Delving into the Latest Updates on JTK-853 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

NS5B polymerase

Mechanism

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

Therapeutic Areas

Infectious DiseasesDigestive System Disorders

Active Indication-

Inactive Indication

Chronic hepatitis C genotype 1Hepatitis C

Originator Organization

Japan Tobacco (Hong Kong) Ltd.

Active Organization-

Inactive Organization

Akros Pharma, Inc.

AKROS AG

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

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Structure

Molecular FormulaC28H23F7N6O4S2

InChIKeyJQLOVYLALGSISI-HXUWFJFHSA-N

CAS Registry954389-09-4

The purpose of this study was to determine the safety, tolerability, pharmacokinetics and anti-viral activity of JTK-853 in hepatitis C virus genotype 1 infected subjects based on reduction in viral load (HCV RNA level) from baseline to end of treatment, followed by genotypic resistance monitoring for up to one year after study drug treatment.

Start Date01 Aug 2010

Sponsor / Collaborator

Akros Pharma, Inc.

NCT01473069 / TerminatedPhase 1

A Phase 1, Randomized, Double-blind, Placebo-controlled Study Evaluating the Safety,Tolerability and Pharmacokinetics of Multiple Ascending Doses of JTK-853 Administered for Two Weeks in Healthy Subjects

The purpose of this study was to determine the safety, tolerability and pharmacokinetics of sequential ascending doses of JTK-853 administered for 14 days in healthy subjects and also to determine the effect of a single dose of ketoconazole on the steady-state pharmacokinetic profile of JTK-853 and its metabolite M2 (one cohort only).

Start Date01 Mar 2010

Sponsor / Collaborator

Akros Pharma, Inc.

NCT01475981 / CompletedPhase 1

Randomized,Double-blind,Placebo-controlled,Ascending Dose Part Evaluating Safety,Tolerability and Pharmacokinetics (PK) of JTK-853 (Fasted/Fed) and Randomized,Open-label,Crossover Part Evaluating Food Effect on PK in Healthy Male Subjects

The purpose of this study was to determine the safety, tolerability and pharmacokinetics of ascending single oral doses of JTK-853 administered under fasted or fed conditions in healthy male subjects.

Start Date01 Jan 2010

Sponsor / Collaborator

Akros Pharma, Inc.

100 Clinical Results associated with JTK-853

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100 Translational Medicine associated with JTK-853

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100 Patents (Medical) associated with JTK-853

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3

Literatures (Medical) associated with JTK-853

01 Jan 2013·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Genotypic and Phenotypic Analyses of Hepatitis C Virus from Patients Treated with JTK-853 in a Three-Day Monotherapy

Q2 · MEDICINE

Article

Author: Ogura, Naoki ; Hirahara, Kunihiro ; Noguchi, Toru ; Ando, Izuru ; Toyonaga, Yukiyo ; Yee, Kan ; Shibata, Tsutomu ; Gerhardt, Barbara ; Pai, Sudhakar ; Turcanu, Gabriela ; Rodriguez-Torres, Maribel

ABSTRACT JTK-853, a palm site-binding NS5B nonnucleoside polymerase inhibitor, shows antiviral activity in vitro and in hepatitis C virus (HCV)-infected patients. Here, we report the results of genotypic and phenotypic analyses of resistant variants in 24 HCV genotype 1-infected patients who received JTK-853 (800, 1,200, or 1,600 mg twice daily or 1,200 mg three times daily) in a 3-day monotherapy. Viral resistance in NS5B was investigated using HCV RNA isolated from serum specimens from the patients. At the end of treatment (EOT) with JTK-853, the amino acid substitutions M414T (methionine [M] in position 414 at baseline was replaced with threonine [T] at EOT), C445R (cysteine [C] in position 445 at baseline was replaced with arginine [R] at EOT), Y448C/H (tyrosine [Y] in position 448 at baseline was replaced with cysteine [C] or histidine [H] at EOT), and L466F (leucine [L] in position 466 at baseline was replaced with phenylalanine [F] at EOT), which are known to be typical resistant variants of nonnucleoside polymerase inhibitors, were observed in a clonal sequencing analysis. These substitutions were also selected by a treatment with JTK-853 in vitro , and the 50% effective concentration of JTK-853 in the M414T-, C445F-, Y448H-, and L466V-harboring replicons attenuated the susceptibility by 44-, 5-, 6-, and 21-fold, respectively, compared with that in the wild-type replicon (Con1). These findings suggest that amino acid substitutions of M414T, C445R, Y448C/H, and L466F are thought to be viral resistance mutations in HCV-infected patients receiving JTK-853 in a 3-day monotherapy.

01 Jan 2013·IntervirologyQ4 · MEDICINE

JTK-853, a Novel Non-Nucleoside Hepatitis C Virus Polymerase Inhibitor, Demonstrates a High Genetic Barrier to Resistance in vitro

Q4 · MEDICINE

Article

Author: Shibata, Tsutomu ; Ando, Izuru ; Ogura, Naoki ; Noguchi, Toru ; Toyonaga, Yukiyo ; Hirahara, Kunihiro

JTK-853 is a novel, non-nucleoside, palm site-binding hepatitis C virus (HCV) polymerase inhibitor that has demonstrated antiviral activity in HCV-infected patients during 3 days of treatment. To estimate the genetic barrier of JTK-853 to resistance in vitro, colony formation assays were conducted using HCV replicon cells (genotypes 1a and 1b). The colony formation assays revealed that the numbers of resistant colonies for JTK-853 were much lower than those for other direct-acting antivirals, including palm site- or thumb pocket-binding non-nucleoside HCV polymerase inhibitors (NNIs), an NS5A inhibitor (NS5Ai), and a protease inhibitor (PI). Furthermore, the numbers of resistant colonies for JTK-853 in combination with the NS5Ai or PI were lower than those for other combinations of NS5Ai + NNI, and NS5Ai + PI. Our findings demonstrate that JTK-853 has a high genetic barrier to resistance, and suggest that its combination therapies will be potent in suppressing the emergence of drug resistance in HCV-infected patients.

01 Aug 2012·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Preclinical Characterization of JTK-853, a Novel Nonnucleoside Inhibitor of the Hepatitis C Virus RNA-Dependent RNA Polymerase

Q2 · MEDICINE

Article

Author: Noguchi, Toru ; Ogura, Naoki ; Toyonaga, Yukiyo ; Ando, Izuru ; Abe, Hiroyuki ; Kamada, Masafumi ; Sugimoto, Kazuyuki ; Adachi, Tsuyoshi

ABSTRACTJTK-853 is a novel piperazine derivative nonnucleoside inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase. JTK-853 showed potent inhibitory activity against genotype 1 HCV polymerase, with a 50% inhibitory concentration in the nanomolar range, and showed potent antiviral activity against the genotype 1b replicon, with a 50% effective concentration of 0.035 μM. The presence of human serum at up to 40% had little effect on the antiviral activity of JTK-853. Structure analysis of HCV polymerase with JTK-853 revealed that JTK-853 associates with the palm site and β-hairpin region of HCV polymerase, and JTK-853 showed decreased antiviral activity against HCV replicons bearing the resistance mutations C316Y, M414T, Y452H, and L466V in the palm site region of HCV polymerase. JTK-853 showed an additive combination effect with other DAAs (direct antiviral agents), such as nucleoside polymerase inhibitor, thumb pocket-binding nonnucleoside polymerase inhibitor, NS5A inhibitor, and protease inhibitor. Collectively, these data demonstrate that JTK-853 is a potent and novel nonnucleoside palm site-binding HCV polymerase inhibitor, suggesting JTK-853 as a potentially useful agent in combination with other DAAs for treatment of HCV infections.

100 Deals associated with JTK-853

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