Preclinical characterization of ABI-H2158, an HBV core inhibitor with dual mechanisms of action.

The HBV core protein plays an integral role in multiple steps of the HBV lifecycle. Consequently, HBV core inhibitors interrupt multiple steps of the replication cycle, including blocking pgRNA encapsidation and prematurely disassembling existing nucleocapsids, thereby preventing them from transporting relaxed circular (rcDNA) to the nucleus for conversion to covalently closed circular DNA (cccDNA). ABI-H2158 is an HBV core inhibitor that advanced into Phase 2 clinical trials for the treatment of chronic hepatitis B virus infection (cHBV) but was discontinued due to hepatotoxicity.

Development of a sensitive, multi-assay platform to monitor low levels of HBV DNA and pgRNA in patients with chronic hepatitis B virus infection.

HBV cure rates remain low despite prolonged nucleos(t)ide (NrtI) therapy, likely due to persistent residual viral replication and an inability to eliminate covalently closed circular DNA (cccDNA). Therapies with novel mechanisms of action against hepatitis B virus (HBV) are being explored with the goal of achieving sustained off-treatment response and a functional cure without requiring lifelong therapy. Recent studies have indicated that serum HBV DNA levels (a biomarker for viral replication) combined with serum pregenomic RNA (pgRNA) levels (a surrogate for intrahepatic cccDNA transcriptional activity), may provide a better prediction for the risk of liver-related complications.

Safety, pharmacokinetics and antiviral activity of ABI-H2158, a hepatitis B virus core inhibitor: A randomized, placebo-controlled phase 1 study.

Treatment for chronic hepatitis B virus infection (cHBV) is mostly indefinite, with new finite-duration therapies needed. We report safety, pharmacokinetics and antiviral activity of the investigational HBV core inhibitor ABI-H2158. This Phase 1a/b study (NCT03714152) had three parts: Part A, participants received a single ascending oral dose of ABI-H2158 (5-500 mg) or placebo; Part B, participants received multiple doses of ABI-H2158 300 mg once (QD) or twice (BID) daily or placebo, for 10 days; Part C, cHBV patients received ABI-H2158 (100, 300, or 500 mg QD or 300 mg BID) or placebo, for 14 days.

Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection.

Background & Aims: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV.

Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection.

Background & Aims: HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs.