A Study to Evaluate the Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of RO7062931in Healthy Volunteers and Subjects With Chronic Hepatitis B

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Sponsor-Open, Placebo-Controlled Study to Evaluate Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of Subcutaneous Administration of RO7062931 With Single Ascending Doses in Healthy Volunteers and Multiple Doses and Modified Regimens in Virologically Suppressed Patients With Chronic Hepatitis B Virus Infection

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: RO7062931
* Drug: Placebo
* Drug: Immune Modulator


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Single-Ascending Dose (SAD)<br>Healthy volunteers will be enrolled in up to 8 cohorts with doses starting from 0.1 mg/kg and escalating sequentially after review of safety and pharmacokinetic (PK) data. | Drug: RO7062931<br>* 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.<br>Drug: Placebo<br>* 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.<br>|
| Experimental: Part 2: Multiple Ascending Dose<br>Participants with Chronic Hepatitis B will enrolled in Part 2. In Part 2a, participants will receive two monthly injections of either 3 doses equivalent to a multiple of the saturation dose or placebo in a 1:1:1:1 ratio. In Part 2b, a dose selected from Part 2a will be administered to participants randomized into 4 cohorts where they will be dosed weekly (QW) or bi-weekly (Q2W). Each of the cohorts in Part 2b will include participants receiving active drug or placebo in a 3:1 ratio. In Part 2c, NUC-suppressed CHB participants will receive either RO7062931+NUC for up to 24 weeks, or RO7062931+NUC+an immune modulator for up to 48 weeks, at a dose determined from Part 2a and 2b. Part 2c may also enroll treatment-naive immune-active CHB participants. | Drug: RO7062931<br>* 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.<br>Drug: Placebo<br>* 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.<br>Drug: Immune Modulator<br>* Participants in Part 2c will receive an immune modulator subcutaneously QW for up to 48 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs) and AEs of Special Interest | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs of Special Interest were defined as: i.) elevated ALT/AST in combination with elevated bilirubin/clinical jaundice, ii.) suspected transmission of infectious agent by the study drug, iii.) severe injection site reactions, iv.) ALT elevation ≥10x ULN, v.) creatinine elevation ≥1.5x ULN or ≥50% from baseline. | Up to day 113 | 
| Percentage of Participants With Laboratory Abnormalities Based on Hematology, Blood Chemistry, Coagulation, and Urinalysis Test Results - Part 1 | Marked reference range has been predefined for each laboratory parameter. The marked reference range is broader than the standard reference range. Values falling outside the marked reference range that also represent a defined change from baseline will be considered marked laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not available for a study subject, the midpoint of the standard reference range will be used as the study participant baseline value for the purposes of determining marked laboratory abnormalities. | Screening, Days -1, 2, 8, 15, 29, 85 | 
| Percentage of Participants With Laboratory Abnormalities Based on Hematology, Blood Chemistry, Coagulation, and Urinalysis Test Results - Part 2 | Marked reference range has been predefined for each laboratory parameter. The marked reference range is broader than the standard reference range. Values falling outside the marked reference range that also represent a defined change from baseline will be considered marked laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not available for a study subject, the midpoint of the standard reference range will be used as the study participant baseline value for the purposes of determining marked laboratory abnormalities. | Screening, Days -1, 2, 8, 15, 29, at discontinuation, Days 36, 43, 57, 85, 113 | 
| Percentage of Participants With Electrocardiogram (ECG) Abnormalities Based on ECG Interpretation - Part 1 | Participants were monitored for clinically-significant RO7062931-related ECG changes, defined as QTcF > 500 msec, or > 60 msec longer than the pre-dose baseline, within the first 48 hours post-dose. | Day 1 (1,4,8,12h), Days 2 and 8, Follow Up Days 15, 29, 85 | 
| Percentage of Participants With Electrocardiogram (ECG) Abnormalities Based on ECG Interpretation - Part 2 | Participants were monitored for clinically-significant RO7062931-related ECG changes, defined as QTcF > 500 msec, or > 60 msec longer than the pre-dose baseline, within the first 48 hours post-dose. | Day 1 (1,4,8h), Days 2,8,15,22 (1h and 8h), Day 23, Day 29 (1,4,8h), Day 30, Follow Up Days 36, 43, 50, 57, 78, 85, 106, 113 | 
| Percentage of Participants With T-Wave Abnormalities Based on T-Wave Assessment - Part 1 | Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug. | Day 1 (1,4,8,12h), Days 2 and 8, Follow Up Days 15, 29, 85 | 
| Percentage of Participants With U-Wave Abnormalities Based on U-Wave Assessment - Part 1 | Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug. | Day 1 (1,4,8,12h), Days 2 and 8, Follow Up Days 15, 29, 85 | 
| Percentage of Participants With T-Wave Abnormalities Based on T-Wave Assessment - Part 2 | Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug. | Day 1 (1,4,8h), Days 2,8,15,22 (1h and 8h), Day 23, Day 29 (1,4,8h), Day 30, Follow Up Days 36, 43, 50, 57, 78, 85, 106, 113 | 
| Percentage of Participants With U-Wave Based on U-Wave Assessment - Part 2 | Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug. | Day 1 (1,4,8h), Days 2,8,15,22 (1h and 8h), Day 23, Day 29 (1,4,8h), Day 30, Follow Up Days 36, 43, 50, 57, 78, 85, 106, 113 | 
| Percentage of Participants With QTcF Values Between 450 Msec - 480 Msec - Part 2 | Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug. | Day 1 (1,4,8h), Days 2,8,15,22 (1h and 8h), Day 23, Day 29 (1,4,8h), Day 30, Follow Up Days 36, 43, 50, 57, 78, 85, 106, 113 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) After Single Ascending Doses - Part 1 | Cmax values are the the peak plasma concentration reached after administration of RO7062931. | Days 1-8 | 
| Cmax After Multiple Ascending Doses - Part 2 | Cmax values are the the peak plasma concentration reached after administration of RO7062931. | Days 1-113 | 
| Time to Reach Maximum Plasma Concentration (Tmax) After Single-Ascending Doses - Part 1 | Tmax values are the amount of time to maximum concentration in plasma after administration of RO7062931. | Days 1-8 | 
| Tmax After Multiple Ascending Doses - Part 2 | Tmax values are the amount of time to maximum concentration in plasma after administration of RO7062931. | Days 1-113 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) After Single-Ascending Doses - Part 1 | AUC0-inf was calculated based on non-compartmental analysis. | Days 1-8 | 
| AUC0-inf After Multiple Ascending Doses - Part 2 | AUC0-inf was calculated based on non-compartmental analysis. | Days 1,22,29 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero Until the Last Quantifiable Time-Point (AUC0-last) After Single Ascending Doses - Part 1 | AUC0-last was calculated based on non-compartmental analysis. | Days 1-8 | 
| AUC0-last After Multiple Ascending Doses - Part 2 | AUC0-last was calculated based on non-compartmental analysis. | Days 1,22,29 | 
| Terminal Elimination Half-Life (t1/2) After Single Ascending Doses - Part 1 | T1/2 was calculated based on non-compartmental analysis. | Days 1-8 | 
| Terminal Elimination Half-Life (t1/2) After Multiple Ascending Doses - Part 2 | T1/2 was calculated based on non-compartmental analysis. | Days 1-113 | 
| Total Clearance (CL) After Single Ascending Doses - Part 1 | Apparent oral clearance was calculated from Dose/AUCinf. | Days 1-8 | 
| Total Clearance (CL) After Multiple Ascending Doses - Part 2 | Apparent oral clearance was calculated from Dose/AUCinf. | Days 1-113 | 
| Volume of Distribution (Vss) After Single Ascending Doses - Part 1 | Vss was calculated from dose/AUCinf | Days 1-8 | 
| Volume of Distribution (Vss) After Multiple Ascending Doses - Part 2 | Vss was calculated from dose/AUCinf | Days 1-113 | 
| Cumulative Amount Excreted Unchanged in Urine (Ae) After Single Ascending Doses - Part 1 | Ae: cumulative amount of drug excreted in urine over a 24 hour period or over defined time periods linked to the pools of urine collected. | Hours 0-4, 0-8, 0-12, and 0-24 | 
| Cumulative Amount Excreted Unchanged in Urine (Ae) After Multiple Ascending Doses - Part 2 | Ae: cumulative amount of drug excreted in urine over a 24 hour period or over defined time periods linked to the pools of urine collected. | Days 1-113 | 
| Change From Baseline of Quantitative HBsAg (qHBsAg) (log10) After Multiple Ascending Doses - Part 2 | HBsAg is a viral parameter that can be affected by the action of RO7062931. A change from baseline in qHBsAg can indicate the drug's effect. | Days 1-113 | 
| Summary of Maximum qHBsAg Decrease on Days 1-113 - Part 2 | HBsAg is a viral parameter that can be affected by the action of RO7062931. A change from baseline in qHBsAg can indicate the drug's effect. | Day 1 - Day 113 | 
| Summary of Time to Maximum qHBsAg Decrease on Day 1-113 - Part 2 | HBsAg is a viral parameter that can be affected by the action of RO7062931. A change from baseline in qHBsAg can indicate the drug's effect. | Day 1 - Day 113 |