Study of GSK3965193 in Healthy Participants and Participants Living With Chronic Hepatitis B Infection

Four-part, Randomized, Double-blind (Parts 1, 2A, 3 and 4), Multi-center, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK3965193 Monotherapy in Healthy Participants and in Participants Living With Chronic Hepatitis B Infection; and GSK3965193 in Combination With Bepirovirsen in Participants Living With Chronic Hepatitis B Infection

This Phase 1/2a multiple part study is a first time-in-human (FTIH) study designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of single (Part 1) and repeat doses (Part 2) of GSK3965193 in healthy participants. Part 3 will evaluate the ability of GSK3965193 to lower hepatitis B virus surface antigen (HBsAg) in participants living with chronic hepatitis B infection (PLWCHB) and will be given the option to subsequently receive treatment with open label bepirovirsen. Part 4 will evaluate the safety and tolerability of combination therapy with GSK3965193 and bepirovirsen and the potential to effect sustained virologic response in PLWCHB.

Study Overview

• Status: Terminated
• Conditions: Hepatitis B
• Intervention / Treatment: Drug: GSK3965193; Drug: Placebo to match GSK3965193; Drug: Bepirovirsen

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • GSK Investigational Site
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • GSK Investigational Site
• France
  • Grenoble, France, 38043
    • GSK Investigational Site
  • Nantes, France, 44000
    • GSK Investigational Site
  • Rennes, France, 35033
    • GSK Investigational Site
• Italy
  • Milan, Italy, 20122
    • GSK Investigational Site
  • Monza MB, Italy, 20900
    • GSK Investigational Site
• South Korea
  • Daegu, South Korea, 41944
    • GSK Investigational Site
  • Pusan, South Korea, 49241
    • GSK Investigational Site
  • Seoul, South Korea, 05505
    • GSK Investigational Site
• Thailand
  • Bangkok, Thailand, 10330
    • GSK Investigational Site
• United Kingdom
  • Cambridge, United Kingdom, CB2 2GG
    • GSK Investigational Site
  • London, United Kingdom, SW17 0QT
    • GSK Investigational Site
  • London, United Kingdom, W2 1NY
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Parts 1 and 2: Participants between 18 and 55 years of age inclusive, at the time of signing the informed consent.

• Parts 3 and 4: Participants between 18 and 65 years of age inclusive, at the time of signing the informed consent.
• Body weight >=50 kilograms (kg) and body mass index within the range 18-32 kilograms per square meter (kg/m^2) (inclusive).
• Male or female participant: a. Parts 1 and 2: woman of nonchildbearing potential only. b. Parts 3 and 4: woman of nonchildbearing potential or woman of child-bearing potential who is not pregnant or breastfeeding and is using a contraceptive method that is highly effective.
• Capable of giving signed informed consent.
• Additional Inclusion Criteria for PLWCHB (Parts 3 and 4).
• Participants who have documented chronic hepatitis B virus (HBV) infection >=6 months prior to screening.
• Participants currently receiving stable NA therapy (e.g., tenofovir disoproxil, tenofovir alafenamide, entecavir).
• Plasma or serum HBsAg concentration >100 IU/mL.
• Plasma or serum HBV deoxyribonucleic acid (DNA) concentration <90 IU/mL.
• Hepatitis B virus e-antigen (HBeAg) positive or negative.
• Alanine aminotransferase (ALT) <=2 times the upper limit of normal (ULN)

Exclusion Criteria:

Exclusion Criteria for Healthy Participants:

• Positive Hepatitis A virus antibody (HAV Ab immunoglobulin M [IgM]), or positive for HBV, hepatitis C virus (HCV) or human immunodeficiency virus (HIV) at screening
• A current diagnosis of migraine headache
• ALT >1 times ULN.
• Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent [%])
• Corrected QT interval (QTc) >450 milliseconds (msec)
• Signs and symptoms suggestive of Coronavirus Disease 2019 (COVID-19)
• Participants with known COVID-19 positive contacts in the past 14 days.
• For participants in Part 2A: i. Personal history or family history of peripheral neuropathy. ii. A score ≥4 on the Toronto clinical scoring system for polyneuropathy
• Current or previous use of tobacco- or nicotine-containing products (for example (e.g.) cigarettes, nicotine patches or electronic devices) within 6 months before screening and/or have a smoking pack history of >5 pack years

Exclusion Criteria for PLWCHB:

• Clinically significant abnormalities affecting physical or mental health in medical history or on physical examination, aside from chronic HBV infection.
• Co-infection with or past history of HCV, HIV or Hepatitis D virus (HDV).
• History of or suspected liver cirrhosis and/or evidence of cirrhosis.
• Diagnosed or suspected hepatocellular carcinoma.
• History of malignancy within the past 5 years with the exception of specific cancers that are cured by surgical resection (e.g., skin cancer).
• History of vasculitis or presence of symptoms and signs of potential vasculitis [e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause] or history/presence of other diseases Exclusion Criteria for Healthy Participants:
• Positive Hepatitis A virus antibody (HAV Ab immunoglobulin M [IgM]), or positive for HBV, hepatitis C virus (HCV) or human immunodeficiency virus (HIV) at screening.
• A current diagnosis of migraine headache
• ALT >1 times ULN.
• Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent [%]).
• Corrected QT interval (QTc) >450 milliseconds (msec).
• Signs and symptoms suggestive of Coronavirus Disease 2019 (COVID-19).
• Participants with known COVID-19 positive contacts in the past 14 days.
• For participants in Part 2A: i. Personal history or family history of peripheral neuropathy. ii. A score ≥4 on the Toronto clinical scoring system for polyneuropathy.
• Current or previous use of tobacco- or nicotine-containing products (for example (e.g.) cigarettes, nicotine patches or electronic devices) within 6 months before screening and/or have a smoking pack history of >5 pack years

Exclusion Criteria for PLWCHB:

• Clinically significant abnormalities affecting physical or mental health in medical history or on physical examination, aside from chronic HBV infection.
• Co-infection with or past history of HCV, HIV or Hepatitis D virus (HDV).
• History of or suspected liver cirrhosis and/or evidence of cirrhosis.
• Diagnosed or suspected hepatocellular carcinoma.
• History of malignancy within the past 5 years with the exception of specific cancers that are cured by surgical resection (e.g., skin cancer).
• History of vasculitis or presence of symptoms and signs of potential vasculitis [e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause] or history/presence of other diseases that may be associated with vasculitis condition (e.g., systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, mononeuritis multiplex).
• History of extrahepatic disorders possibly related to HBV immune conditions (e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinaemia, uncontrolled hypertension).
• History of alcohol or drug abuse/dependence: a. Current alcohol use as judged by investigator to potentially interfere with participant compliance. b. History of or current drug abuse/dependence as judged by the investigator to potentially interfere with participant compliance.
• History or other evidence of bleeding from esophageal varices.
• Documented history or other evidence of metabolic liver disease within 1 year of randomization.
• Personal history or family history of peripheral neuropathy.
• A score >4 on the Toronto clinical scoring system for polyneuropathy.
• History of having received or currently receiving any systemic anti-neoplastic (including radiation) or immune-modulatory treatment (including systemic oral corticosteroids, interferon or pegylated interferon) within the 3 months prior to randomization or the expectation that such treatment will be needed at any time during the study.
• Abnormal and clinically significant 12-lead ECG finding.
• Currently taking, or taken within 3 months prior to randomization, any immunosuppressing drugs (e.g., prednisone), other than a short course of therapy (≤2 weeks) or topical/inhaled steroid use.
• Participants requiring anti-coagulation therapies.
• Prior treatment with any oligonucleotide or small interfering RNA (siRNA) within 12 months prior to the first dosing day.
• Positive test for COVID-19 infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

18

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Cohort 1 - Placebo/GSK3965193 Dose 2/Dose 3/Dose 4; Healthy participants received a single dose of placebo oral solution on Day 1 in Treatment Period 1; followed by a single dose of GSK3965193 Dose 2 oral solution on Day 1 in Treatment Period 2; followed by a single dose of GSK3965193 Dose 3 oral solution on Day 1 in Treatment Period 3; further followed by a single dose of GSK3965193 Dose 4 oral solution on Day 1 in Treatment Period 4. Dose 4 of GSK3965193 was higher than Dose 3 and Dose 3 was higher than Dose 2.	Drug: GSK3965193; GSK3965193 was administered; Drug: Placebo to match GSK3965193; Placebo to match GSK3965193 was administered
Experimental: Part 1: Cohort 1 - GSK3965193 Dose 1/Placebo/Dose 3/Dose 4; Healthy participants received a single dose of GSK3965193 Dose 1 oral solution on Day 1 in Treatment Period 1; followed by a single dose of placebo oral solution on Day 1 in Treatment Period 2; followed by a single dose of GSK3965193 Dose 3 oral solution on Day 1 in Treatment Period 3; further followed by a single dose of GSK3965193 Dose 4 oral solution on Day 1 in Treatment Period 4. Dose 4 of GSK3965193 was higher than Dose 3 and Dose 3 was higher than Dose 1.	Drug: GSK3965193; GSK3965193 was administered; Drug: Placebo to match GSK3965193; Placebo to match GSK3965193 was administered
Experimental: Part 1: Cohort 1 - GSK3965193 Dose 1/Dose 2/Placebo/Dose 4; Healthy participants received a single dose of GSK3965193 Dose 1 oral solution on Day 1 in Treatment Period 1; followed by a single dose of GSK3965193 Dose 2 oral solution on Day 1 in Treatment Period 2; followed by a single dose of placebo oral solution on Day 1 in Treatment Period 3; further followed by a single dose of GSK3965193 Dose 4 oral solution on Day 1 in Treatment Period 4. Dose 4 of GSK3965193 was higher than Dose 2 and Dose 2 was higher than Dose 1.	Drug: GSK3965193; GSK3965193 was administered; Drug: Placebo to match GSK3965193; Placebo to match GSK3965193 was administered
Experimental: Part 1: Cohort 1 - GSK3965193 Dose 1/Dose 2/Dose 3/Placebo; Healthy participants received a single dose of GSK3965193 Dose 1 oral solution on Day 1 in Treatment Period 1; followed by a single dose of GSK3965193 Dose 2 oral solution on Day 1 in Treatment Period 2; followed by a single dose of GSK3965193 Dose 3 oral solution on Day 1 in Treatment Period 3; further followed by a single dose of placebo oral solution on Day 1 in Treatment Period 4. Dose 3 of GSK3965193 was higher than Dose 2 and Dose 2 was higher than Dose 1.	Drug: GSK3965193; GSK3965193 was administered; Drug: Placebo to match GSK3965193; Placebo to match GSK3965193 was administered
Experimental: Part 1: Cohort 2 - Placebo/GSK3965193 Dose 6/Dose 7/Dose 8; Healthy participants received a single dose of placebo oral solution on Day 1 in Treatment Period 1; followed by a single dose of GSK3965193 Dose 6 oral solution on Day 1 in Treatment Period 2; followed by a single dose of GSK3965193 Dose 7 oral solution on Day 1 in Treatment Period 3; further followed by a single dose of GSK3965193 Dose 8 oral solution on Day 1 in Treatment Period 4. Dose 8 of GSK3965193 was higher than Dose 7 and Dose 7 was higher than Dose 6.	Drug: GSK3965193; GSK3965193 was administered; Drug: Placebo to match GSK3965193; Placebo to match GSK3965193 was administered
Experimental: Part 1: Cohort 2 - GSK3965193 Dose 5/Placebo/Dose 7/Dose 8; Healthy participants received a single dose of GSK3965193 Dose 5 oral solution on Day 1 in Treatment Period 1; followed by a single dose of placebo oral solution on Day 1 in Treatment Period 2; followed by a single dose of GSK3965193 Dose 7 oral solution on Day 1 in Treatment Period 3; further followed by a single dose of GSK3965193 Dose 8 oral solution on Day 1 in Treatment Period 4. Dose 8 of GSK3965193 was higher than Dose 7 and Dose 7 was higher than Dose 5.	Drug: GSK3965193; GSK3965193 was administered; Drug: Placebo to match GSK3965193; Placebo to match GSK3965193 was administered
Experimental: Part 1: Cohort 2 - GSK3965193 Dose 5/Dose 6/Placebo/Dose 8; Healthy participants received a single dose of GSK3965193 Dose 5 oral solution on Day 1 in Treatment Period 1; followed by a single dose of GSK3965193 Dose 6 oral solution on Day 1 in Treatment Period 2; followed by a single dose of placebo oral solution on Day 1 in Treatment Period 3; further followed by a single dose of GSK3965193 Dose 8 oral solution on Day 1 in Treatment Period 4. Dose 8 of GSK3965193 was higher than Dose 6 and Dose 6 was higher than Dose 5.	Drug: GSK3965193; GSK3965193 was administered; Drug: Placebo to match GSK3965193; Placebo to match GSK3965193 was administered
Experimental: Part 1: Cohort 2 - GSK3965193 Dose 5/Dose 6/Dose 7/Placebo; Healthy participants received a single dose of GSK3965193 Dose 5 oral solution on Day 1 in Treatment Period 1; followed by a single dose of GSK3965193 Dose 6 oral solution on Day 1 in Treatment Period 2; followed by a single dose of GSK3965193 Dose 7 oral solution on Day 1 in Treatment Period 3; further followed by a single dose of placebo oral solution on Day 1 in Treatment Period 4. Dose 7 of GSK3965193 was higher than Dose 6 and Dose 6 was higher than Dose 5.	Drug: GSK3965193; GSK3965193 was administered; Drug: Placebo to match GSK3965193; Placebo to match GSK3965193 was administered
Placebo Comparator: Part 2A: Placebo; Healthy participants received repeat doses of placebo oral solution twice daily (BID) for 14 days.	Drug: Placebo to match GSK3965193; Placebo to match GSK3965193 was administered
Experimental: Part 2A: Cohort 5 - GSK3965193 Dose 9 BID; Healthy participants received repeat doses of GSK3965193 Dose 9 oral solution BID for 14 days. Dose 9 of GSK3965193 was higher than Dose 4 but lower than Dose 5.	Drug: GSK3965193; GSK3965193 was administered
Experimental: Part 2A: Cohort 3 - GSK3965193 Dose 5 BID; Healthy participants received repeat doses of GSK3965193 Dose 5 oral solution BID for 14 days. Dose 5 of GSK3965193 was higher than Dose 9 but lower than Dose 10.	Drug: GSK3965193; GSK3965193 was administered
Experimental: Part 2A: Cohort 4 - GSK3965193 Dose 6 BID; Healthy participants received repeat doses of GSK3965193 Dose 6 oral solution BID for 14 days. Dose 6 of GSK3965193 was higher than Dose 10 but lower than Dose 7.	Drug: GSK3965193; GSK3965193 was administered
Experimental: Part 2B: Cohort 6 - GSK3965193 Dose 10 Fasted/Fed; Healthy participants received GSK3965193 Dose 10 oral tablets under fasted condition in Treatment Period 1, followed by GSK3965193 Dose 10 oral tablets under fed condition in Treatment Period 2. Dose 10 of GSK3965193 was higher than Dose 5 but lower than Dose 6.	Drug: GSK3965193; GSK3965193 was administered
Experimental: Part 2B: Cohort 6 - GSK3965193 Dose 10 Fed/Fasted; Healthy participants received GSK3965193 Dose 10 oral tablets under fed condition in Treatment Period 1, followed by GSK3965193 Dose 10 oral tablets under fasted condition in Treatment Period 2. Dose 10 of GSK3965193 was higher than Dose 5 but lower than Dose 6.	Drug: GSK3965193; GSK3965193 was administered
Placebo Comparator: Part 3: Cohort 7 - Placebo; Participants living with chronic hepatitis B infection (PLWCHB) on stable nucleos(t)ide analog (NA) therapy received repeat doses of placebo oral tablets for 28 days. Participants who completed placebo monotherapy were given the option to receive subsequent treatment of optional open label bepirovirsen subcutaneous (SC) injection from Day 43.	Drug: Placebo to match GSK3965193; Placebo to match GSK3965193 was administered; Drug: Bepirovirsen; Bepirovirsen was administered
Experimental: Part 3: Cohort 7 - GSK3965193 Dose 9; PLWCHB on stable NA therapy received repeat doses of GSK3965193 Dose 9 oral tablets for 28 days. Participants who completed GSK3965193 monotherapy were given the option to receive subsequent treatment of optional open label bepirovirsen SC injection from Day 43. Dose 9 of GSK3965193 was higher than Dose 4 but lower than Dose 5.	Drug: GSK3965193; GSK3965193 was administered; Drug: Bepirovirsen; Bepirovirsen was administered
Experimental: Part 4: Cohort 8 - Placebo + Bepirovirsen; PLWCHB on stable NA therapy were planned to receive placebo oral tablets plus bepirovirsen SC injection for 28 days. All participants were further planned to continue receiving bepirovirsen SC injection after 28 days.	Drug: Placebo to match GSK3965193; Placebo to match GSK3965193 was administered; Drug: Bepirovirsen; Bepirovirsen was administered
Experimental: Part 4: Cohort 8 - GSK3965193 + Bepirovirsen; PLWCHB on stable NA therapy were planned to receive GSK3965193 oral tablets plus bepirovirsen SC injection for 28 days. All participants were further planned to continue receiving bepirovirsen SC injection after 28 days.	Drug: GSK3965193; GSK3965193 was administered; Drug: Bepirovirsen; Bepirovirsen was administered

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Treatment Emergent Adverse Events (STEAEs), and Treatment Withdrawals Due to TEAEs	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any serious adverse event that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; abnormal pregnancy outcomes or other situations as per the medical or scientific judgment of the investigator. An AE was considered treatment emergent if the AE onset date was on or after study intervention start date (i.e., Day 1) till Day 5 after study intervention administration. Any AE which started post Day 5 of study intervention administration was not considered as TEAE.	From the start of study intervention (Day 1) up to 12 weeks
Part 2A: Number of Participants With TEAEs, STEAEs, and Treatment Withdrawals Due to TEAEs	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any serious adverse event that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; abnormal pregnancy outcomes or other situations as per the medical or scientific judgment of the investigator. An AE was considered treatment emergent if the AE onset date was on or after study intervention start date.	From the start of study intervention (Day 1) up to 6 weeks
Part 2B: Number of Participants With TEAEs, STEAEs, and Treatment Withdrawals Due to TEAEs	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any serious adverse event that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; abnormal pregnancy outcomes or other situations as per the medical or scientific judgment of the investigator. An AE was considered treatment emergent if the AE onset date was on or after study intervention start date (i.e., Day 1) till Day 5 after study intervention administration. Any AE which started post Day 5 of study intervention administration was not considered as TEAE.	From the start of study intervention (Day 1) up to 9 weeks
Part 3: Number of Participants With TEAEs, STEAEs, and Treatment Withdrawals Due to TEAEs	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any serious adverse event that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; abnormal pregnancy outcomes or other situations as per the medical or scientific judgment of the investigator. An AE was considered treatment emergent if the AE onset or worsen date was on or after study intervention start date. Data for the placebo or GSK3965193 monotherapy phase were presented.	From the start of study intervention (Day 1) up to 6 weeks
Part 4: Number of Participants With TEAEs, STEAEs, and Treatment Withdrawals Due to TEAEs	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any serious adverse event that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; abnormal pregnancy outcomes or other situations as per the medical or scientific judgment of the investigator. An AE would be considered treatment emergent if the AE onset or worsen date was on or after study intervention start date.	From the start of study intervention (Day 1) up to 48 weeks
Part 1: Number of Participants With Clinically Significant Hematology and Clinical Chemistry Parameters	Blood samples were collected to analyze hematology and clinical chemistry parameters: platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, RBC indices (mean corpuscular volume [MCV] and mean corpuscular hemoglobin [MCH]), white blood cell (WBC) count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), blood urea nitrogen (BUN), creatinine, glucose (non-fasting), potassium, sodium, calcium, aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT), alkaline phosphatase, total bilirubin, indirect bilirubin, direct bilirubin, total protein, and albumin. Clinical significance of laboratory parameters was determined by the investigator.	At Day 2
Part 2A: Number of Participants With Clinically Significant Hematology, Clinical Chemistry, and Urinalysis Parameters	Blood samples were collected to analyze hematology and clinical chemistry parameters: platelet count, RBC count, hemoglobin, hematocrit, RBC indices (MCV and MCH), WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), BUN, creatinine, glucose (non-fasting), potassium, sodium, calcium, AST/SGOT, ALT/SGPT, alkaline phosphatase, total bilirubin, indirect bilirubin, direct bilirubin, total protein, and albumin. Urine samples were analyzed using automated urinalysis or urine dipstick. Microscopic examination was performed if abnormal blood or protein was present in the urine sample. Clinical significance of laboratory parameters was determined by the investigator.	Up to 21 days
Part 2B: Number of Participants With Clinically Significant Hematology, Clinical Chemistry, and Urinalysis Parameters	Blood samples were collected to analyze hematology and clinical chemistry parameters: platelet count, RBC count, hemoglobin, hematocrit, RBC indices (MCV and MCH), WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), BUN, creatinine, glucose (non-fasting), potassium, sodium, calcium, AST/SGOT, ALT/SGPT, alkaline phosphatase, total bilirubin, indirect bilirubin, direct bilirubin, total protein, and albumin. Urine samples were analyzed using automated urinalysis or urine dipstick. Microscopic examination was performed if abnormal blood or protein was present in the urine sample. Clinical significance of laboratory parameters was determined by the investigator.	Up to 9 weeks
Part 3: Number of Participants With Clinically Significant Hematology and Clinical Chemistry Parameters	Blood samples were collected to analyze hematology and clinical chemistry parameters: platelet count, RBC count, hemoglobin, hematocrit, RBC indices (MCV and MCH), WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), BUN, creatinine, glucose (non-fasting), potassium, sodium, calcium, AST/SGOT, ALT/SGPT, alkaline phosphatase, total bilirubin, indirect bilirubin, direct bilirubin, total protein, and albumin. Clinical significance of laboratory parameters was determined by the investigator. Data for the placebo or GSK3965193 monotherapy phase were presented.	Up to 35 days
Part 3: Number of Participants With Clinically Significant Urinalysis Parameters	Urine samples were analyzed using automated urinalysis or urine dipstick. Microscopic examination was performed if abnormal blood or protein was present in the urine sample. Clinical significance of laboratory parameters was determined by the investigator. Data for the placebo or GSK3965193 monotherapy phase were presented.	Up to 28 days
Part 4: Number of Participants With Clinically Significant Hematology, Clinical Chemistry, and Urinalysis Parameters	Blood samples were planned to be collected to analyze hematology and clinical chemistry parameters: platelet count, RBC count, hemoglobin, hematocrit, RBC indices (MCV and MCH), WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), BUN, creatinine, glucose (non-fasting), potassium, sodium, calcium, AST/SGOT, ALT/SGPT, alkaline phosphatase, total bilirubin, indirect bilirubin, direct bilirubin, total protein, and albumin. Urine samples were planned to be analyzed using automated urinalysis or urine dipstick. Microscopic examination was planned to be performed if abnormal blood or protein was present in the urine sample. Clinical significance of laboratory parameters would be determined by the investigator.	Up to 48 weeks
Part 1: Number of Participants With Clinically Significant Vital Sign Findings	Vital signs included systolic blood pressure (SBP) and diastolic blood pressure (DBP), pulse and respiratory rate and were measured with the participant in semi-supine position after 5 minutes rest. Clinical significance of the vital sign findings was determined by the investigator.	Up to 12 weeks
Part 2A: Number of Participants With Clinically Significant Vital Sign Findings	Vital signs included SBP and DBP, pulse and respiratory rate and were measured with the participant in semi-supine position after 5 minutes rest. Clinical significance of the vital sign findings was determined by the investigator.	Up to 21 days
Part 2B: Number of Participants With Clinically Significant Vital Sign Findings	Vital signs included SBP and DBP, pulse and respiratory rate and were measured with the participant in semi-supine position after 5 minutes rest. Clinical significance of the vital sign findings was determined by the investigator.	Up to 9 weeks
Part 3: Number of Participants With Clinically Significant Vital Sign Findings	Vital signs included temperature, SBP and DBP, pulse and respiratory rate and were measured with the participant in semi-supine position after 5 minutes rest. Clinical significance of the vital sign findings was determined by the investigator. Data for the placebo or GSK3965193 monotherapy phase were presented.	Up to 35 days
Part 4: Number of Participants With Clinically Significant Vital Signs Findings	Vital signs were planned to include temperature, SBP and DBP, pulse and respiratory rate and were planned to be measured with the participant in semi-supine position after 5 minutes rest. Clinical significance of the vital sign findings would be determined by the investigator.	Up to 48 weeks
Part 1: Number of Participants With Clinically Significant Electrocardiogram [ECG] Findings	A 12-lead ECG was recorded with the participant in a semi-supine position after 5 minutes of rest using an ECG machine. The parameters collected were PR, QRS, QT, and corrected QT (QTc) intervals. Clinical significance of ECG parameters was determined by the investigator.	Up to 12 weeks
Part 2A: Number of Participants With Clinically Significant ECG Findings	A 12-lead ECG was recorded with the participant in a semi-supine position after 5 minutes of rest using an ECG machine. The parameters collected were PR, QRS, QT, and QTc intervals. Clinical significance of ECG parameters was determined by the investigator.	Up to 21 days
Part 3: Number of Participants With Clinically Significant ECG Findings	A 12-lead ECG was recorded with the participant in a semi-supine position after 5 minutes of rest using an ECG machine. The parameters collected were PR, QRS, QT, and QTc intervals. Clinical significance of ECG parameters was determined by the investigator. Data for the placebo or GSK3965193 monotherapy phase were presented.	Up to 35 days
Part 4: Number of Participants With Clinically Significant ECG Findings	A 12-lead ECG was planned to be recorded with the participant in a semi-supine position after 5 minutes of rest using an ECG machine. The parameters planned to be collected were PR, QRS, QT, and QTc intervals. Clinical significance of ECG findings would be determined by the investigator.	Up to 25 weeks
Part 2A: Number of Participants With Changes in Sensory Nerve Conduction at Day 7	Sensory nerve conduction testing was performed to detect neuropathy in participants. Nerve conduction velocity (NCV) and nerve conduction amplitude were determined. Sensory nerve conduction studies at Baseline were collected twice, one at the time of screen and one prior to dosing. Mean (arithmetic mean) of two measurements were considered as Baseline. Number of participants with 25 percent (%) decrease in NCV and 50% decrease in nerve conduction amplitude from Baseline at Day 7 was reported.	Baseline and Day 7
Part 2A: Number of Participants With Changes in Sensory Nerve Conduction at Day 14	Sensory nerve conduction testing was performed to detect neuropathy in participants. NCV and nerve conduction amplitude were determined. Sensory nerve conduction studies at Baseline were collected twice, one at the time of screen and one prior to dosing. Mean (arithmetic mean) of two measurements were considered as Baseline. Number of participants with 25% decrease in NCV and 50% decrease in nerve conduction amplitude from Baseline at Day 14 was reported.	Baseline and Day 14
Part 2A: Number of Participants With Changes in Sensory Nerve Conduction at Day 42	Sensory nerve conduction testing was performed to detect neuropathy in participants. NCV and nerve conduction amplitude were determined. Sensory nerve conduction studies at Baseline were collected twice, one at the time of screen and one prior to dosing. Mean (arithmetic mean) of two measurements were considered as Baseline. Number of participants with 25% decrease in NCV and 50% decrease in nerve conduction amplitude from Baseline at Day 42 was reported.	Baseline and Day 42
Part 3: Number of Participants With Changes in Sensory Nerve Conduction at Day 15	Sensory nerve conduction testing was performed to detect neuropathy in participants. NCV and nerve conduction amplitude were determined. The best measurement out of Screening and Day -1 was considered as Baseline, best being the higher measurement. Number of participants with 25% decrease in NCV and 50% decrease in nerve conduction amplitude from Baseline at Day 15 for the placebo or GSK3965193 monotherapy phase was reported.	Baseline and Day 15
Part 3: Number of Participants With Changes in Sensory Nerve Conduction at Day 29	Sensory nerve conduction testing was performed to detect neuropathy in participants. NCV and nerve conduction amplitude were determined. The best measurement out of Screening and Day -1 was considered as Baseline, best being the higher measurement. Number of participants with 25% decrease in NCV and 50% decrease in nerve conduction amplitude from Baseline at Day 29 for the placebo or GSK3965193 monotherapy phase was reported.	Baseline and Day 29
Part 4: Number of Participants With Changes in Sensory Nerve Conduction	Sensory nerve conduction testing was planned to be performed to detect neuropathy in participants. NCV and nerve conduction amplitude were planned to be determined. Number of participants with 25% decrease in NCV and 50% decrease in nerve conduction amplitude from baseline was planned to be reported.	Baseline up to 29 days
Part 1: Area Under the Concentration-time Curve (AUC) From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of GSK3965193 Following Single Dose Administration	Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours (h) post-dose
Part 2A: AUC Over the Dosing Interval Tau (AUC[0-tau]) of GSK3965193 Following Repeat Dose Administration	Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods. As the dosing interval Tau was 12 hours, AUC(0-tau) is the same as AUC from time zero to 12 hours after dosing (AUC[0-12]).	Pre-dose and 15 minutes (min), 30 min, 1 h, 2 h, 3 h, 4, h, 8 h, and 12 h post-first dose on Day 1; pre-dose and 15 min, 30 min, 1 h, 2h, 4 h, 8 h, and 12 h post-first dose on Day 14
Part 1: Maximum Observed Concentration (Cmax) of GSK3965193 Following Single Dose Administration	Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours post-dose
Part 2A: Cmax of GSK3965193 Following Repeat Dose Administration	Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.	Pre-dose and 15 min, 30 min, 1 h, 2 h, 3 h, 4, h, 8 h, and 12 h post-first dose on Day 1; pre-morning dose on Days 2 through 6 and Days 12 through 13; pre-dose and 15 min, 30 min, 1 h, 2h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h post-first dose on Day 14
Part 1: Time to Maximum Observed Plasma Drug Concentration (Tmax) of GSK3965193 Following Single Dose Administration	Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours post-dose
Part 2A: Tmax of GSK3965193 Following Repeat Dose Administration	Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.	Pre-dose and 15 min, 30 min, 1 h, 2 h, 3 h, 4, h, 8 h, and 12 h post-first dose on Day 1; pre-morning dose on Days 2 through 6 and Days 12 through 13; pre-dose and 15 min, 30 min, 1 h, 2h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h post-first dose on Day 14
Part 1: Apparent Terminal Half-life (T1/2) of GSK3965193 Following Single Dose Administration	Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours post-dose
Part 2A: T1/2 of GSK3965193 Following Repeat Dose Administration	Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.	Pre-dose and 15 min, 30 min, 1 h, 2 h, 3 h, 4, h, 8 h, and 12 h post-first dose on Day 1; pre-morning dose on Days 2 through 6 and Days 12 through 13; pre-dose and 15 min, 30 min, 1 h, 2h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h post-first dose on Day 14
Part 3: Maximum Reduction of Serum HBsAg Levels From Baseline	Blood samples were collected from participants to assess HBsAg levels for the placebo or GSK3965193 monotherapy phase. Baseline was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Posterior mean and associated 95 percent (%) credible interval were derived for maximum reduction of serum HBsAg levels from Baseline using Bayesian mixed model repeated measures. The data presented are mean referring to posterior mean, with 95% confidence interval referring to 95% credible interval.	From Baseline (Pre-dose on Day 1) up to 6 weeks
Part 4: Number of Participants Achieving Complete Response	Blood samples were planned to be collected to assess HBsAg and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Complete response is defined HBsAg and HBV DNA below lower limit of quantification (LLOQ) for 6 consecutive months after the planned end of treatment.	Up to 48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 2B: AUC(0-inf) of GSK3965193 Following Single Dose Administration	Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.	Pre-dose and 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 48 h, and 72 h post-dose
Part 2B: Cmax of GSK3965193 Following Single Dose Administration	Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.	Pre-dose and 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 48 h, and 72 h post-dose
Part 3: AUC(0-tau) of GSK3965193 Following Repeat Dose Administration	Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.25 h, 0.5 h, 1 h, 2, h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose on Day 1; pre-dose on Day 4, Day 8, Day 11, Day 15, Day 22; pre-dose and 0.25 h, 0.5 h, 1 h, 2, h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose on Day 28
Part 3: Cmax of GSK3965193 Following Repeat Dose Administration	Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.25 h, 0.5 h, 1 h, 2, h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose on Day 1; pre-dose on Day 4, Day 8, Day 11, Day 15, Day 22; pre-dose and 0.25 h, 0.5 h, 1 h, 2, h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose on Day 28
Part 3: Tmax of GSK3965193 Following Repeat Dose Administration	Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.25 h, 0.5 h, 1 h, 2, h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose on Day 1; pre-dose on Day 4, Day 8, Day 11, Day 15, Day 22; pre-dose and 0.25 h, 0.5 h, 1 h, 2, h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose on Day 28
Part 3: T1/2 of GSK3965193 Following Repeat Dose Administration	Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.25 h, 0.5 h, 1 h, 2, h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose on Day 1; pre-dose on Day 4, Day 8, Day 11, Day 15, Day 22; pre-dose and 0.25 h, 0.5 h, 1 h, 2, h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose on Day 28
Part 3: Number of Participants With Greater Than or Equal to [≥] 0.5 Times Log International Units Per Milliliters [IU/mL] Reduction From Baseline in Serum HBsAg Levels	Blood samples were collected from participants at indicated time points to assess HBsAg levels.	From Baseline (Day 1) up to 42 days
Part 3: Number of Participants With TEAEs, STEAEs, and Treatment Withdrawals Due to TEAEs Among Participants Opting for Optional Bepirovirsen Treatment	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any serious adverse event that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; abnormal pregnancy outcomes or other situations as per the medical or scientific judgment of the investigator.	From the start of study intervention up to 54 weeks
Part 3: Number of Participants With Clinically Significant Hematology, Clinical Chemistry, and Urinalysis Parameters Among Participants Opting for Optional Bepirovirsen Treatment	Blood samples were planned to be collected to analyze clinical chemistry and hematology parameters: hemoglobin, leukocytes, lymphocytes/leukocytes, neutrophils/leukocytes, platelets, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red blood cells, reticulocytes, ALT, albumin, alkaline phosphatase, AST, bilirubin, calcium corrected for albumin, creatinine, glucose, potassium, and sodium. Urine samples were planned to be analyzed using automated urinalysis or urine dipstick. Microscopic examination was performed if abnormal blood or protein was present in the urine sample. Number of participants with clinically significant clinical chemistry, hematology, and urinalysis parameters were reported. Clinical significance was determined by the investigator.	From Week 7 up to 54 weeks
Part 3: Number of Participants With Clinically Significant Vital Signs Among Participants Opting for Optional Bepirovirsen Treatment	Vital signs were planned to include temperature and were planned to be measured with the participant in semi-supine position after 5 minutes rest. Clinical significance of vital signs was determined by the investigator.	From Week 7 up to 54 weeks
Part 4: Number of Participants With HBsAg Loss	Blood samples were collected from participants at indicated time points to assess HBsAg levels. HBsAg loss is defined by two consecutive measurements of HBsAg below the LLOQ any time during the study (on-treatment and post-treatment).	Up to 48 weeks

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Investigators: Study Director: GSK Clinical Trials, GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2022
• Primary Completion (Actual): May 19, 2025
• Study Completion (Actual): April 8, 2026

Study Registration Dates

• First Submitted: April 8, 2022
• First Submitted That Met QC Criteria: April 8, 2022
• First Posted (Actual): April 15, 2022

Study Record Updates

• Last Update Posted (Actual): June 16, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: First-time-in-human; Chronic hepatitis B; Bepirovirsen; GSK3965193
• Additional Relevant MeSH Terms: Blood-Borne Infections; Pathologic Processes; Chronic Disease; Disease Attributes; Infections; Virus Diseases; Digestive System Diseases; Liver Diseases; Hepatitis, Viral, Human; Communicable Diseases; DNA Virus Infections; Hepadnaviridae Infections; Hepatitis, Chronic; Hepatitis; Pathological Conditions, Signs and Symptoms; Hepatitis B; Hepatitis B, Chronic
• Other Study ID Numbers: 214760; 2021-005117-13 (EudraCT Number); 2023-509684-24 (Other Identifier: EU CTR)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, a key secondary endpoints and safety data of the study.
• IPD Sharing Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No