A Randomized, Double Blind, Dose Escalation, Fusion, First Time in Human Study to Assess the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Single and Repeat Doses of GSK2485852 in Chronically Infected Hepatitis C Subjects

GSK2485852 is a Hepatitis C NS5B site IV non-nucleoside polymerase inhibitor being developed for the treatment of chronic HCV infection. HBI115040 is the first administration of GSK2485852 in humans to establish the initial safety, tolerability, pharmacokinetic, and antiviral profile. The study design is a fusion of single and repeat dosing cohorts in HCV infected subjects to evaluate the safety, pharmacokinetics, and antiviral activity of GSK2485852.
HBI115040 describes a Phase I, randomized, double-blind, placebo-controlled, dose escalation fusion study to determine the safety, tolerability, pharmacokinetic, and antiviral profile of GSK2485852 in single doses (Part 1), repeat doses (Part 2), and ritonavir co-administration (Part 3) in chronically infected HCV subjects. The study will also explore the effect of a moderate (30%) fat meal on pharmacokinetic endpoints in HCV subjects in Part 1.

Start Date14 Jan 2011

Sponsor / Collaborator

GSK Plc

100 Clinical Results associated with GSK-5852

100 Translational Medicine associated with GSK-5852

100 Patents (Medical) associated with GSK-5852

Literatures (Medical) associated with GSK-5852

11 Apr 2019·Journal of Medicinal ChemistryQ1 · MEDICINE

Resurrecting the Condemned: Identification of N-Benzoxaborole Benzofuran GSK8175 as a Clinical Candidate with Reduced Metabolic Liability

Q1 · MEDICINE

Article

Author: Liu, Xinyong ; Zhan, Peng ; Kang, Dongwei

Recently, in a program designed to improve the metabolic stability of the HCV inhibitor GSK5852, N-benzoxaborole benzofuran (GSK8175) emerged as a clinical candidate that not only retains the broad-spectrum activity against HCV subgenomic replicons but is free of the N-benzylboronic acid structure, which is a metabolic liability, and probably the cause of low in vivo clearance in preclinical species. This Viewpoint discusses some medicinal chemistry issues involved in the identification of GSK8175.

01 Nov 2014·Clinical Pharmacology in Drug DevelopmentQ4 · MEDICINE

A randomized, double blind, dose escalation, first time in human study to assess the safety, tolerability, pharmacokinetics, and antiviral activity of single doses of GSK2485852 in chronically infected hepatitis C subjects

Q4 · MEDICINE

Article

Author: Lovern, Mark ; Adkison, Kimberly ; Lee, Daniel ; Wilfret, David A. ; Voitenleitner, Christian ; Mathis, Amanda ; Walker, Jill ; Shotwell, Brad ; Baptiste‐Brown, Sharon ; Moss, Lee ; Gan, Jianjun ; Spaltenstein, Andrew ; Kim, Joseph ; Yu, Lou

AbstractThis first‐time‐in‐human, randomized, double‐blind, placebo‐controlled, dose‐escalation study assessed the safety, tolerability, pharmacokinetics, and antiviral activity of GSK2485852, a hepatitis C virus (HCV) NS5B inhibitor, in 27 chronically infected HCV genotype‐1 subjects. Subjects received GSK2485852 70, 420, and 70 mg with a moderate fat/caloric meal. Safety, pharmacokinetics, antiviral activity, HCV genotype/phenotype, and interleukin 28B genotype were evaluated. A statistically significant reduction in HCV ribonucleic acid (RNA) was observed after a single dose of 420 mg GSK2485852 (−1.33 log10 IU/mL) compared with placebo (−0.09 log10 IU/mL) at 24 hours post‐dose. Subjects receiving 70 mg GSK2485852 were exposed to concentrations above the protein‐adjusted 90% effective concentration for a short time; none experienced a significant decline in HCV RNA (−0.47 log10 copies/mL). GSK2485852 was readily absorbed; however, the observed geometric mean maximum plasma concentration (Cmax) and area under the curve (AUC) values were significantly lower than expected due to a higher‐than‐predicted‐oral clearance. Co‐administration with food reduced the AUC and Cmax of GSK2485852 by 40% and 70%, respectively. Two metabolites were detected in human blood with one having approximately 50% higher concentrations than those of the parent. GSK2485852 was well‐tolerated and exhibited antiviral activity after a single 420 mg dose in HCV subjects.

01 Nov 2013·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

In Vitro Characterization of GSK2485852, a Novel Hepatitis C Virus Polymerase Inhibitor

Q2 · MEDICINE

Article

Author: Vamathevan, Jessica ; Van Horn, Stephanie ; Hong, Zhi ; Wang, Amy ; Horton, Joseph ; Shotwell, J. Brad ; Walker, Jill ; Hamatake, Robert ; Voitenleitner, Christian ; Remlinger, Katja ; Creech, Katrina ; You, Shihyun ; Johnson, John ; Crosby, Renae ; Woldu, Ermias

ABSTRACT GSK2485852 (referred to here as GSK5852) is a hepatitis C virus (HCV) NS5B polymerase inhibitor with 50% effective concentrations (EC 50 s) in the low nanomolar range in the genotype 1 and 2 subgenomic replicon system as well as the infectious HCV cell culture system. We have characterized the antiviral activity of GSK5852 using chimeric replicon systems with NS5B genes from additional genotypes as well as NS5B sequences from clinical isolates of patients infected with HCV of genotypes 1a and 1b. The inhibitory activity of GSK5852 remained unchanged in these intergenotypic and intragenotypic replicon systems. GSK5852 furthermore displays an excellent resistance profile and shows a <5-fold potency loss across the clinically important NS5B resistance mutations P495L, M423T, C316Y, and Y448H. Testing of a diverse mutant panel also revealed a lack of cross-resistance against known resistance mutations in other viral proteins. Data from both the newer 454 sequencing method and traditional population sequencing showed a pattern of mutations arising in the NS5B RNA-dependent RNA polymerase in replicon cells exposed to GSK5852. GSK5852 was more potent than HCV-796, an earlier inhibitor in this class, and showed greater reductions in HCV RNA during long-term treatment of replicons. GSK5852 is similar to HCV-796 in its activity against multiple genotypes, but its superior resistance profile suggests that it could be an attractive component of an all-oral regimen for treating HCV.

100 Deals associated with GSK-5852

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis C, Chronic	Phase 1	US	GSK Plc	14 Jan 2011

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