性肝硬化。磷酸萘坦司韦是一款NS5A抑制剂，艾考磷布韦是一款NS5B抑制剂，两款药均为东阳光药自主研发的1类新药。该联合疗法治疗慢性丙肝的2期临床研究显示，该方案在基因1型、2型、3型和6型受试者中SVR12（治疗结束后12周时实现持续病毒学应答的受试者百分比）分别为96.2%、100.0%、83.3%、100.0%。代偿期肝硬化和无肝硬化受试者总体SVR12分别为100%和96.2%。全分析集分析结果显示总体SVR12为96.7%。以此出发，我们回顾一下丙肝药物开发的重要时刻。干扰素治疗丙肝的困境 HCV于1989年被发现，是一种常见的血源性病原体，主要感染部位是肝脏，一经感染，如果不采取进一步治疗，HCV可能引发急性或慢性肝炎，并增加感染者发展为肝硬化、肝功能衰竭和肝癌的风险。HCV共存在6种基因型（1-6），丙肝患者以基因1型居多，占大约70%。 2020年，三位科学家因发现了HCV获得诺贝尔生理学或医学奖。当年诺奖颁发时，已经有了很多治疗HCV的药物。而在此之前，丙肝的治疗主要采用聚乙二醇干扰素（一种具有抗病毒、抗肿瘤和免疫调节特性的多效性细胞因子）联合利巴韦林（一种广谱抗病毒药物）。其方案为连续在24至48周内注射聚乙二醇干扰素和服用利巴韦林，但这种疗法不仅费用昂贵且毒副作用强，例如干扰素会引起流感样症状，利巴韦林则可能引起溶血性贫血。在许多情况下，严重的副作用导致患者停止治疗。在疗效方面，根据《丙型肝炎防治指南》，“干扰素+利巴韦林”治愈率大概只有54%-82%，且治愈者有不小的几率会复发。 20世纪末，随着HCV体外培养难题被攻克，新的机会出现了。科学家们终于有了能用来筛选丙肝药物的工具，这为开发直接抗病毒药物（DAAs）奠定了基础。 NS3/4A蛋白酶抑制剂宣布HCV治疗进入DAA时代研究发现，HCV是一条单链正义RNA病毒，基因组包含10个基因，编码膜蛋白E1和E2，核心蛋白、p7以及非结构蛋白NS2、NS3、NS4A、NS4B、NS5A和NS5B。其中NS3/4A、NS5A、NS5B是HCV复制过程中三个重要的作用靶点 DAAs的作用靶点（图片来源：参考来源2）针对这三个靶点，科学家们研发了HCV特异的直接抗病毒药物：NS3/4A 蛋白酶抑制剂、NS5A 抑制剂及NS5B 聚合酶抑制剂。 NS3/4A蛋白酶抑制剂是最早上市的丙肝特异的DAA。NS3/4A复合体主要催化丙肝病毒非结构蛋白水解成熟，是丙肝病毒生活周期所必须的。 2011年，第一个NS3/4A蛋白酶抑制剂Boceprevir（波西普韦）获FDA批准上市，用于与聚乙二醇干扰素和利巴韦林联合治疗HCV患者，该药由默沙东开发。后续分别上市了Vertex/强生的Incivek(特拉瑞韦，已退市)、强生的Olysio(西美瑞韦，Simeprevir)，以及BMS在日本上市的Sunvepra（asunaprevir）。 NS3/4A蛋白酶抑制剂的出现，使“干扰素注射+利巴韦林+DAA”成为丙肝临床标准治疗方案，并将临床治愈率从40%提高到了80%以上。 NS5B 聚合酶抑制剂使口服治愈丙肝成为可能 NS5B是HCV的RNA聚合酶，抑制它将会直接抑制RNA合成，从而终止病毒复制。而且在不同基因型的HCV中，NS5B 聚合酶均高度保守，且抑制它不会产生宿主毒性，因此，NS5B成为一个理想的抗HCV病毒靶点。尽管从蛋白编号上来看，NS5B似乎是在NS5A之后。但是从成药速度而言，NS5B抑制剂却早于NS5A抑制剂出现。 2013年，吉利德的小分子药NS5B抑制剂索非布韦(sofosbuvir)获FDA批准上市。索非布韦最初由Pharmasset公司开发，后该公司被吉利德收购，索非布韦被成功纳入麾下。索非布韦对多个基因型HCV感染均疗效惊人，直接把疾病治愈率提高到近乎100%，而且索非布韦是首个获批可用于慢性丙型肝炎全口服治疗方案的药物，在用于特定基因型慢丙肝治疗时，可消除对干扰素的需求。 2014年，索非布韦上市的第一年，销售收入就达102.83亿美元，创下新药上市首年销售突破100亿美元的记录。市场上另外两种NS5B抑制剂分别是艾伯维的达拉他韦（Viekira Pak，2014年）和BMS的贝卡布韦（Ximency，2016年，仅在日本获批），它们都是复方药物的成分。 NS5A 抑制剂，复合DAA方案中的骨干与HCV基因组中的许多其他蛋白质不同，NS5A （非结构蛋白5A）实际上没有酶的活性，但它却是HCV RNA复制和病毒粒子组装所必需的，被称为HCV生命周期的主调节器。 2014年，BMS的达卡他韦（Daclatasvir）在日本获批上市，用于治疗基因1型慢丙肝、丙肝代偿性肝硬化和病毒血症。达卡他韦通过结合NS5A蛋白N末端二聚体，抑制NS5A从而抑制HCV复制。达卡他韦上市后，多个NS5A抑制剂陆续推出。在慢丙肝治疗中，由于单一靶点药物不足以满足全口服、短疗程、多基因型有效、高治愈率的要求，因此一般采用DAA联合治疗方案。目前所有多靶点组合DAA方案中，都含有NS5A抑制剂作为骨干。与之配伍的可以是一个NS3/4A蛋白酶抑制剂（如elbasvir/grazoprevir）、一个NS5B聚合酶抑制剂（如sofosbuvir/ledipasvir）或者两种均有（如sofosbuvir/velpatasvir/voxilaprevir）。这些方案都达到了95%甚至更高的治愈率。自HCV被发现以来，政府机构以及制药行业均投入大量资源，发现了许多有效的抗丙肝药物。现在可以通过持续病毒学应答（SVR）来实现治愈。由于丙肝的高治愈率，用药患者人数在大幅减少，在患者群体日益萎缩的情况下，丙肝药物市场正在大幅缩水。该赛道相关玩家，早已开始转型。参考来源： 1.https://www.nmpa.gov.cn/zhuanti/cxylqx/cxypxx/20250208172031130.html. 2.Palese P. Profile of Charles M. Rice, Ralf F. W. Bartenschlager, and Michael J. Sofia, 2016 Lasker-DeBakey Clinical Medical Research Awardees. Proc Natl Acad Sci U S A. 2016 Dec 6;113(49):13934-13937. doi: 10.1073/pnas.1616592113. Epub 2016 Nov 18. PMID: 27864510; PMCID: PMC5150379. 3.Tiffany Benzine, Ryan Brandt, William C. Lovell et al. NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains. PLoS Pathogens, Published: June 8, 2017, doi:10.1371/journal.ppat.1006343. 扫码领取CPHI & PMEC China 2025展会门票【智药研习社近期直播】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

上市批准申请上市

100 项与 Daclatasvir dihydrochloride/Asunaprevir/Beclabuvir hydrochloride 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
-	-	J05AP58	-

研发状态

批准上市

10 条最早获批的记录,

后查看更多信息

适应症	国家/地区	公司	日期
纤维化	日本	Bristol Myers Squibb Co.	2016-12-19
丙型肝炎	日本	Bristol Myers Squibb Co.	2016-12-19

未上市

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
慢性丙型肝炎基因型 1	临床3期	美国	Bristol Myers Squibb Co.	2013-12-01
慢性丙型肝炎基因型 1	临床3期	澳大利亚	Bristol Myers Squibb Co.	2013-12-01
慢性丙型肝炎基因型 1	临床3期	加拿大	Bristol Myers Squibb Co.	2013-12-01
慢性丙型肝炎基因型 1	临床3期	法国	Bristol Myers Squibb Co.	2013-12-01
慢性丙型肝炎基因型 1	临床3期	波多黎各	Bristol Myers Squibb Co.	2013-12-01
终末期肾脏病	临床1期	美国	Bristol Myers Squibb Co.	2014-04-01

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02175966 (FOURward, CTgov)	临床2期	慢性丙型肝炎	35	DCV 3DAA+SOF (4 Weeks DCV 3DAA + SOF)	糧夢顧餘製醖遞鹹製顧 = 範鏇齋鏇醖製顧築顧簾選願廠簾淵顧製蓋製艱 (襯醖壓艱積窪膚網網蓋, 範夢鬱遞獵鬱鑰鬱襯壓 ~ 壓繭鹽簾觸糧窪顧獵襯) 更多	-	2019-05-29
				DCV 3DAA+SOF (6 Weeks DCV 3DAA + SOF)	糧夢顧餘製醖遞鹹製顧 = 餘壓顧簾淵顧構醖選艱選願廠簾淵顧製蓋製艱 (襯醖壓艱積窪膚網網蓋, 積夢顧選窪淵積夢獵獵 ~ 憲夢鑰網糧齋膚鹹襯鑰) 更多
NCT02170727 (UNITY-4, Pubmed) 人工标引	临床3期	慢性丙型肝炎基因型 1	169	Daclatasvir/asunaprevir/beclabuvir (treatment-naive patients)	糧鑰鑰繭築選窪範觸糧(醖窪膚餘鹹衊衊選衊壓) = 夢鏇齋觸製醖齋網願醖鬱憲鏇餘窪鹽簾鑰鑰繭 (顧積遞艱構夢鹽餘網網, 94.9 ~ 99.8)	积极	2017-12-01
				Daclatasvir/asunaprevir/beclabuvir (treatment-experienced patients)	糧鑰鑰繭築選窪範觸糧(醖窪膚餘鹹衊衊選衊壓) = 獵廠觸構艱餘窪壓築壓鬱憲鏇餘窪鹽簾鑰鑰繭 (顧積遞艱構夢鹽餘網網, 88.8 ~ 100)