A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of RO7049389 in Healthy Volunteers and Chronic Hepatitis B Virus (HBV) Infected Participants
A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of RO7049389 in Healthy Volunteers and Chronic Hepatitis B Virus (HBV) Infected Participants
This study is a multicenter, three-part study. Parts 1 and 2 are randomized, investigator-
 and participant-blinded, placebo-control, single-ascending dose (SAD) and multiple-ascending
 dose (MAD) study to evaluate the safety, tolerability, pharmacokinetics (PK) and
 pharmacodynamics (PD) of RO7049389 following oral administration in healthy volunteers and
 chronic HBV infected participants. Part 3 is a non-randomized, non-controlled, open-label
 part to assess the efficacy and safety of RO7049389 when administered in combination with
 standard-of-care therapies for up to 48 weeks in nucleos(t)ide (NUC)-suppressed and
 treatment-naive chronic hepatitis B (CHB) participants.
Inclusion Criteria:

 Part 1- Healthy Volunteers only:

 -  Absence of evidence of any active or chronic disease following a detailed medical and
 surgical history, a complete physical examination including vital signs, 12-lead
 Electrocardiogram (ECG), hematology, blood chemistry, serology and urinalysis

 -  A Body Mass Index (BMI) between 18 to 30 kilograms per square meter (kg/m^2) inclusive

 -  Female participants must be either surgically sterile or post-menopausal for at least
 one year

 -  For men: agreement to remain abstinent or use contraceptive measures, and agreement to
 refrain from donating sperm

 Part 2- Chronic HBV-infected participants only:

 -  A BMI between 18 to 30 kg/m^2 inclusive

 -  Chronic Hepatitis B infection, defined as positive test for Hepatitis B surface
 antigen (HBsAg) for more than 6 months prior to randomization

 -  HBV DNA at screening greater than or equal to (>/=) 2 × 10^4 international units per
 milliliter (IU/mL) for Hepatitis B e antigen (HBeAg) positive participants, or >/=2 ×
 10^3 IU/mL for HBeAg-negative participants

 -  Liver biopsy, fibroscan or equivalent test obtained within the past 6 months
 demonstrating liver disease consistent with chronic HBV infection with absence of
 extensive bridging fibrosis and absence of cirrhosis

 -  For men: agreement to remain abstinent or use contraceptive measures, and agreement to
 refrain from donating sperm

 -  For women of childbearing potential: agreement to remain abstinent or use non-hormonal
 contraceptive methods that result in a failure rate of less than (<)1 percent (%) per
 year during the treatment period and for at least 3 months after the last dose of
 study drug

 Part 3- Chronic HBV Participants Only:

 -  A BMI between 18 to 32 kg/m^2 inclusive

 -  Chronic hepatitis B infection, defined as positive test for HBsAg or HBV DNA, or
 positive HBeAg, for more than 6 months prior to screening

 -  For Cohorts only enrolling NUC-suppressed CHB participants (e.g. POM Cohort A),
 participants must have been treated with a single NUC (entecavir, tenofovir
 alafenamide, or tenofovir disoproxil fumarate) for at least 12 months. Participants
 must be on the same NUC therapy for at least 3 months prior to screening

 -  For Cohorts only enrolling anti-HBV treatment-naive and immune-active participants
 (e.g. POM Cohort B and Cohort C), previous anti-HBV treatments <30 days in total, and
 did not receive any anti-HBV treatments within 3 months prior to the first study dose

 -  Liver biopsy, fibroscan, or equivalent test obtained within the past 6 months
 demonstrating liver disease consistent with chronic HBV infection with absence of
 extensive bridging fibrosis and absence of cirrhosis

 -  For men: agreement to remain abstinent or use contraceptive measures, and agree to
 refrain from donating sperm

 -  For women of childbearing potential: agreement to remain abstinent or to use two
 approved contraceptive methods during the study and for at least 6 months after the
 last dose of study drug

 Exclusion Criteria:

 Part 1- Healthy Volunteers only:

 -  History or symptoms of any clinically significant gastrointestinal, renal, hepatic,
 broncho-pulmonary, neurological, psychiatric, cardio-vascular, endocrinological,
 hematological or allergic disease, metabolic disorder, cancer or cirrhosis

 -  History of Gilbert's syndrome

 -  Participants who have had significant acute infection, e.g., influenza, local
 infection, acute gastrointestinal symptoms or any other clinically significant illness
 within two weeks of dose administration

 -  Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any
 drug, or multiple drug allergies

 -  Any clinically significant concomitant diseases or condition that could interfere
 with, or treatment of which might interfere with, the conduct of the study, or that
 would, in the opinion of the Investigator, pose an unacceptable risk to the
 participant in this study

 -  Positive test at screening of any of the following: Hepatitis A (HAV IgM Ab),
 Hepatitis B (HBsAg), Hepatitis C (HCV RNA or HCV Ab) or human immunodeficiency virus
 (HIV Ab)

 -  Acute narrow-angle glaucoma (for MAD-midazolam cohorts)

 Part 2- Chronic HBV-infected participants only:

 -  History or other evidence of bleeding from esophageal varices

 -  Evidence of liver cirrhosis or decompensated liver disease such as ascites, esophageal
 or gastric varices, splenomegaly, nodular liver, jaundice, hepatic encephalopathy

 -  History or other evidence of a medical condition associated with chronic liver disease
 other than HBV infection (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver
 disease, toxin exposure, thalassemia, nonalcoholic steatohepatitis, etc.)

 -  Documented history or other evidence of metabolic liver disease within one year of
 randomization

 -  Positive test for hepatitis A (IgM anti-HAV), hepatitis C, hepatitis D, or human
 immunodeficiency virus

 -  History of or suspicion of hepatocellular carcinoma or alphafetoprotein >/= Upper
 limit of normal (ULN) at screening

 -  History of clinically significant gastrointestinal, cardiovascular, endocrine, renal,
 ocular, pulmonary, psychiatric or neurological disease

 -  History of organ transplantation

 -  Previous or concurrent HBV treatments in the past 6 months

 -  Significant acute infection (e.g., influenza, local infection) or any other clinically
 significant illness within 2 weeks of randomization

 Part 3- Chronic Hepatitis B Participants Only:

 -  History or other evidence of bleeding from esophageal varices

 -  Evidence of liver cirrhosis or decompensated liver disease such as ascites, esophageal
 or gastric varices, splenomegaly, nodular liver, jaundice, or hepatic encephalopathy

 -  History or other evidence of a medical condition associated with chronic liver disease
 other than HBV infection (e.g. hemochromatosis, autoimmune hepatitis, alcoholic liver
 disease, toxin exposure, thalassemia, nonalcoholic statohepatitis, etc.)

 -  History of thyroid disease poorly controlled on prescribed medications or clinically
 relevant abnormal thyroid function tests

 -  Documented history or other evidence of metabolic liver disease within one year of
 screening

 -  Positive test for hepatitis A (IgM anti-HAV), hepatitis C, hepatitis D, HEV, or HIV

 -  Diagnosed or suspected hepatocellular carcinoma

 -  History of clinically significant gastrointestinal, cardiovascular, endocrine, renal,
 ocular, pulmonary, psychiatric, or neurological disease

 -  History of organ transplantation

 -  Significant acute infection (e.g. influenza, local infection) or any other clinically
 significant illness within 2 weeks of screening