ARO-HBV
HBV Introduction
Hepatitis B virus (HBV) is a partially double-stranded DNA virus that replicates in the liver. HBV is transmitted through blood contact, or other body fluids, of infected individuals. Persons are considered to have a chronic infection if hepatitis B surface antigen (HBsAg) persists for >6 months. The current treatment goal of HBV therapy is to reduce the risk of progression to cirrhosis- and liver-related complications. The HBV lifecycle and targets for investigational agents in the HBV lifecycle are shown in Figure 1. Investigational HBV agents can be divided into direct-acting antivirals and immune modulators. These agents could be further classified into entry inhibitor, capsid assembly modulators, secretion inhibitor, RNA interference (RNAi) and immunomodulators. A combination of both classes and/or with existing therapies will be required to maximize HBsAg loss.
RNAi and ARO-HBV
RNAi compounds are short RNA molecules that target the transcripts of viral RNA. These compounds overlap the sequence of the viral mRNA which triggers the degradation of viral transcripts. ARO-HBV (also known as JNJ-3989), a third-generation subcutaneously administered RNAi therapeutic candidate, was developed as a potential treatment for patients with chronic HBV infection. ARO-HBV contains two siRNAs that are both directly conjugated to N-acetyl galactosamine for hepatocyte delivery. ARO-HBV silences all mRNAs that are formed from covalently closed circular DNA (cccDNA) and host integrated viral DNA. ARO-HBV is administered subcutaneous, so no absorption-related drug-drug interactions (DDI) occur. Compared with ARC-520, ARO-HBV targets a different region of the HBV genome, also elicits dose-related reductions of serum HBsAg of 1.3 to 3.8 log10 IU/mL, as well as reductions of HBV DNA, HBV RNA, HBeAg, and hepatitis B core-related antigen. Viral antigen responses were similar with or without concomitant nucleos(t)ide analogue (NA) therapy and in both HBeAg-positive and HBeAg-negative patients, in contrast to previous results with ARC-520.
AROHBV1001
AROHBV1001 (NCT03365947) is a Phase 1/2 study evaluating the safety, tolerability, and pharmacokinetic effects of single-ascending doses (SAD) of ARO-HBV in healthy adult volunteers, and evaluating the safety, tolerability, and pharmacodynamic effects of multiple-ascending doses (MAD) of ARO-HBV in patients with chronic HBV. Dosing in the SAD portion of the study is complete, and included five cohorts at dose levels of 35, 100, 200, 300, and 400 mg. Dosing in the MAD portion of the study is ongoing, and includes ten cohorts receiving three doses of ARO-HBV either weekly, bi-weekly, or monthly, and includes dose levels of 100, 200, 300, and 400 mg. The 25 and 50 mg dose cohorts were recently added, and cohort sizes were increased to n=8 in the dose-escalation HBV patient cohorts to better characterize ARO-HBV dose-response. The study is also evaluating whether there is added effect with weekly or bi-weekly loading doses. AROHBV1001 is designed to enroll 30 healthy volunteers and up to 72 HBV patients.
ARO-HBV: Key Design Elements for the Next Generation
- Addresses full HBV transcriptome
- Works for cccDNA and integrated HBV-derived transcripts
- Subcutaneous dosing, monthly or less frequent
- No need for active endosomal escape agent
- Multiple triggers to avoid developing resistance
- Powerful HBsAg reduction
- Expectation of wide therapeutic index
- Efficacy and safety in HBV patients
Clinical studies have identified ARO-HBV as a well-tolerated siRNA drug, which significantly reduces HBsAg levels. ARO-HBV continues to achieve high levels of activity across all HBV patient types in the AROHBV1001 study. Additionally, ARO-HBV's tolerability profile supports its continued development.
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