(Adafosbuvir) - 药物靶点：NS5B polymerase_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Adafosbuvir (USAN)

+ [5]

靶点

NS5B polymerase

作用机制

NS5B polymerase抑制剂(丙型肝炎病毒NS5B RNA依赖的RNA聚合酶抑制剂)

治疗领域

感染消化系统疾病其他疾病

在研适应症-

非在研适应症

慢性丙型肝炎基因型 1慢性丙型肝炎基因型 3代偿期肝硬化+ [2]

原研机构

Alios BioPharma, Inc.

在研机构-

非在研机构

Janssen Research & Development LLC

Alios BioPharma, Inc.

Janssen Pharmaceuticals, Inc.

最高研发阶段终止临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C22H29FN3O10P

InChIKeyNIJYGVDQZBBONK-SEUXLIJBSA-N

CAS号1613589-09-5

关联

11

项与 Adafosbuvir 相关的临床试验

EUCTR2016-002845-46-GB / Not yet recruiting临床2期

A Phase 2a, Open-Label Study to Evaluate the Safety, Pharmacokinetics and Efficacy of the Combination of AL-335 and Odalasvir, with or without Simeprevir, in Treatment-Naïve Subjects with Genotype 1, 2 or 3 Chronic Hepatitis C infection with or without compensated Child Pugh A Cirrhosis

开始日期2017-02-03

申办/合作机构

Alios BioPharma, Inc.

JPRN-JapicCTI-163468 / Unknown status临床2期

A Phase 2a, Multicenter, Open-label Study to Investigate the Safety, Pharmacokinetics, and Efficacy of Combination Treatment of AL-335, Odalasvir, and Simeprevir in Japanese Subjects With Chronic Hepatitis C Genotype 1 or 2 Virus Infection, With or Without Compensated Cirrhosis who are Direct acting Antiviral Treatment-naive

开始日期2016-12-21

申办/合作机构

Janssen Pharmaceuticals, Inc.

NCT02993250 / Completed临床2期

A Phase 2a, Multicenter, Open-label Study to Investigate the Safety, Pharmacokinetics, and Efficacy of Combination Treatment of AL-335, Odalasvir, and Simeprevir in Japanese Subjects With Chronic Hepatitis C Genotype 1 or 2 Virus Infection, With or Without Compensated Cirrhosis Who Are Direct Acting Antiviral Treatment-naïve

The main purpose of this study is to evaluate the safety and tolerability of a combination treatment of AL-335, odalasvir (ODV), and simeprevir (SMV) for 8 weeks in Japanese participants with genotype 1 or 2 chronic hepatitis C virus (HCV) infection without cirrhosis and for 12 weeks in direct-acting antiviral (DAA)-naive Japanese participants with genotype 1 or 2 chronic HCV infection with compensated cirrhosis.

开始日期2016-12-21

申办/合作机构

Janssen Pharmaceuticals, Inc.

100 项与 Adafosbuvir 相关的临床结果

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100 项与 Adafosbuvir 相关的转化医学

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100 项与 Adafosbuvir 相关的专利（医药）

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8

项与 Adafosbuvir 相关的文献（医药）

2022-02-15·Accounts of Chemical Research1区 · 化学

4′-Modified Nucleosides for Antiviral Drug Discovery: Achievements and Perspectives

1区 · 化学

Article

作者: Chang, Junbiao

Modified nucleosides show therapeutic promise for antiviral therapies. However, issues including the emergence of drug resistance, toxicity, and coinfections have posed new challenges for nucleoside-based antiviral drug discovery, particularly in the era of the coronavirus disease 2019 (COVID-19) pandemic. Chemical manipulation could impact the antiviral potency, safety, and drug resistance of nucleosides. Generally, modified nucleosides are difficult to recognize by intracellular important enzymes as substrates and thus exhibit low toxicity. 4'-Modified nucleosides represent an important subclass of modified nucleosides for antiviral therapies. To prevent the occurrence of drug resistance, 4'-modified nucleosides should have 3'-OH, which should also be chemically unreactive for proviral DNA biosynthesis. The absence of 3'-OH may explain the occurrence of drug resistance for censavudine. The introduction of 4'-substituents improves enzymatic and acidic stability and makes the nucleosides more lipophilic, thus improving cell permeability and bioavailability. Steric hindrance between the 4'-substituent and 3'-OH changes the furanose conformation to the 3'-endo type, in which the oxygen lone pair on the furanose ring could not form an oxocarbonium ion for glycolysis. Currently, seven 4'-modified nucleoside drug candidates such as azvudine (also known as FNC), islatravir, censavudine, balapiravir, lumicitabine, AL-335, and 4-azidothymidine have progressed into clinical stages for treating viral infections. Of note, FNC was officially approved by NMPA in July 2021 for use in adult patients with high HIV-1 virus loads (nos. H20210035 and H20210036), providing an alternative therapeutic for patients with HIV-1. The long-term cellular retention of FNC suggests its potential as a long-lasting pre-exposure prophylaxis (PrEP) agent for preventing HIV-1 infection. Mechanistically, FNC not only inhibited HIV-1 reverse transcription and replication but also restored A3G expression in peripheral blood CD4⁺ T cells in HIV-1 patients receiving FNC. The 4'-azido group in azvudine stabilizes the 3'-C-endo (north) conformation by steric effects and the formation of an intramolecular hydrogen bond with the 3'-OH group, thus decreasing the nucleophilicity of 3'-OH. The north conformation may also enhance the phosphorylation efficiency of FNC by cellular kinases. Encouragingly, FNC, islatravir, and balapiravir show promise for the treatment of coronaviruses, of which FNC has advanced to phase 3 clinical trials in different countries to treat patients with COVID-19 (clinical trial numbers: NCT04668235 and NCT04425772). FNC cured the COVID-19 disease in almost all patients and showed better therapeutic efficacy than remdesivir. In this Account, we provide an overview of 4'-modified nucleoside analogs in clinical stages for antiviral therapies, highlighting the drug discovery strategies, structure-activity relationship studies, and preclinical/clinical studies and also give our perspectives on nucleoside-based antiviral drug discovery.

2020-06-01·Journal of Gastroenterology1区 · 医学

JNJ-4178 (adafosbuvir, odalasvir, and simeprevir) in Japanese patients with chronic hepatitis C virus genotype 1 or 2 infection with or without compensated cirrhosis: the Phase IIa OMEGA-3 study

1区 · 医学

Article

作者: Yoshida, Hiroki ; Hiramatsu, Naoki ; Nozaki, Akito ; Asahina, Yasuhiro ; Vijgen, Leen ; Kurosaki, Masayuki ; Huang, Yuhan ; Biermer, Michael ; Hayashi, Norio ; Tanaka, Yasuhito ; Nakano, Toshikazu ; Shimizu, Hiroko ; Hagiwara, Yosuke ; Sakamoto, Naoya ; Takehara, Tetsuo ; Chayama, Kazuaki ; Yatsuhashi, Hiroshi

AbstractBackgroundThe efficacy, safety, and pharmacokinetics of the combination of three direct-acting antiviral (DAA) agents (adafosbuvir [also known as AL-335], odalasvir, and simeprevir) were investigated in DAA treatment-naïve Japanese patients with genotype (GT)1 or GT2 chronic hepatitis C virus (HCV) infection, with or without compensated cirrhosis.MethodsIn this Phase IIa, open-label, multicenter study—OMEGA-3 (NCT02993250)—patients received JNJ-4178 (adafosbuvir 800 mg once daily [QD], odalasvir 25 mg QD, and simeprevir 75 mg QD) for 8 (non-cirrhotic patients; Cohort 1) or 12 (cirrhotic patients; Cohort 2) weeks. Patients were followed-up to 24 weeks following the end of treatment (EOT). The primary endpoint was safety, including adverse events (AEs).ResultsOverall, 33 patients were enrolled into Cohort 1 (N = 22) or 2 (N = 11) and received combined treatment with JNJ-4178. During the treatment and follow-up phases, a higher percentage of patients in Cohort 2 (81.8%) experienced AEs compared with Cohort 1 (68.2%), but the incidence of treatment-related AEs was similar. Most AEs were mild-to-moderate in severity and no patients discontinued due to an AE. There was one serious AE (cataract) in a patient in Cohort 2, which was not considered related to treatment. All patients achieved sustained virologic response 12 weeks after EOT (SVR12). No incidences of viral relapse were observed during follow-up.ConclusionsIn HCV GT1- and GT2-infected Japanese patients, treatment with JNJ-4178 was well tolerated and resulted in 100% of patients achieving SVR12.

2019-06-01·Hepatology

JNJ‐4178 (AL‐335, Odalasvir, and Simeprevir) for 6 or 8 Weeks in Hepatitis C Virus‐Infected Patients Without Cirrhosis: OMEGA‐1

Article

作者: Biermer, Michael ; Vijgen, Leen ; Corbett, Chris ; Aghemo, Alessio ; Janczewska, Ewa ; Tam, Edward ; Ackaert, Oliver ; Ouwerkerk-Mahadevan, Sivi ; Moreno, Christophe ; Buggisch, Peter ; Lim, Seng Gee ; Buti, Maria ; Zeuzem, Stefan ; Willems, Wouter ; Fevery, Bart ; Lampertico, Pietro ; Kalmeijer, Ronald ; Beumont, Maria ; Bourgeois, Stefan ; Greenbloom, Susan ; Sinha, Rekha

The combination of three direct‐acting antiviral agents (AL‐335, odalasvir, and simeprevir: JNJ‐4178 regimen) for 6 or 8 weeks demonstrated good efficacy and safety in a phase IIa study in chronic hepatitis C virus (HCV) genotype (GT)‐1‐infected patients without cirrhosis and has now been evaluated in a larger phase IIb study, OMEGA‐1. This multicenter, randomized, open‐label study (NCT02765490) enrolled treatment‐naïve and interferon (±ribavirin) treatment‐experienced patients with HCV GT1, 2, 4, 5, or 6 infection. Patients with HCV GT3 infection and/or liver cirrhosis were excluded. Patients received AL‐335 800 mg, odalasvir 25 mg, and simeprevir 75 mg once daily for 6 or 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). In total, 365 patients (GT1a, 29.3%; GT1b, 42.5%; GT2, 12.3%; GT4, 14.2%; GT5, 1.4%; GT6, 0%) were randomized to receive 6 weeks (n = 183) or 8 weeks (n = 182) of treatment. SVR12 rates after 6 weeks (98.9%) or 8 weeks (97.8%) of treatment were noninferior to a historical control (98%). Viral relapse occurred in 5 patients (1.4%; 4 with HCV GT2c; 1 with GT1a). With the exception of 4 patients in the 8‐week group, including 3 patients with missing data at the SVR24 timepoint, all patients who achieved SVR12 also achieved SVR24. One GT1a‐infected patient experienced late viral relapse after achieving SVR18. Most adverse events (AEs) were mild with no treatment‐related serious AEs. All randomized patients completed treatment. Conclusion: In HCV‐infected patients, 6 and 8 weeks of treatment with JNJ‐4178 resulted in SVR12 rates of 98.9% and 97.8%, respectively, and was well tolerated.

100 项与 Adafosbuvir 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11364	-	-	DB14906

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
慢性丙型肝炎	临床3期	加拿大	Janssen Research & Development LLC	2017-04-10
慢性丙型肝炎	临床3期	新西兰	Janssen Research & Development LLC	2017-04-10
慢性丙型肝炎	临床3期	加拿大	Janssen Research & Development LLC	2017-04-10
慢性丙型肝炎	临床3期	新加坡	Janssen Research & Development LLC	2017-04-10
慢性丙型肝炎	临床3期	波兰	Janssen Research & Development LLC	2017-04-10
慢性丙型肝炎	临床3期	新加坡	Janssen Research & Development LLC	2017-04-10
慢性丙型肝炎	临床3期	波兰	Janssen Research & Development LLC	2017-04-10
慢性丙型肝炎	临床3期	新西兰	Janssen Research & Development LLC	2017-04-10
纤维化	临床3期	新西兰	Alios BioPharma, Inc.	2015-10-31
纤维化	临床2期	摩尔多瓦	Alios BioPharma, Inc.	2015-10-31

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临床结果

适应症

分期

评价

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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


NCT02993250 (OMEGA-3, CTgov)	临床2期	纤维化 \| 慢性丙型肝炎 \| 代偿期肝硬化	33	odalasvir (ODV)+AL-335 (Cohort 1: Chronic Hepatitis C Without Cirrhosis)	艱廠願獵糧壓範繭窪繭(顧製窪築糧膚築遞淵遞) = 艱築選憲糧襯蓋觸憲鬱窪鬱鬱壓襯憲願鹹範餘 (憲廠遞鹽餘鹽範築蓋網, 齋壓簾窪繭膚艱鹽糧鹽 ~ 鹹糧夢蓋憲餘願鏇膚淵) 更多	-	2019-09-11
				SMV+ODV+AL-335 (Cohort 2: Chronic Hepatitis C With Compensated Cirrhosis)	艱廠願獵糧壓範繭窪繭(顧製窪築糧膚築遞淵遞) = 願築範餘蓋醖積鬱觸壓窪鬱鬱壓襯憲願鹹範餘 (憲廠遞鹽餘鹽範築蓋網, 餘襯遞壓簾鑰顧願壓鹹 ~ 網襯顧遞觸鏇襯夢襯築) 更多
NCT02765490 (OMEGA-1, CTgov)	临床2期	纤维化 \| 慢性丙型肝炎	365	SMV+ODV+AL-335 (Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks)	鏇築築廠淵糧蓋膚淵網(齋顧獵選鑰衊鹽蓋遞餘) = 膚範壓遞鏇夢夢廠鏇網願製壓顧艱願艱願選鹽 (顧觸築憲夢觸鬱願鑰醖, 獵夢淵膚襯簾糧壓蓋繭 ~ 鹽築糧艱願選網醖糧壓) 更多	-	2019-01-22
				SMV+ODV+AL-335 (Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks)	鏇築築廠淵糧蓋膚淵網(齋顧獵選鑰衊鹽蓋遞餘) = 網願鏇觸構壓糧壓鏇築願製壓顧艱願艱願選鹽 (顧觸築憲夢觸鬱願鑰醖, 網願艱夢窪鏇積鑰簾顧 ~ 艱構積鏇範壓壓鹹製製) 更多