A Multicenter Study to Determine the Depth and Duration of Hepatitis B Surface Antigen (HBsAg) Reduction After Single or Multiple Doses of ARC-520, in Combination With Entecavir in Patients With Chronic Hepatitis B Virus (HBV) Infection

A Multicenter Study to Determine the Depth and Duration of Hepatitis B Surface Antigen (HBsAg) Reduction After Single or Multiple Doses of ARC-520, in Combination With Entecavir in Patients With Chronic Hepatitis B Virus (HBV) Infection

A Multicenter, Randomized, Double-blind, Placebo-controlled, Dose-escalation Study to Determine the Depth and Duration of Hepatitis B Surface Antigen (HBsAg) Reduction After a Single Intravenous Dose of ARC-520 in Combination With Entecavir in Patients With Chronic Hepatitis B Virus (HBV) Infection, Followed by a Two-dose Open-label Cohort and Three Open-label Single-dose Cohorts in Treatment Naïve Patients, Including a Multi-dose Open-label Extension at a Single Center

The purpose of this study is to determine whether ARC-520 in combination with entecavir is effective in the treatment of patients with chronic HBV Infection.

Treatment with ARC-520 for injection is expected to reduce all HBV proteins and replicative intermediates via ribonucleic acid (RNA) interference. The magnitude of the reduction and duration of effect will depend on the dose. Since to date ARC-520 has not been administered to patients with chronic HBV infection, the effective therapeutic dose in patients with chronic HBV infection is unknown. This study is designed to assess the antiviral activity of ARC-520, especially its effect on HBsAg, in patients with chronic HBV infection at different dose levels. This is a multicenter, randomized, double-blind, placebo-controlled, single-dose escalation study of ARC 520 in combination with entecavir administered to participants with hepatitis B virus e antigen (HBeAg)-negative (Cohorts 1 through 4) or HBeAg-positive (Cohort 5) immune active, chronic HBV infection, followed by a two-dose open-label cohort (Cohort 6), three open-label single-dose cohorts in treatment-naïve participants (Cohorts 7, 11 and 12) and an open-label multi-dose extension study (Cohorts 8, 9, 10). Cohort 6 will investigate ARC-520 in combination with entecavir administered in two doses to participants with HBeAg-positive immune-active chronic HBV infection. Cohorts 7, 11 and 12 will enroll treatment-naïve participants. Cohort 8 will only enroll participants previously completing Cohorts 1-4. Cohort 9 will only enroll participants previously completing Cohort 5 or 6. Cohort 10 will only enroll participants previously completing Cohort 7. Participants will undergo the following evaluations at regular intervals during the study: medical history, physical examinations, vital sign measurements (blood pressure, heart rate, respiratory rate, and temperature), weight, adverse events (AEs), 12-lead electrocardiograms (ECGs), concomitant medication, blood sample collection for hematology, coagulation, chemistry, pharmacokinetic (PK) and exploratory pharmacodynamic (PD) measures, urinalysis, HBV serology, HBV genotyping and sequencing, follicle stimulating hormone (FSH) testing and pregnancy testing for females of childbearing potential. Clinically significant changes including AEs will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the participant is lost to follow-up.

a single intravenous (IV) dose of double-blind ARC-520 Injection 1.0 mg/kg in combination with entecavir administered to participants with HBeAg-negative immune active chronic HBV infection

a single IV dose of double-blind ARC-520 Injection 2.0 mg/kg in combination with entecavir administered to participants with HBeAg-negative immune active chronic HBV infection

a single IV dose of double-blind ARC-520 Injection 3.0 mg/kg in combination with entecavir administered to participants with HBeAg-negative immune active chronic HBV infection

a single IV dose of double-blind ARC-520 Injection 4.0 mg/kg in combination with entecavir administered to participants with HBeAg-negative immune active chronic HBV infection

a single IV dose of double-blind ARC-520 Injection 4.0 mg/kg in combination with entecavir administered to participants with HBeAg-positive immune active chronic HBV infection

a single IV dose of double-blind normal saline in combination with entecavir administered to participants with HBeAg-negative or -positive immune active chronic HBV infection

two IV doses of open-label ARC-520 2.0 mg/kg administered to participants with HBeAg-positive immune active chronic HBV

a single IV dose of open-label ARC-520 4.0 mg/kg administered to treatment-naïve, HBeAg-negative or -positive participants with chronic hepatitis B (CHB)

open-label multi-dose extension cohort: multiple IV doses of open-label ARC-520 (4.0 mg/kg every [Q]4 weeks) administered to HBeAg-negative participants with CHB receiving chronic entecavir therapy who completed Cohorts 1 through 4

open-label multi-dose extension cohort: multiple IV doses of open-label ARC-520 (4.0 mg/kg Q6 weeks or Q8 weeks) administered to HBeAg-positive participants with CHB receiving chronic entecavir therapy who completed Cohorts 5 or 6

open-label multi-dose extension cohort: multiple IV doses of open-label ARC-520 (4.0 mg/kg Q4 weeks) administered to a mixed cohort (HBeAg-negative and -positive participants) who were naïve (within the last 6 months) to entecavir treatment and completed Cohort 7

a single IV dose of open-label ARC-520 5.0 mg/kg administered to treatment-naïve, HBeAg-positive participants with CHB

a single IV dose of open-label ARC-520 6.0 mg/kg administered to treatment-naïve, HBeAg-positive participants with CHB

In all cohorts, each participant received an 8 mg dose of oral chlorpheniramine 2 hours prior to each administration of ARC-520 Injection.

Baseline, through Day 85 (Cohorts 1-7) and through 24 weeks post-last dose (last dose: Day 85 Cohort 9; Day 253 Cohort 10)

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

An adverse event (AE) is any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. An SAE is any AE that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is a medically important event or reaction.Events were categorized as mild, moderate or severe. TEAEs were defined as all AEs starting or worsening after commencement of treatment with investigational product. A treatment-related TEAE was one whose relationship to treatment was noted as unlikely, possibly, or probably related.

through Day 85 (Cohorts 1-7) and through 24 weeks post-last dose (last dose: Day 85 Cohort 9; Day 225 Cohort 10)

Bee venom allergy tests were used to assess immunoglobulin E (IgE) in Cohorts 1-7. Analysis values less than 0.35 kU/L were taken as negative.

Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24), Cohorts 1-5

Pharmacokinetics of ARC-520 of ARC-520 Product Constituents AD0009 and AD0010: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Quantifiable Plasma Concentration (AUClast), Cohorts 1-5

Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf), Cohorts 1-5 Only

Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Maximum Observed Plasma Concentration (Cmax), Cohorts 1-5

Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Apparent Volume of Distribution During the Terminal Phase (Vz), Cohorts 1-5

Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Volume in Steady State (Vss), Cohorts 1-5

Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Terminal Elimination Rate Constant (Kel), Cohorts 1-5

Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Terminal Elimination Half-Life (t1/2), Cohorts 1-5

Key Inclusion Criteria: Diagnosis of HBeAg negative and immune active chronic HBV infection (Cohorts 1-4, 8) Diagnosis of HBeAg positive and immune active chronic HBV infection (Cohorts 5-6, 9) Diagnosis of HBeAg negative or HBeAg positive and immune active or tolerant chronic HBV infection (Cohorts 7, 10, 11 & 12) Patients with > 6 months of continuous, 0.5 mg/day oral entecavir, and a willingness to continue taking entecavir throughout the study (Cohorts 1-6, 8-9). Patients naive to entecavir (never on entecavir or on entecavir <30 days prior to screening) and a willingness to take entecavir and willingness to continue taking entecavir throughout the study (Cohorts 7, 11 & 12). Key Exclusion Criteria: Female patients that have a positive pregnancy test or are lactating. Acute signs of hepatitis/other infection (eg, moderate fever, jaundice, nausea, vomiting, and abdominal pain) evident within 4 weeks of screening and/or at the screening examination. Patients with antiviral therapy other than entecavir within 3 months of screening or prior treatment with interferon or a toll receptor agonist in the last 5 years. Use within the last 6 months or an anticipated requirement for anticoagulants, corticosteroids, immunomodulators, or immunosuppressants. Has any history of autoimmune disease especially autoimmune hepatitis. Has human immunodeficiency virus (HIV) infection, as shown by the presence of anti-HIV antibody (sero-positive). Is sero-positive for hepatitis C virus (HCV), and/or a history of delta virus hepatitis. Has a history of allergy to bee venom or history of hypersensitivity reaction requiring an emergency visit to a physician or hospital and/or requirement for treatment with steroids and/or epinephrine.

Yuen MF, Wong DK, Schluep T, Lai CL, Ferrari C, Locarnini S, Lo RC, Gish RG, Hamilton J, Wooddell CI, Mak LY, Given BD. Long-term serological, virological and histological responses to RNA inhibition by ARC-520 in Chinese chronic hepatitis B patients on entecavir treatment. Gut. 2022 Apr;71(4):789-797. doi: 10.1136/gutjnl-2020-323445. Epub 2021 Mar 12.