gs-9256 and Hepatitis-C

Monotherapy is an ineffective way to treat hepatitis C and it leads to rapid development of resistance. An increasing number of drugs are currently being developed for the treatment of hepatitis C. This allows combination strategies that can overcome the development of resistance and improve sustained virologic response rates. This article focuses on the 2 main strategies in development: quadruple combination therapies, including pegylated-interferon and triple/quadruple pegylated-interferon free combination therapies. If the first combinations are leading to extremely high sustained virologic responses, the second ones offer hope that the era of pegylated-interferon will end soon.

Topics: Antiviral Agents; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Humans; Interferons; Peptides, Cyclic; Phosphinic Acids; Polyethylene Glycols; Protease Inhibitors; Quinolines; Ribavirin; Sofosbuvir; Uridine Monophosphate

Topics: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance, Viral; Female; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Mutation; Peptides, Cyclic; Phosphinic Acids; Protease Inhibitors; Viral Load; Viral Nonstructural Proteins

Tegobuvir (GS-9190), a non-nucleoside nonstructural protein (NS)5B polymerase inhibitor, and GS-9256, an NS3 serine protease inhibitor, individually have activity against hepatitis C virus (HCV) genotype 1. The antiviral activity of tegobuvir and GS-9256 as oral combination therapy, or together with ribavirin (RBV) or pegylated interferon (Peg-IFN) alpha-2a and RBV, was assessed in a phase II, randomized, open-label trial. Treatment-naïve patients with genotype 1 HCV were assigned 28 days of tegobuvir 40 mg twice-daily (BID) and GS-9256 75 mg BID (n = 16), tegobuvir and GS-9256 plus RBV 1,000-1,200 mg daily (n = 15), or tegobuvir and GS-9256 plus Peg-IFN alpha-2a (180 μg once-weekly)/RBV (n = 15). The primary efficacy endpoint was rapid virologic response (RVR), with HCV RNA <25 IU/mL at day 28. After 28 days, all patients received Peg-IFN/RBV. All patients with viral rebound or nonresponse, defined as >0.5-log(10) increase in HCV RNA from nadir or <2-log decrease at day 5, initiated Peg-IFN/RBV immediately. Median maximal reductions in HCV RNA were -4.1 log(10) IU/mL for tegobuvir/GS-9256, -5.1 log(10) IU/mL for tegobuvir/GS-9256/RBV, and -5.7 log(10) IU/mL for tegobuvir/9256/Peg-IFN/RBV. RVR was observed in 7% (1 of 15) of patients receiving tegobuvir/GS-9256, 38% (5 of 13) receiving tegobuvir/GS-9256/RBV, and 100% (14 of 14) receiving tegobuvir/9256/PEG-IFN/RBV. The addition of Peg-IFN/RBV at day 28 or earlier resulted in HCV RNA <25 IU/mL at week 24 in 67% (10 of 15), 100% (13 of 13), and 94% (13 of 14) of patients in the three treatment groups. Transient elevations in serum bilirubin occurred in all treatment groups.. In genotype 1 HCV, adding RBV or RBV with Peg-IFN provides additive antiviral activity to combination therapy with tegobuvir and GS-9256.

Topics: Adult; Antiviral Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Inhibitors; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Interferon-alpha; Male; Middle Aged; Peptides, Cyclic; Phosphinic Acids; Polyethylene Glycols; Protease Inhibitors; Purines; Pyridazines; Recombinant Proteins; Ribavirin; RNA, Viral; Treatment Outcome

GS-9256 is an inhibitor of HCV NS3 protease with a macrocyclic structure and novel phosphinic acid pharmacophore.. Key preclinical properties of GS-9256 including in vitro antiviral activity, cross-resistance and pharmacokinetic properties were investigated in non-human species.. In genotype (GT) 1b Huh-luc cells with a replicon encoding luciferase, GS-9256 had a mean 50% effective concentration (EC. GS-9256 showed a favourable preclinical profile supportive of clinical development for the treatment of chronic HCV infection in GT1 patients.

Topics: Animals; Antiviral Agents; Biological Availability; Cell Line; Cells, Cultured; Dogs; Drug Evaluation, Preclinical; Drug Resistance, Viral; Hepacivirus; Hepatitis C; Humans; Macaca fascicularis; Mice; Peptides, Cyclic; Phosphinic Acids; Protease Inhibitors; Rats; Viral Nonstructural Proteins; Virus Replication

Protease inhibitors for the treatment of HCV can cause mild and reversible elevations of unconjugated bilirubin. We sought to characterize genetic determinants of bilirubin elevations using a genome-wide approach among patients with genotype 1 HCV who received combination therapy that included GS-9256, a novel potent inhibitor of HCV NS3 serine protease, as part of a Phase IIb trial.. Of the 200 patients sampled, 176 had confirmed European ancestry and were included in the analysis. Infinium HumanOmni5BeadChip (Illumina, Inc., San Diego, CA, USA) was used for genotyping. A categorical analysis of low (grade 0-1) versus high (grade 2-4) bilirubin toxicity grade and a quantitative trait locus mapping of peak bilirubin concentrations was performed.. A total of 4,466,809 genetic markers were analysed. No single variant showed a statistically significant association with observed bilirubin elevations in this patient population. In a targeted analysis of single nucleotide polymorphisms in genes known to be involved in bilirubin transport, no significant differences in allele frequency between high and low bilirubin toxicity grade were observed.. These results indicate that risk for bilirubin elevation in patients receiving GS-9256 is unlikely to be strongly influenced by common genetic variants with large effects. The current study cannot rule out a role for common variants of weak effect, or a more complex model, including multiple contributing factors, such as rare variants and as yet unidentified environmental influences.

Topics: Adult; Aged; Antiviral Agents; Bilirubin; Computational Biology; Female; Genome-Wide Association Study; Genotype; Hepacivirus; Hepatitis C; Humans; Liver-Specific Organic Anion Transporter 1; Male; Microbial Sensitivity Tests; Middle Aged; Organic Anion Transporters; Organic Anion Transporters, Sodium-Independent; Peptides, Cyclic; Pharmacogenetics; Phenotype; Phosphinic Acids; Polymorphism, Single Nucleotide; Solute Carrier Organic Anion Transporter Family Member 1B3; Viral Nonstructural Proteins; Young Adult

The high genetic variation of hepatitis C virus (HCV) results in rapid selection of drug resistance mutations (DRMs) during monotherapy with direct-acting antivirals (DAAs). It has been proposed that each possible single mutant preexists in infected individuals; however, the levels of preexisting DRMs are too low to be directly quantified in most patients using current techniques. In this study, we evaluated the presence of DRMs in HCV-infected patients treated with the HCV protease inhibitors GS-9256 or GS-9451 as monotherapy using deep sequencing in 137 longitudinal samples from 45 patients. Software was developed to analyze deep-sequencing results with an assay cutoff of 0.25%. No NS3 DRMs that confer resistance to GS-9256 and GS-9451 (R155K, A156T, and D168V/E) were observed in 33 baseline samples at >0.25%. In contrast, these and other substitutions at NS3 positions 155, 156, and 168 were detected in 19/27 patients at day 2 (24 h) and 21/21 at day 4 (84 h) of monotherapy but not in placebo-treated patients. Based on the DRM growth kinetics during drug treatment, pretreated NS3 mutations at amino acids 155, 156, and 168 were estimated on average at 0.025% and 0.015% per genotype 1a and 1b HCV-infected patients, respectively. Relative fitness of the DRM viruses was shown to be significantly lower than the wild type. Deep-sequencing analyses of NS3 protease inhibitor-treated HCV-infected patients suggest a limit of HCV viral load suppression of 3.6 to 3.8 log(10) with NS3 protease inhibitor monotherapy that does not suppress the identified preexisting NS3 DRMs and thus a need for a combination therapy.

Topics: Amino Acid Substitution; Antiviral Agents; Computational Biology; Drug Resistance, Viral; Hepacivirus; Hepatitis C; High-Throughput Nucleotide Sequencing; Humans; Mutation, Missense; Peptides, Cyclic; Phosphinic Acids; Protease Inhibitors; Quinolines; Selection, Genetic; Software; Viral Nonstructural Proteins