A Study of ARC-521 Injection in Normal Adult Volunteers and Patients With Chronic Hepatitis B (CHB)

Phase 1

Terminated

Conditions: Hepatitis B

Interventions: Drug: ARC-521 Injection
Other: Placebo
Drug: antihistamine
Drug: acetaminophen
Drug: entecavir
Drug: tenofovir

Registration Number: NCT02797522

Lead Sponsor: Arrowhead Pharmaceuticals

Brief Summary: Normal healthy volunteer (NHV) participants will enroll sequentially into a total of 6 escalating dose levels (6 subjects per dose level), randomized to receive a single dose of ARC-521 Injection or placebo. The maximum study duration for NHVs is approximately 21 weeks.

Hepatitis B e Antigen (HBeAg)-negative participants with (CHB) will enroll sequentially into 3 dose levels (8 patients per dose level) to receive multiple doses of open label ARC-521 Injection. For each CHB participant the maximum study duration is approximately 37 weeks.

Detailed Description: Phase 1a/1b multicenter dose-escalation study of ARC-521 Injection in normal healthy volunteers and patients with CHB. Eligible participants who have signed an Ethics Committee (EC)/Institutional Review Board (IRB) approved informed consent form and have met all of the protocol eligibility criteria.

Patients 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 assessment (AEs), concomitant medications/therapies assessment, electrocardiograms (ECGs), telemetry \[NHVs only\], measures of hepatic fibrosis \[CHBs only\], blood sample collection for hematology, coagulation, chemistry, Pharmacokinetics (PK) \[NHVs only\], metabolic analysis \[NHVs only\], exploratory Pharmacodynamic (PD) measures, urinalysis, hepatitis B virus (HBV) serology, immunogenicity, Follicle Stimulating Hormone (FSH) testing (post-menopausal females) 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 patient is lost to follow-up. Prior to enrollment there is a 60 day screening period.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 47

Inclusion Criteria

Male or female, 18 to 55 years of age inclusive (NHVs) or 18-65 years of age inclusive (CHBs), at the time of informed consent
Able to provide written informed consent prior to the performance of any study specific procedures
Body mass index (BMI) between 19.0 and 35.0 kg/m2, inclusive
A 12-lead ECG at Screening and pre-dose assessment that, in the opinion of the investigator, has no abnormalities that compromise participant's safety in this study
Must use 2 effective methods of contraception (double barrier contraception or hormonal contraceptive along with a barrier contraceptive (both male and female partners)
Have suitable venous access for blood sampling
No abnormal finding of clinical relevance at the Screening evaluation (NHVs only)
Have a diagnosis of HbeAg-negative chronic HBV infection (CHB patients only)
Treatment-naive or currently on entecavir/tenofovir for 6 months or longer

Exclusion Criteria

Pregnant or lactating
Acute signs of hepatitis/other infection at Screening or at baseline
Use within last 14 days or anticipated requirement for anticoagulants, systemic corticosteroids, immunomodulators, or immunosuppressants
Use of prescription medication within 14 days prior to study treatment that in the opinion of the PI or the Sponsor would interfere with study conduct.
Known diagnosis of non-alcoholic steatohepatitis [NHVs only] or familial hypercholesterolemia
Taking interferon alpha (INFalpha) within 6 months of screening [CHBs only]
History of poorly controlled autoimmune disease or history of autoimmune hepatitis
Human immunodeficiency virus (HIV) infection
Seropositive for HBV (NHVs only) or hepatitis C virus (HCV), and/or history of delta virus hepatitis
Hypertension defined as blood pressure > 170/100 mmHg at screening [NHVs only]
A history of cardiac rhythm disturbances
Family history of congenital long QT syndrome, Brugada syndrome or unexplained sudden cardiac death
Symptomatic heart failure, unstable angina, myocardial infarction, severe cardiovascular disease within 6 months prior to study entry
History of malignancy within the last 5 years except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer
History of major surgery within 3 months of Screening
Regular use of alcohol within one month prior to the Screening visit (more than fourteen units of alcohol per week)
Evidence of severe systemic acute inflammation, sepsis, or hemolysis [NHVs only]
Use within 3 months of illicit drugs (cocaine, phencyclidine [PCP], 3,4-methylenedioxymethamphetamine [MDMA], others) or positive test for drugs of abuse at screening.
History of allergy to bee venom or history of severe hypersensitivity reaction, such as anaphylaxis
Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study
Clinically significant history of any alcoholic liver disease, cirrhosis, Wilson's disease, hemochromatosis, or alpha-1 antitrypsin deficiency, liver or kidney disease
Clinically significant history/presence of poorly controlled or decompensated neurological, endocrine, cardiovascular, pulmonary, hematological, immunologic, psychiatric, metabolic, or other uncontrolled systemic disease
Blood donation (500 mL) within 7 days prior to study treatment administration [NHVs only]
History of fever (>38.0ºC/100.4ºF) within 2 weeks of Screening [NHVs only]
Any concomitant medical or psychiatric condition or social situation that impacts compliance or involves additional safety risk
History of coagulopathy (including deep vein thrombosis and pulmonary embolism) or stroke within 6 months of baseline, and/or concurrent anticoagulant medication(s)
Presence of cholangitis, cholecystitis, cholestasis, or duct obstruction

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CHB Participants: Cohort 3c	tenofovir	Participants with CHB currently on NUCs (entecavir or tenofovir for at least 6 months) administered 3 doses of ARC-521 Injection at 2 mg/kg once every 4 weeks.
NHV Participants: Cohort 1	ARC-521 Injection	NHV participants administered a single dose of ARC-521 Injection at a dose of 0.6 mg/kg.
NHV Participants: Cohort 3	ARC-521 Injection	NHV participants administered a single dose of ARC-521 Injection at a dose of 2 mg/kg.
NHV Participants: Cohort 4	ARC-521 Injection	NHV participants administered a single dose of ARC-521 Injection at a dose of 4 mg/kg.
NHV Participants: Cohort 5	ARC-521 Injection	NHV participants administered a single dose of ARC-521 Injection at a dose of 5 mg/kg.
NHV Participants: Cohort 6	ARC-521 Injection	NHV participants administered a single dose of ARC-521 Injection at a dose of 6 mg/kg.
NHV Participants: Placebo	Placebo	NHV participants administered 0.9% normal saline to match ARC-521 Injection at doses of 0.6, 1, 2, 4, 5 and 6 mg/kg.
NHV Participants: Cohort 1	antihistamine	NHV participants administered a single dose of ARC-521 Injection at a dose of 0.6 mg/kg.
NHV Participants: Cohort 2	ARC-521 Injection	NHV participants administered a single dose of ARC-521 Injection at a dose of 1 mg/kg.
NHV Participants: Cohort 4	antihistamine	NHV participants administered a single dose of ARC-521 Injection at a dose of 4 mg/kg.
NHV Participants: Cohort 5	antihistamine	NHV participants administered a single dose of ARC-521 Injection at a dose of 5 mg/kg.
NHV Participants: Cohort 6	antihistamine	NHV participants administered a single dose of ARC-521 Injection at a dose of 6 mg/kg.
NHV Participants: Cohort 2	antihistamine	NHV participants administered a single dose of ARC-521 Injection at a dose of 1 mg/kg.
NHV Participants: Placebo	antihistamine	NHV participants administered 0.9% normal saline to match ARC-521 Injection at doses of 0.6, 1, 2, 4, 5 and 6 mg/kg.
CHB Participants: Cohort 4b	antihistamine	Treatment-naive participants with CHB administered 3 doses of ARC-521 Injection at 4 mg/kg once every 4 weeks. Participants are treatment-naive if they have not been on continual NUC therapy (any NUC) for at least 6 months prior to screening (or have never been on NUCs).
NHV Participants: Cohort 3	antihistamine	NHV participants administered a single dose of ARC-521 Injection at a dose of 2 mg/kg.
CHB Participants: Cohort 3c	antihistamine	Participants with CHB currently on NUCs (entecavir or tenofovir for at least 6 months) administered 3 doses of ARC-521 Injection at 2 mg/kg once every 4 weeks.
CHB Participants: Cohort 4c	ARC-521 Injection	Participants with CHB currently on NUCs (entecavir or tenofovir for at least 6 months) administered 3 doses of ARC-521 Injection at 4 mg/kg once every 4 weeks.
CHB Participants: Cohort 3b	ARC-521 Injection	Treatment-naive participants with CHB administered 3 doses of ARC-521 Injection at 2 mg/kg once every 4 weeks. Participants are treatment-naive if they have not been on continual nucleoside analog (NUC) therapy (any NUC) for at least 6 months prior to screening (or have never been on NUCs).
CHB Participants: Cohort 3b	antihistamine	Treatment-naive participants with CHB administered 3 doses of ARC-521 Injection at 2 mg/kg once every 4 weeks. Participants are treatment-naive if they have not been on continual nucleoside analog (NUC) therapy (any NUC) for at least 6 months prior to screening (or have never been on NUCs).
CHB Participants: Cohort 4b	ARC-521 Injection	Treatment-naive participants with CHB administered 3 doses of ARC-521 Injection at 4 mg/kg once every 4 weeks. Participants are treatment-naive if they have not been on continual NUC therapy (any NUC) for at least 6 months prior to screening (or have never been on NUCs).
CHB Participants: Cohort 3c	ARC-521 Injection	Participants with CHB currently on NUCs (entecavir or tenofovir for at least 6 months) administered 3 doses of ARC-521 Injection at 2 mg/kg once every 4 weeks.
CHB Participants: Cohort 4c	antihistamine	Participants with CHB currently on NUCs (entecavir or tenofovir for at least 6 months) administered 3 doses of ARC-521 Injection at 4 mg/kg once every 4 weeks.
NHV Participants: Cohort 1	acetaminophen	NHV participants administered a single dose of ARC-521 Injection at a dose of 0.6 mg/kg.
NHV Participants: Cohort 2	acetaminophen	NHV participants administered a single dose of ARC-521 Injection at a dose of 1 mg/kg.
NHV Participants: Cohort 3	acetaminophen	NHV participants administered a single dose of ARC-521 Injection at a dose of 2 mg/kg.
NHV Participants: Cohort 4	acetaminophen	NHV participants administered a single dose of ARC-521 Injection at a dose of 4 mg/kg.
NHV Participants: Cohort 5	acetaminophen	NHV participants administered a single dose of ARC-521 Injection at a dose of 5 mg/kg.
NHV Participants: Cohort 6	acetaminophen	NHV participants administered a single dose of ARC-521 Injection at a dose of 6 mg/kg.
NHV Participants: Placebo	acetaminophen	NHV participants administered 0.9% normal saline to match ARC-521 Injection at doses of 0.6, 1, 2, 4, 5 and 6 mg/kg.
CHB Participants: Cohort 3b	acetaminophen	Treatment-naive participants with CHB administered 3 doses of ARC-521 Injection at 2 mg/kg once every 4 weeks. Participants are treatment-naive if they have not been on continual nucleoside analog (NUC) therapy (any NUC) for at least 6 months prior to screening (or have never been on NUCs).
CHB Participants: Cohort 4b	acetaminophen	Treatment-naive participants with CHB administered 3 doses of ARC-521 Injection at 4 mg/kg once every 4 weeks. Participants are treatment-naive if they have not been on continual NUC therapy (any NUC) for at least 6 months prior to screening (or have never been on NUCs).
CHB Participants: Cohort 3c	acetaminophen	Participants with CHB currently on NUCs (entecavir or tenofovir for at least 6 months) administered 3 doses of ARC-521 Injection at 2 mg/kg once every 4 weeks.
CHB Participants: Cohort 3c	entecavir	Participants with CHB currently on NUCs (entecavir or tenofovir for at least 6 months) administered 3 doses of ARC-521 Injection at 2 mg/kg once every 4 weeks.
CHB Participants: Cohort 4c	acetaminophen	Participants with CHB currently on NUCs (entecavir or tenofovir for at least 6 months) administered 3 doses of ARC-521 Injection at 4 mg/kg once every 4 weeks.
CHB Participants: Cohort 4c	entecavir	Participants with CHB currently on NUCs (entecavir or tenofovir for at least 6 months) administered 3 doses of ARC-521 Injection at 4 mg/kg once every 4 weeks.
CHB Participants: Cohort 4c	tenofovir	Participants with CHB currently on NUCs (entecavir or tenofovir for at least 6 months) administered 3 doses of ARC-521 Injection at 4 mg/kg once every 4 weeks.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-Emergent Adverse Events (TEAEs): Healthy Volunteers	From first dose of study drug through Day 29 (± 1 day)	An adverse event (AE) is any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. A serious AE 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.
Number of Participants With TEAEs: CHB Participants	From first dose of study drug through Day 142 (± 3 days)	An AE is any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. A serious AE 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.
Pharmacokinetics of ARC-521 Injection: Area Under the Plasma-Concentration-Time Curve From Time 0-24 Hours (AUC0-24), Healthy Volunteers	Through 48 hours post-dose on Day 1
Pharmacokinetics of ARC-521 Injection: Area Under the Plasma-Concentration-Time Curve From Time 0 to the Last Quantifiable Plasma Concentration (AUClast), Healthy Volunteers	Through 48 hours post-dose on Day 1
Pharmacokinetics of ARC-521 Injection: Area Under the Plasma-Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf), Healthy Volunteers	Through 48 hours post-dose on Day 1
Pharmacokinetics of ARC-521 Injection: Maximum Observed Plasma Concentration (Cmax), Healthy Volunteers	Through 48 hours post-dose on Day 1
Pharmacokinetics of ARC-521 Injection: Terminal Elimination Rate Constant (Kel), Healthy Volunteers	Through 48 hours post-dose on Day 1
Pharmacokinetics of ARC-521 Injection: Terminal Elimination Half-Life (t1/2), Healthy Volunteers	Through 48 hours post-dose on Day 1
Pharmacokinetics of ARC-521 Injection: Clearance (CL), Healthy Volunteers	Through 48 hrs post-dose on Day 1
Pharmacokinetics of ARC-521 Injection: Apparent Volume of Distribution (V), Healthy Volunteers	Through 48 hours post-dose on Day 1
Change Over Time in Viral Antigens and DNA in CHB Participants as a Measure of Activity of ARC-521 Injection	Baseline to Day 142

Secondary Outcome Measures

Name	Time	Method
Change Over Time in Complement Levels After Single and Multiple Doses of ARC-521 Injection	Through 24 hours post-dose (Day 1 for NHVs, and Days 1, 29 & 57 for CHB participants)
Change Over Time in Cytokine Levels After Single and Multiple Doses of ARC-521 Injection	Through 24 hours post-dose (Day 1 for NHVs, and Days 1, 29 & 57 for CHB participants)