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

NCT05330455 | Active Not Recruiting Phase 1 DMC

• 3 other identifiers: 2147602021-005117-132023-509684-24
• Study Type: interventional
• Target: 74
• Locations: 6 countries
• Sites: 16

Brief Summary

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.

Conditions

Hepatitis B

Keywords

Bepirovirsen; Chronic hepatitis B; First-time-in-human; GSK3965193

Outcome Measures

Primary Outcomes (25)

• Parts 1 and 2B: Number of participants with adverse events (AEs), serious adverse events (SAEs), and withdrawals due to AEs

  Up to 14 days

• Part 2A: Number of participants with AEs, SAEs, and withdrawals due to AEs

  Up to 42 Days

• Parts 1: Number of participants with clinically significant changes in laboratory parameters

  Up to 2 days

• Parts 2B: Number of participants with clinically significant changes in laboratory parameters

  Up to 14 days

• Parts 1 and 2B: Number of participants with clinically significant changes in vital signs and cardiac parameters (electrocardiogram [ECG])

  Up to 14 days

• Part 2A: Number of participants with clinically. significant changes in laboratory parameters, vital signs, cardiac parameters (ECG)

  Up to 21 days

• Part 2A: Number of participants with clinically. significant nerve changes

  Up to 42 days

• Part 1 and 2B: Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-inf]) of GSK3965193 following single dose administration

  Up to 4 days

• Part 2A: AUC(0-tau) of GSK3965193 following repeat dose administration

  Up to 17 days

• Part 1 and 2B: maximum observed concentration (Cmax) of GSK3965193 following single dose administration

  Up to 4 days

• Part 2A: Cmax of GSK3965193 following repeat dose administration

  Up to 17 days

• Part 1 and 2B: Time to maximum observed plasma drug concentration (Tmax) of GSK3965193 following single dose administration

  Up to 4 days

• Part 2A: Tmax of GSK3965193 following repeat dose administration

  Up to 17 days

• Part 1 and 2B: Apparent terminal half-life (T1/2) of GSK3965193 following single dose administration

  Up to 4 days

• Part 2A: T1/2 of GSK3965193 following repeat. dose administration

  Up to 17 days

• Part 3: Number of participants with AEs, SAEs, and withdrawals due to AEs

  Up to 42 days

• Part 4: Number of participants with AEs, SAEs, and withdrawals due to AEs

  Up to 48 weeks

• Part 3: Number of participants with clinically. significant changes in laboratory parameters and vital signs

  Up to 42 days

• Part 3: Number of participants with clinically. significant changes in cardiac parameters (ECG)

  Up to 42 days

• Part 4: Number of participants with clinically. significant changes in laboratory parameters and vital signs

  Up to 48 weeks

• Part 4: Number of participants with clinically. significant changes in cardiac parameters (ECG)

  Up to 48 weeks

• Part 3: Number of participants with clinically. significant nerve changes

  Up to 42 days

• Part 4: Number of participants with clinically. significant nerve changes

  Up to 48 weeks

• Part 3: Maximum reduction of serum HBsAg levels from Baseline

  Baseline and up to 6 weeks

• Part 4: Number of participants achieving. complete response

  Up to 48 weeks

Secondary Outcomes (10)

• Part 2B: AUC (0-inf) of GSK3965193 following. single dose administration

  Up to 4 days

• Part 2B: Cmax of GSK3965193 following single dose administration

  Up to 4 days

• Part 3: AUC(0-tau) of GSK3965193 following. repeat dose administration

  Up to 42 days

• Part 3: Cmax of GSK3965193 following repeat dose administration

  Up to 42 days

• Part 3: Tmax of GSK3965193 following repeat. dose administration

  Up to 42 days

Study Arms (9)

Part 1 Cohort 1: GSK3965193 and placebo

EXPERIMENTAL

Healthy participants will be randomized to receive single ascending doses of GSK3965193 and placebo in one of 4 treatment sequences in a 3:1 ratio in fasted conditions. In period 1, participants will receive GSK3965193 (Dose 1) + Placebo; in period 2: GSK3965193 (Dose 2) + Placebo; in period 3: GSK3965193 (Dose 3) + Placebo and in period 4: GSK3965193 (Dose 4) + Placebo. There will be a minimum of 7 days washout between dosing in each treatment period.

Drug: GSK3965193; Drug: Placebo to match GSK3965193

Part 1 Cohort 2: GSK3965193 and placebo

EXPERIMENTAL

Healthy participants will be randomized to receive single ascending doses of GSK3965193 and placebo in one of 4 treatment sequences in a 3:1 ratio in fasted conditions. In period 1, participants will receive GSK3965193 (Dose 5) + Placebo; in period 2: GSK3965193 (Dose 6) + Placebo; in period 3: GSK3965193 (Dose 7) + Placebo and in period 4: GSK3965193 (Dose 8) + Placebo. There will be a minimum of 7 days washout between dosing in each period.

Drug: GSK3965193; Drug: Placebo to match GSK3965193

Part 2A Cohort 3: GSK3965193 or placebo

EXPERIMENTAL

Healthy participants will be randomized 3:1 to receive repeat doses of either GSK3965193 (Dose X) or placebo under fasted conditions. Part 2A may start while Part 1 is still ongoing. The starting dose in Part 2 will be at least 3-fold below the highest dose completed in Part 1.

Drug: GSK3965193; Drug: Placebo to match GSK3965193

Part 2A Cohort 4: GSK3965193 or placebo

EXPERIMENTAL

Healthy participants will be randomized 3:1 to receive repeat doses of either GSK3965193 (Dose X) or placebo under fasted conditions. Part 2A may start while Part 1 is still ongoing. The starting dose in Part 2 will be at least 3-fold below the highest dose completed in Part 1.

Drug: GSK3965193; Drug: Placebo to match GSK3965193

Part 2A Cohort 5: GSK3965193 or placebo

EXPERIMENTAL

Healthy participants will be randomized 3:1 to receive repeat doses of either GSK3965193 (Dose X) or placebo under fasted conditions. Part 2A may start while Part 1 is still ongoing. The starting dose in Part 2 will be at least 3-fold below the highest dose completed in Part 1.

Drug: GSK3965193; Drug: Placebo to match GSK3965193

Part 2B Cohort 6: GSK3965193

EXPERIMENTAL

Healthy Participants will be randomized 1:1 to receive single doses of GSK3965193 (Dose A) under fasted and fed conditions in treatment period 1. In period 2, the participants who received GSK3965193 (Dose A) under fasted conditions in treatment period 1 will receive the same dose under fed conditions, and vice versa. In the third period, all participants will receive a single dose of GSK3965193 (Dose B) different strength under fasted conditions. The dose level for the third period will be selected based on the results of the first two periods. There will be a minimum of 7 days washout between dosing in each treatment period.

Drug: GSK3965193

Part 3 Cohort 7: GSK3965193 or placebo

EXPERIMENTAL

PLWCHB on stable nucleos(t)ide analog (NA) therapy will be randomized 3:1 to receive repeat dose of either GSK3965193 (Dose E) or placebo. This part will commence after completion of both Part 1 and Part 2.

Drug: GSK3965193; Drug: Placebo to match GSK3965193

Part 3 Sub-Cohort 7: Open label bepirovirsen

EXPERIMENTAL

PLWCHB participants on stable NA therapy who have completed GSK3965193/placebo monotherapy (Part 3, Cohort 7) will be given the option to receive subsequent treatment of optional open label bepirovirsen only for 24 weeks.

Drug: Bepirovirsen

Part 4 Cohort 8: GSK3965193 and bepirovirsen or placebo and bepirovirsen

EXPERIMENTAL

PLWCHB participants on stable NA therapy who have not participated in Part 3 of the study will be randomized 3:1 to receive repeat dose either GSK3965193 or placebo. In addition, all participants in this cohort will also receive bepirovirsen. This part will commence after completion of Part 3, contingent on the clinical safety and efficacy data from Part 3.

Drug: GSK3965193; Drug: Placebo to match GSK3965193; Drug: Bepirovirsen

Interventions

GSK3965193 DRUG

GSK3965193 will be administered

Part 1 Cohort 1: GSK3965193 and placebo; Part 1 Cohort 2: GSK3965193 and placebo; Part 2A Cohort 3: GSK3965193 or placebo; Part 2A Cohort 4: GSK3965193 or placebo; Part 2A Cohort 5: GSK3965193 or placebo; Part 2B Cohort 6: GSK3965193; Part 3 Cohort 7: GSK3965193 or placebo; Part 4 Cohort 8: GSK3965193 and bepirovirsen or placebo and bepirovirsen

Placebo to match GSK3965193 DRUG

Placebo to match GSK3965193 will be administered

Part 1 Cohort 1: GSK3965193 and placebo; Part 1 Cohort 2: GSK3965193 and placebo; Part 2A Cohort 3: GSK3965193 or placebo; Part 2A Cohort 4: GSK3965193 or placebo; Part 2A Cohort 5: GSK3965193 or placebo; Part 3 Cohort 7: GSK3965193 or placebo; Part 4 Cohort 8: GSK3965193 and bepirovirsen or placebo and bepirovirsen

Bepirovirsen DRUG

Bepirovirsen will be administered

Part 3 Sub-Cohort 7: Open label bepirovirsen; Part 4 Cohort 8: GSK3965193 and bepirovirsen or placebo and bepirovirsen

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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)

You may not qualify if:

• 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
• 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).
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (16)

GSK Investigational Site

Calgary, Alberta, T2N 4Z6, Canada

Location

GSK Investigational Site

Ottawa, Ontario, K1H 8L6, Canada

Location

GSK Investigational Site

Grenoble, 38043, France

Location

GSK Investigational Site

Lyon, 69004, France

Location

GSK Investigational Site

Nantes, 44000, France

Location

GSK Investigational Site

Rennes, 35033, France

Location

GSK Investigational Site

Milan, 20122, Italy

Location

GSK Investigational Site

Monza MB, 20900, Italy

Location

GSK Investigational Site

Daegu, 700-721, South Korea

Location

GSK Investigational Site

Pusan, 49241, South Korea

Location

GSK Investigational Site

Seoul, 05505, South Korea

Location

GSK Investigational Site

Bangkok, 10330, Thailand

Location

GSK Investigational Site

Cambridge, CB2 2GG, United Kingdom

Location

GSK Investigational Site

London, SE5 9RS, United Kingdom

Location

GSK Investigational Site

London, SW17 0QT, United Kingdom

Location

GSK Investigational Site

London, W2 1NY, United Kingdom

Location

MeSH Terms

Conditions

Hepatitis B; Hepatitis B, Chronic

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis; Liver Diseases; Digestive System Diseases; Hepatitis, Chronic; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: This is a double-blind study
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Parts 1 and Part 2B are crossover and Part 2A, Part 3 and Part 4 are parallel group

Study Record Dates

• First Submitted: April 8, 2022
• First Posted: April 15, 2022
• Study Start: April 14, 2022
• Primary Completion: May 19, 2025
• Study Completion: April 3, 2026
• Last Updated: August 19, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• 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.
• 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.

Locations

IT (2); CA (2); FR (4); KR (3); TH (1); GB (4)