Bemnifosbuvir (BEM, AT-527), a novel nucleotide analogue inhibitor of the hepatitis C virus NS5B polymerase

ABSTRACT

Introduction

Chronic hepatitis C virus (HCV) persists as a public health concern worldwide. Consequently, optimizing HCV therapy remains an important objective. While current therapies are generally highly effective, advanced antiviral agents are needed to maximize cure rates with potentially shorter treatment durations in a broader patient population, particularly those patients with advanced diseases who remain difficult to treat.

Areas covered

This review summarizes the in vitro anti-HCV activity, preclinical pharmacological properties of bemnifosbuvir (BEM, AT-527), a novel prodrug that is metabolically converted to AT-9010, the active guanosine triphosphate analogue that potently and selectively inhibits several viral RNA polymerases, including the HCV NS5B polymerase. Results from clinical proof-of-concept and phase 2 combination studies are also discussed.

Expert opinion

BEM exhibits potent pan-genotype activity against HCV, and has favorable safety, and drug interaction profiles. BEM is approximately 10-fold more potent than sofosbuvir against HCV genotypes (GT) tested in vitro. When combined with a potent NS5A inhibitor, BEM is expected to be a promising once-daily oral antiviral for chronic HCV infection of all genotypes and fibrosis stages with potentially short treatment durations.

KEYWORDS:

• Bemnifosbuvir
• AT-527
• AT-511
• antiviral
• hepatitis C virus
• nucleotide analogue
• RNA polymerase

Article highlights

• Chronic HCV infection continues to be a threat to public health worldwide despite multiple available direct-acting antiviral regimens; novel advanced antiviral agents are still needed to optimize HCV therapy particularly for more difficult to treat populations.

• Bemnifosbuvir is a guanosine nucleotide protide with structural features that facilitate target cell uptake, prevent formation of mutagenic metabolites, and maximize formation of the intracellular active triphosphate AT-9010, a potent and selective inhibitor of several viral RNA polymerases, including the HCV NS5B polymerase.

• Bemnifosbuvir exhibits pan-genotype antiviral activity against all HCV variants tested in vitro and is approximately 10-fold more potent than sofosbuvir; bemnifosbuvir is also active against sofosbuvir-resistant HCV variant S282T.

• As a single agent, bemnifosbuvir demonstrated high and dose-dependent clinical anti-HCV activity across HCV genotypes regardless of cirrhosis status.

• When combined with daclatasvir, a first-generation HCV NS5A inhibitor, a high SVR rate was achieved after mostly 8 weeks of therapy with a satisfactory safety profile.

• Bemnifosbuvir has a low risk for clinical drug-drug interaction.

• Bemnifosbuvir in combination with ruzasvir, a novel pan-genotypic HCV NS5A inhibitor, is under clinical development and is expected to be a convenient oral once daily therapy for chronic HCV infection of all genotypes and fibrosis stages with potentially shorter treatment durations.

Declaration of interest

All authors are employees of Atea Pharmaceuticals Inc. and may own stock, stock options, and other forms of equity.

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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgments

Patrick Scoble, PharmD, and Richard Boehme, PhD, provided writing and editorial support for preparation of this manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

Preparation of this manuscript was supported by Atea Pharmaceuticals, Inc.