NS5B polymerase inhibitors in phase II clinical trials for HCV infection

ABSTRACT

Introduction: 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.

KEYWORDS:

• Hepatitis C
• HCV
• NS5B
• direct-acting antiviral agents
• Uprifosbuvir
• TMC-647
• 055
• AL-335
• Radalbuvir

Article Highlights

• The anti-HCV therapy has been completely revolutionized by DAAs. Nevertheless, not all patients achieve SVR 12 with the first wave of new drugs.

• NS5B polymerase is a crucial viral target and its inhibitors are one of the mainstays of current recommended regimens, starting from Sofosbuvir, the first drug to allow a total oral anti-HCV combination.

• To date, there are four novel NS5B inhibitors which have completed a phase 2 trial.

• Uprifosbuvir, combined with other drugs, for its good results in patients who have failed a previous course of first generation DAA, seemed to be a promising agent, but its development program has been currently suspended.

This box summarizes key points contained in the article.

Declaration of interest

In the last two years, I. Gentile has received a grant from Gilead Sciences (In the Framework of Fellowship Program) for Hepatitis C. He acts as a consultant for AbbVie and MSD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.