NS5B polymerase inhibitors in phase II clinical trials for HCV infection

Abstract

Hepatitis C virus (HCV) infection might be the first chronic viral disease to be eradicated without the introduction of a prophylactic vaccine. This is essentially due to therapeutic revolution encapsulated by the advent of direct-acting antivirals (DAA) agents, whose efficacy, safety and tolerability (all oral regimens) have made the previous standard of care (interferon plus ribavirin) a vestige of the past. The new regimens achieve very high response rates and have an excellent tolerability profile. Notwithstanding, the first wave of DAAs has brought over problems regarding costs and failures which warrant research and development of further antiviral molecules. Areas covered: This review outlines the main clinical data concerning novel NS5B polymerase inhibitors currently in pipeline, focusing on the ones that have completed a phase 2 trial. Expert opinion: NS5B is one the main viral target for anti-HCV therapy. The large majority of the approved regimens so far include a NS5B inhibitor. Although not frequently, failure related to mutations can occur. The potential place in therapy in the mid-term of new NS5B inhibitors may be, in the first instance, the role of backbone in salvage combinations with DAAs of other classes.

Genetically Modified Mouse Mesenchymal Stem Cells Expressing Non-Structural Proteins of Hepatitis C Virus Induce Effective Immune Response

“…This protein is an RNA-dependent RNA polymerase, the key component of HCV replicase. NS5B is a target for direct-acting antivirals in the treatment of hepatitis C [56]; NS5B has the largest number of conserved T-cell epitopes that are important for vaccine design and induction of an effective immune response [57]. Thus, when immunizing with mMSCs, we achieve a functionally active T-cell response to several HCV proteins simultaneously, including different genotypes.…”

Taming a beast: lessons from the domestication of hepatitis C virus

“…Only a year after this first approval, a non-nucleoside polymerase inhibitor was approved as part of an HCV combination therapy. The past few years have seen identification of additional HCV polymerase inhibitors, some of which are in phase III clinical trials (reviewed in [80]). HCV NS5A inhibitors: One of the most unexpected breakthroughs in HCV drug discovery was the development of NS5A inhibitors.…”

Hepatitis C virus genotype 3: clinical features, current and emerging viral inhibitors, future challenges

“…In phase II of C-CREST-2, a triple combination of uprifosbuvir, ruzasvir and grazoprevir was tested [ 101 ]. The overall SVR in genotype 3, treatment-naïve, non-cirrhotic patients ranged from 86-95%, suggesting that the 8-week treatment duration was suboptimal [ 102 ]. In phase III of the C-CREST 2 trial, the same triple combination, with and without RBV, was investigated at 8, 12, and 16 weeks [ 102 ].…”

“…The overall SVR in genotype 3, treatment-naïve, non-cirrhotic patients ranged from 86-95%, suggesting that the 8-week treatment duration was suboptimal [ 102 ]. In phase III of the C-CREST 2 trial, the same triple combination, with and without RBV, was investigated at 8, 12, and 16 weeks [ 102 ]. The overall SVR for genotype 3 patients was 96%.…”