Phase 1
Completed N=192
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
Hepatitis B, Chronic
Source: ClinicalTrials.gov NCT02952924 ↗
Enrolled (actual)
192
Serious AEs
2.6%
Results posted
Oct 2024
Primary outcomePrimary: Part 1: Percentage of Participants With Adverse Events — 27.3; 33.3; 50.0; 100 Percentage of participants
Summary
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part 1: Percentage of Participants With Adverse Events |
27.3; 33.3; 50.0; 100; 83.3; 33.3 | — |
| PRIMARY Parts 1a and 1b: SAD Cohort: Time to Reach Maximum Concentration (Tmax) of RO7049389 |
2.0; 1.25; 3.0; 1.5; 2.0; 1.5 | — |
| PRIMARY Parts 1a and 1b: SAD Cohort: Maximum Observed Plasma Concentration (Cmax) of RO7049389 |
250; 1900; 4610; 8990; 14700; 8990 | — |
| PRIMARY Parts 1a and 1b: SAD Cohort: AUC From Time Zero to Infinity (AUC0-inf) of RO7049389 |
879; 4690; 10900; 34400; 46300; 34400 | — |
| PRIMARY Parts 1a and 1b: SAD Cohort: Area Under the Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of RO7049389 |
868; 4660; 10900; 34300; 46200; 34300 | — |
| PRIMARY Parts 1a and 1b: SAD Cohort: Half-life (T1/2) of RO7049389 |
3.34; 8.80; 4.20; 7.23; 12.1; 7.23 | — |
| PRIMARY Parts 1a and 1b: SAD Cohort: Apparent Oral Clearance (CL/F) of RO7049389 |
171; 128; 61.5; 64.9; 63.3; 64.9 | — |
| PRIMARY Parts 1a and 1b: SAD Cohort: Cumulative Amount Excreted Unchanged in Urine (Ae) of RO7049389 |
0.312; 1.88; 3.56; 1.88; 6.89 | — |
| PRIMARY Parts 1a and 1b: SAD Cohort: Renal Clearance (CLr) of RO7049389 |
1.60; 1.55; 1.41; 1.55; 0.82 | — |
| PRIMARY Part 2: Percentage of Participants With Adverse Events |
50.0; 66.7; 66.7; 83.3; 57.1; 33.3 | — |
| PRIMARY Part 2: Quantitative Plasma HBV DNA Level |
5.94; 4.50; 7.80; 4.43; 5.10; 7.14 | — |
| PRIMARY Part 3: Proportion of Patients Achieving Functional Cure |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Part 1b: Food Effect on Cmax of RO7049389 |
2.42 | — |
| SECONDARY Part 1b: Food Effect on AUCinf of RO7049389 |
2.17 | — |
| SECONDARY Part 1c: Cmax of Midazolam |
0.892; 1.01; 1.12; 0.940 | — |
| SECONDARY Part 1c: AUCinf of Midazolam |
1.10; 1.18; 1.25; 1.16 | — |
| SECONDARY Part 1c: Tmax of RO7049389 |
2.0; 2.0; 3.0; 3.0; 3.0; 1.5 | — |
| SECONDARY Part 1c: Cmax of RO7049389 |
483; 840; 4840; 14500; 10600; 735 | — |
| SECONDARY Part 1c: AUC0-12hr of RO7049389 |
1304.09; 1819.92; 9760.31; 32459.87; 27041.94; 1806.59 | — |
| SECONDARY Part 1c: CLr of RO7049389 |
1.06; 1.08; 1.43; 2.04; 1.19; 1.96 | — |
| SECONDARY Part 1c: Accumulation Ratio of RO7049389 |
1.45; 1.05; 0.880; 1.09 | — |
| SECONDARY Part 1c: T1/2 of RO7049389 |
2.27; 2.44; 2.09; 1.70; 1.53; 5.79 | — |
| SECONDARY Part 1c: Ae of RO7049389 |
0.0926; 0.0900; 0.859; 3.58; 1.77; 0.243 | — |
| SECONDARY Part 1c: Ctrough of RO7049389 |
12.1; 15.2; 42.1; 88.9 | — |
| SECONDARY Part 2: HBV DNA < Lower Limit of Quantification (LLOQ) |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Part 2: Tmax of RO7049389 |
2.0; 3.0; 1.97; 1.98; 1.5; 2.5 | — |
| SECONDARY Part 2: Cmax of RO7049389 |
1450; 8110; 5030; 23900; 910; 1500 | — |
| SECONDARY Part 2: AUCtau of RO7049389 |
2870; 19900; 11500; 80000; 3500; 3350 | — |
| SECONDARY Part 2: Accumulation Ratio of RO7049389 |
1.01; 0.971; 1.65; 0.823; 0.917 | — |
| SECONDARY Part 2: T1/2 of RO7049389 |
1.68; 1.15; 1.09; 1.40; 2.33; 3.38 | — |
| SECONDARY Part 2: Ctrough of RO7049389 |
26.7; 68.2; 7.94; 27.0; 3.37 | — |
| SECONDARY Part 3: Percentage of Participants With AEs |
68.8; 90; 100 | — |
| SECONDARY Part 3: Hepatitis B Surface Antigen (HBsAg) Level |
3.04; 3.51; 4.10; 3.08; 3.51; 4.14 | — |
| SECONDARY Part 3: Hepatitis B e-Antigen (HBeAg) Levels |
0.17; 1.07; 2.84; 0.16; 1.01; 2.79 | — |
| SECONDARY Part 3: HBV RNA Level |
0.99; 4.02; 5.30; 0.69; 1.04; 2.37 | — |
| SECONDARY Part 3: HBV Core-Related Antigen (HBcrAg) Levels |
4.10; 6.15; 7.95; 4.10; 5.95; 7.80 | — |
| SECONDARY Part 3: Alanine Transaminase (ALT) Normalization in Participants With Baseline ALT Elevation |
66.67; 35.71; 88.89; 62.96; 88.89; 77.78 | — |
| SECONDARY Part 3: Percentage of Participants With Anti-Hepatitis B Core Antigen (HBc) Antibodies |
100; 100; 100 | — |
| SECONDARY Part 3: HBV DNA Level |
1.28; 6.06; 7.37; 1.28; 3.14; 3.89 | — |
| SECONDARY Part 3: HBV DNA < Lower Limit of Quantification (LLOQ) |
100; 0; 0; 100; 10; 10.3 | — |
| SECONDARY Part 3: Tmax of RO7049389 |
1.99; 2.00; 1.96; 2.02; 1.94; 2.00 | — |
| SECONDARY Part 3: Cmax of RO7049389 |
7140; 5390; 5910; 4630; 2500; 3900 | — |
| SECONDARY Part 3: AUCtau of RO7049389 |
18700; 16700; 20900; 13600; 15400; 10500 | — |
| SECONDARY Part 3: T1/2 of RO7049389 |
1.16; 1.13; 1.31; 1.38; 1.30; 1.43 | — |
Eligibility Criteria
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 ( /= 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
Data sourced from ClinicalTrials.gov (NCT02952924). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.