Delving into the Latest Updates on Adafosbuvir with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Adafosbuvir (USAN)

+ [6]

Target

NS5B polymerase

Mechanism

NS5B polymerase inhibitors(Hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors)

Therapeutic Areas

Infectious DiseasesDigestive System DisordersOther Diseases

Active Indication-

Inactive Indication

Chronic hepatitis C genotype 1Chronic hepatitis C genotype 3Compensated cirrhosis+ [2]

Originator Organization

Alios BioPharma, Inc.

Active Organization-

Inactive Organization

Alios BioPharma, Inc.Janssen Research & Development LLC

Janssen Pharmaceuticals, Inc.

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

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Structure

Molecular FormulaC22H29FN3O10P

InChIKeyNIJYGVDQZBBONK-SEUXLIJBSA-N

CAS Registry1613589-09-5

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

Start Date21 Dec 2016

Sponsor / Collaborator

Janssen Pharmaceuticals, Inc.

NCT02993250 / CompletedPhase 2

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.

Start Date21 Dec 2016

Sponsor / Collaborator

Janssen Pharmaceuticals, Inc.

100 Clinical Results associated with Adafosbuvir

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100 Translational Medicine associated with Adafosbuvir

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100 Patents (Medical) associated with Adafosbuvir

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8

Literatures (Medical) associated with Adafosbuvir

15 Feb 2022·Accounts of Chemical ResearchQ1 · CHEMISTRY

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

Q1 · CHEMISTRY

Article

Author: 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.

01 Jun 2020·Journal of GastroenterologyQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: 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.

01 Jun 2019·Hepatology

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

Article

Author: 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 ; Bourgeois, Stefan ; Kalmeijer, Ronald ; Beumont, Maria ; 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 Deals associated with Adafosbuvir

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External Link

KEGG	Wiki	ATC	Drug Bank
D11364	-	-	DB14906

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis C, Chronic	Phase 3	PL	Janssen Research & Development LLC	10 Apr 2017
Hepatitis C, Chronic	Phase 3	PL	Janssen Research & Development LLC	10 Apr 2017
Hepatitis C, Chronic	Phase 3	NZ	Janssen Research & Development LLC	10 Apr 2017
Hepatitis C, Chronic	Phase 3	CA	Janssen Research & Development LLC	10 Apr 2017
Hepatitis C, Chronic	Phase 3	SG	Janssen Research & Development LLC	10 Apr 2017
Hepatitis C, Chronic	Phase 3	SG	Janssen Research & Development LLC	10 Apr 2017
Hepatitis C, Chronic	Phase 3	CA	Janssen Research & Development LLC	10 Apr 2017
Hepatitis C, Chronic	Phase 3	NZ	Janssen Research & Development LLC	10 Apr 2017
Fibrosis	Phase 3	GB	Alios BioPharma, Inc.	31 Oct 2015
Fibrosis	Phase 3	NZ	Alios BioPharma, Inc.	31 Oct 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02993250 (OMEGA-3, CTgov)	Phase 2	Fibrosis \| Hepatitis C, Chronic \| Compensated cirrhosis	33	odalasvir (ODV)+AL-335 (Cohort 1: Chronic Hepatitis C Without Cirrhosis)	ussnbeehkd(xebyoghujh) = gcjetwgepz spvvshdcop (euekfxdhrq, nakvnuxlgs - zseckplxxt) View more	-	11 Sep 2019
				SMV+ODV+AL-335 (Cohort 2: Chronic Hepatitis C With Compensated Cirrhosis)	ussnbeehkd(xebyoghujh) = rwpimwltwc spvvshdcop (euekfxdhrq, bgmievvupv - fjzzllzzns) View more
NCT02765490 (OMEGA-1, CTgov)	Phase 2	Hepatitis C, Chronic	365	SMV+ODV+AL-335 (Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks)	sulnuggxev(ctoqzmrvov) = eknhsybfqb ozzkluguxj (adqkmnvpid, onfowxrzcg - mtbjhglnns) View more	-	22 Jan 2019
				SMV+ODV+AL-335 (Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks)	sulnuggxev(ctoqzmrvov) = dmlxuxcmyl ozzkluguxj (adqkmnvpid, pewmluedaw - jlnvpgojze) View more