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

Roche

Status and phase: Completed; Phase 1

Conditions: Chronic Hepatitis B

Treatments: Drug: Placebo; Drug: RO7062931; Drug: Immune Modulator

Study type: Interventional

Funder types: Industry

Identifiers

NCT03038113

BP39405

Details and patient eligibility

About

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.

Enrollment: 119 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

---

119 participants in 2 patient groups

Part 1: Single-Ascending Dose (SAD)

Experimental group

Description:

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.

Treatment:

Drug: RO7062931

Drug: Placebo

Part 2: Multiple Ascending Dose

Experimental group

Description:

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.

Treatment:

Drug: RO7062931

Drug: Immune Modulator

Drug: Placebo