Chronic Hepatitis B Infection

Primary Objectives  To assess the dose-related safety and tolerability and of ABI-H0731 after oral doses from 100 mg/day up to a maximum predicted dose of 1600 mg/day, in patients with chronic HBV infection

ABI-H0731

ABI-H0731

Oral

100 mg and Placebo Tablet

Primary Outcome Measures :
Number of patients with chronic HBV infection with treatment-related adverse events and laboratory abnormalities as assessed by CTCAE v4.0. [ Time Frame: Up to 57 days ]

Inclusion Criteria
To be eligible for this study, patients must meet the following Inclusion Criteria:
1. Male or female, 18 to 65 years of age
2. Female participants must be surgically sterile for at least 6 months, or at least
two years post-menopausal with serum FSH levels consistent with a
post-menopausal status, and they must have a negative serum pregnancy test at
Screen
3. All heterosexually active male patients must agree to use dual effective birth control
methods for the duration of the study and follow up. Effective birth control methods
include male or female condom (may not be used together due to increased risk of
breakage), vasectomy, hormone based contraception, intrauterine device (IUD),
diaphragm, or cervical cap.
4. Chronic HBV infection, documented by:
a. Compatible clinical history
b. Serologic profile consistent with chronic HBV infection, i.e.:
i. Serum HBsAg positive or viral load positive: history of 2 repeat positive
HBsAg or viral load measurements ≥ 6 months apart with no history of
hepatic decompensation. One of these measurements may be at
Screening.
ii. IgM anti-HBc negative
iii. For Cohorts B1-B4: HBV viral load requirements are
 HBeAg positive: ≥ 2x104
IU/mL
 HBeAg negative: ≥ 2x103
IU/mL
iv. For Cohorts B1-B4, subjects will be stratified by HBeAg status in a 7:5
ratio (HBeAg+
: HBeAg-
)
v. For optional Cohorts B5 and B6:
(1) Patients must be HBeAg positive, with serum HBsAg
>1000 IU/mL
(2) Patients must have a viral load below the limit of quantification
(LOQ) on two visits at least 6 months apart. One measurement
may be from the Screen visit.
(3) For Cohort B5, patients must be on entecavir (ETV) or tenofovir
(TDF) for at least 6 months prior to Screening
 50% of patients must be on ETV
 50% of patients must be on TDF
vi. For Cohort B6, patients may be on any stable nucleos(t)ide regimen
(≥ 6 months) with an approved standard of care nucleos(t)ide
5. Body Mass Index (BMI) 18-38 kg/m2
and a minimum body weight of 45 kg
6. Resting heart rate (HR) must be between 45 to 90 bpm, inclusive, at Screen and
Baseline
7. Clinical history compatible with compensated liver disease, with no evidence of
cirrhosis:
a. No history of bleeding from oesophageal or gastrointestinal varices
b. No history of ascites
c. No history of jaundice attributed to chronic liver disease
d. No history of hepatic encephalopathy
e. No physical stigmata of portal hypertension
f. A previous liver biopsy within 12 months of screening demonstrating F0-F2
or equivalent by metavir scoring or Fibroscan or other approved hepatic
imaging study within 6 months of screening indicating lack of cirrhosis or
advanced liver disease (F0-F2 or equivalent)
g. APRI score ≤1.05
8. Study patients in cohort B1-B4 may have received previous commercially approved
HBV nucleos(t)ide or interferon therapy, as long as such treatment ended at least 3
months prior to Screening for the present study
 For Cohorts B5 and B6, patients must be on a stable regimen of a
nucleos(t)ide with HBV viral load below the LOQ for at least 2 consecutive
visits 6 months apart and prior to Screening
9. Patient is willing and able to provide informed consent

Exclusion Criteria
Patients will be excluded if they meet any of the following exclusion criteria:
1. Seropositive for HIV, HCV, or HDV antibody at Screen
2. History of any medical condition that may interfere with the absorption,
distribution, or elimination of study drug (ABI-H0731), or with the clinical and
laboratory assessments in this study, including (but not limited to); chronic or
recurrent renal disease, functional bowel disorders (e.g., frequent diarrhoea or
constipation), gastrointestinal tract disease, pancreatitis, seizure disorder, mucocutaneous or musculoskeletal disorder, history of suicidal attempt(s) or
suicidal ideation, or clinically significant depression or other neuropsychiatric
disorder requiring pharmacologic intervention
3. Participant is febrile, temperature > 37.5°C at Screening
4. Previous treatment with any investigational HBV antiviral treatments within the
last 6 months, or previous treatment at any time with an investigational HBV
antiviral treatment of the same class (core protein targeted therapies)
5. Other known cause of liver disease, including NASH
6. Clinically significant cardiopulmonary disease, chronic or recurrent renal or urinary
tract disease; endocrine disorder, autoimmune disorder, diabetes mellitus requiring
treatment with insulin or hypoglycaemic agents; neuromuscular, musculoskeletal,
or mucocutaneous conditions requiring frequent treatment; seizure disorders
requiring treatment, or other medical conditions requiring frequent medical
management or pharmacologic or surgical treatment
7. Clinically significant ECG abnormalities at Screen
8. Poorly controlled or unstable hypertension; or sustained systolic blood pressure
≥ 160 mmHg or < 90 mmHg, or diastolic BP > 95 mmHg or < 50 mmHg at Screen
9. History of asthma requiring hospital admission within the preceding 12 months
10. History of persistent ethanol abuse (> 40 gm ethanol/day) or illicit drug use within
the preceding 3 years. A urine drug screen for illicit drugs (e.g., amphetamines,
barbiturates, opiates, or cocaine) will be conducted to facilitate the investigator’s
evaluation of the patient
11. Use of grapefruit juice or other citrus juices for 7 days prior to Day 1 dosing and
through the completion of dosing (Day 28)
12. History of persistent or recurrent hyperbilirubinaemia unless known Gilbert’s
Disease or Dubin-Johnson Syndrome
13. History of chronic or recurrent urinary tract infection (UTI), or UTI within 28 days
prior to Screen
14. History of hepatocellular carcinoma (HCC)
15. A history of malignancy other than HCC unless the patient’s malignancy has been
in complete remission off chemotherapy and without additional medical or surgical
interventions during the preceding three years
16. Donated or lost > 500 mL of blood within 2 months prior to Screen, or plasma
donation within 7 days prior to Screen
17. If patient is persistently using herbal supplements or systemic over-the-counter
medications (except for paracetamol), he/she must be willing to stop for the
duration of the study period and within 7 days prior to Day 1. Use of any
prescription medication is prohibited within the 14 days prior to the Day 1 or 5 halflives, whichever is longer, and for the duration of the study unless clinically
indicated for the health or safety of study participants.
18. Participation in another clinical trial of a drug or device whereby the last
investigational drug/device administration is within 60 days prior to the first study
drug administration or 5 half-lives, whichever is longer
19. History of drug allergy
20. Exclusionary laboratory results at Screen:
a. Hgb < 12 g/dL (males) or < 11 g/dL (females)
b. Total white blood cell (WBC) count < 4,000/mm3
c. Absolute neutrophil count (ANC) < 1,500/mm3
d. Platelet count < 100,000/mm3
e. Albumin < 3.5 g/dL
f. Total bilirubin > ULN (unless known Gilbert’s Disease or Dubin-Johnson
Syndrome)
g. Direct bilirubin > ULN
h. Serum AST ≥ 7x ULN
i. Serum BUN > ULN
j. GFR <60 mL/min/1.73 m2 by CKD-EPI equation
k. Serum amylase or lipase > 1.25x ULN
l. Serum HgbA1c > 8%
m. Prothrombin time: Institutional Normalised Ratio (INR) > ULN
n. Serum alpha fetoprotein (AFP) value ≥100 ng/mL is exclusionary. If AFP
at Screening is > ULN but < 100 ng/mL, patient is eligible if a hepatic
imaging study reveals no lesions suspicious of possible hepatocellular
carcinoma (HCC)
o. Serum ALT ≥ 7x ULN at Screen and Baseline
p. Any other toxicity of grade 2 or higher by the modified DAIDS grading
scale in Appendix 1