A Study to Evaluate the Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of RO7062931in Healthy Volunteers and Subjects With Chronic Hepatitis B
Condition: Chronic Hepatitis B
MeSH terms: Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Hepatitis; Hepatitis, Chronic
Intervention: RO7062931; Placebo; Immune Modulator
Intervention description: Administered subcutaneously in Parts 1 and 2. Part 1 will be administered in single-ascending doses after 0.1 mg/kg starting dose. Subsequent doses of 0.3, 1, 2 and 4 mg/kg may be administered based upon tolerability. In Part 2a, participants will receive two monthly doses of either 0.4, 0.8, 1.2 times the saturation dose or placebo. In Part 2b, a dose selected from Part 2a will be administered to participants randomized into 4 cohorts QW or Q2W. In Part 2c, participants will receive RO7062831 QW on top of another therapy for up to 24 or 48 weeks.; Part 1 cohorts: active drug vs placebo 4:1. Part 2a 4 parallel cohorts of 3 active drug doses and placebo in 1:1:1:1. Part 2b active drug vs placebo in 3:1 in 2 parallel cohorts.; Participants in Part 2c will receive an immune modulator subcutaneously QW for up to 48 weeks.
Intervention MeSH terms: Immunomodulating Agents
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 119.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This randomized study will be conducted in two parts to evaluate the safety, tolerability,
      pharmacodynamics, and pharmacokinetics of subcutaneous administration of RO7062931. Part 1
      will include only healthy participants and Part 2 will include only participants with chronic
      hepatitis B (CHB). Part 1 is an adaptive, single-ascending dose study with an adaptive
      dose-escalating schedule to determine the best dose to be evaluated in participants with CHB.
      Part 2 is an adaptive, parallel multiple-dose study comprised of three sub-parts which will
      be used to further refine the dose and dosing regimen, and to evaluate the safety and
      efficacy of RO7062931 when administered with standard-of-care (SoC) therapy.
    

Eligibility criteria:

        Inclusion Criteria:

        FOR HEALTHY VOLUNTEERS ONLY - PART 1 -

          -  A Body Mass Index (BMI) between 18 to 30 kg/m2 inclusive and a body weight of at least
             50 kg.

          -  Women should be of non-childbearing potential. A woman is considered to be of
             childbearing potential if she is post-menarcheal but has not reached a post-menopausal
             state and has not undergone surgical sterilization (removal of ovaries and/or uterus).

          -  Men must agree to remain abstinent (refrain from heterosexual intercourse) or use
             contraceptive measures during treatment and up to 105 days after the last dose, and
             agree to refrain from donating sperm.

          -  Non-smoker (nor tobacco containing products) for at least 90 days prior to dosing on
             Day 1 and agree to remain as non-smoker during the study.

        FOR CHB PARTICIPANTS ONLY - PARTS 2a and 2b:

          -  A BMI between 18 to 32 kg/m2 inclusive.

          -  Chronic hepatitis B (HBV) infection.

          -  Positive test for HBsAg for more than 6 months prior to randomization and HBsAg titer
             ≥ 10^3 IU/mL at screening.

          -  On entecavir, tenofovir, adefovir or telbivudine treatment for at least 6 months prior
             to randomization and will remain on stable treatment during the study.

          -  HBV deoxyribonucleic acid (DNA) ≤ 90 IU/mL for at least the preceding 6 months.

          -  Screening laboratory values (hematology, chemistry, urinalysis) obtained up to 56 days
             prior to first study treatment within normal ranges.

          -  Liver biopsy, fibroscan® or equivalent test obtained within the past 6 months
             demonstrating liver disease consistent with chronic HBV infection without evidence of
             bridging fibrosis or cirrhosis

          -  Women should be of non-childbearing potential. A woman is considered to be of
             childbearing potential if she is post-menarcheal but has not reached a post-menopausal
             state and has not undergone surgical sterilization (removal of ovaries and/or uterus).

          -  Men must agree to remain abstinent (refrain from heterosexual intercourse) or use
             contraceptive measures during treatment and up to 105 days after the last dose, and
             agree to refrain from donating sperm.

        FOR CHB PARTICIPANTS ONLY - PART 2c

          -  BMI between 18 to 32 kg/m2 inclusive

          -  CHB infection (HBsAg-positive for at least 6 months)

          -  For NUC-suppressed CHB participants: Must have been treated with a single NUC for at
             least 12 months, and have been on the same NUC therapy for at least 3 months prior to
             screening; HBV DNA <lower limit of quantification (LLOQ) at screening and in the 6
             months prior to screening (at least one measurement must be >30 days prior to
             screening); alanine aminotransferase (ALT) </=2x upper limit of normal (ULN) for >6
             months prior to screening and confirmed at screening; total bilirubin within normal
             range at screening, except for patients with Gilbert's syndrome

          -  For treatment-naive and immune-active participants: HBV DNA at screening >/=2x10^4
             IU/mL for HBeAg positive participants, or >/=2x10^3 IU/mL for HBeAg negative
             participants; elevated serum ALT>2 ULN to </=5, 2 values within 6 months, at least one
             of which is at screening and that are at least 14 days apart; total bilirubin within
             normal range except for participants with Gilbert's syndrome

          -  Screening laboratory values (hematology, chemistry, urinalysis) obtained up to 28 days
             prior to first study treatment within normal ranges

          -  Liver biopsy, fibroscan, or equivalent test obtained within the last 6 months
             demonstrating liver disease consistent with chronic HBV infection without evidence of
             bridging fibrosis or cirrhosis

          -  Women should be of non-childbearing potential

          -  Men must agree to remain abstinent or use contraception, and agree to refrain from
             donating sperm

        Exclusion Criteria:

        FOR HEALTHY VOLUNTEERS ONLY - PART 1:

          -  History of drug or alcohol abuse or dependence in previous 6 months.

          -  Positive urine drug and alcohol screen or positive cotinine test at screening or Day
             -1.

          -  Positive result on hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency
             virus (HIV) 1 and 2.

          -  Confirmed blood pressure or resting pulse rate outside of accepted ranges.

          -  Participation in an investigational drug or device study within 90 days prior to
             screening.

          -  Donation of blood over 500 mL within three months prior to screening.

          -  Any major illness within the one month, or any febrile illness within two weeks
             preceding the screening visit.

          -  Alcohol consumption of more than 2 standard drinks per day on average.

        FOR CHB PARTICIPANTS ONLY - PARTS 2a and 2b:

          -  History or other evidence of bleeding from esophageal varices.

          -  Decompensated liver disease.

          -  History of or suspicion of hepatocellular carcinoma or alpha fetoprotein (AFP) ≥ 13
             ng/mL at Screening

          -  History or other evidence of a medical condition associated with chronic liver disease
             other than HBV infection.

          -  Documented history or other evidence of metabolic liver disease within one year of
             randomization or documented history of infection with hepatitis D virus.

          -  Positive test for hepatitis A (IgM anti-HAV), hepatitis C, or HIV.

          -  Organ transplantation.

          -  Significant acute infection or any other clinically significant illness within 2 weeks
             of randomization.

          -  Abnormal renal function.

          -  Participation in an investigational drug or device study within 30 days prior to
             randomization.

          -  Donation or loss of blood over 500 mL within 3 months prior to starting study
             medication.

          -  Administration of any blood product within 3 months of randomization.

          -  History or evidence of alcohol abuse (consumption of more than 2 standard drinks per
             day on average).

        FOR CHB PARTICIPANTS ONLY - PART 2c

          -  History or other evidence of bleeding from esophageal varices

          -  Evidence of liver cirrhosis or decompensated liver disease

          -  One or more of the following laboratory abnormalities at screening: Total serum
             bilirubin > ULN (except for participants with Gilbert's disease); international
             normalized ratio (INR) > 1.1 ULN; serum albumin < 3.5 g/dL; AFP >13 ng/mL; positive
             results for anti-mitochondrial antibodies (AMA > 1:80), anti-nuclear antibody (ANA >
             1:80), anti-smooth muscle antibody (ASMA > 1:40), anti-thyroperoxidase antibodies
             (a-TPO), anti-thyroglobulin, or anti-platelet antibodies; thyroid stimulating hormone
             (TSH) outside of normal range; platelet count <100,000 cells/mm^3; hemoglobin <12 g/dL
             (females) or <13 g/dL (males); white blood cell count <2500 cells/mm^3; and neutrophil
             count <1500 cells/mm^3

          -  History or other evidence of a medical condition associated with chronic liver disease
             other than HBV infection

          -  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
             randomization

          -  Positive test for hepatitis A, hepatitis C, or HIV

          -  History of organ transplantation

          -  Participation in an investigational drug or device study within 30 days prior to
             screening or previous treatment with an investigational agent for HBV within 6 months
             prior to screening

          -  Significant acute infection or any other clinically significant illness within 2 weeks
             of randomization

          -  Abnormal renal function, including serum creatinine > ULN or calculated creatinine
             clearance < 70 mL/min

          -  Donation or loss of blood over 500 mL within 3 months prior to randomization

          -  Administration of any blood product within 3 months prior to randomization

          -  History of alcohol abuse and/or drug abuse