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

Study Overview
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Brief Summary
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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). 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.

Official Title
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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

Conditions
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Hepatitis B

Intervention / Treatment
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* Drug: GSK3965193
* Drug: Placebo to match GSK3965193
* Drug: Bepirovirsen


Participation Criteria
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Eligibility Criteria
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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 non-childbearing potential only. b. Parts 3 and 4: woman of non-childbearing 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 in medical history, 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 8 weeks prior to the first dose of study drug 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 of screening, 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.

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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Parts 1 and Part 2B are crossover and Part 2A, Part 3 and Part 4 are parallel group
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Cohort 1: GSK3965193 and placebo<br>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<br>* GSK3965193 will be administered<br>Drug: Placebo to match GSK3965193<br>* Placebo to match GSK3965193 will be administered<br>|
| Experimental: Part 1 Cohort 2: GSK3965193 and placebo<br>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<br>* GSK3965193 will be administered<br>Drug: Placebo to match GSK3965193<br>* Placebo to match GSK3965193 will be administered<br>|
| Experimental: Part 2A Cohort 3: GSK3965193 or placebo<br>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<br>* GSK3965193 will be administered<br>Drug: Placebo to match GSK3965193<br>* Placebo to match GSK3965193 will be administered<br>|
| Experimental: Part 2A Cohort 4: GSK3965193 or placebo<br>Healthy participants will be randomized 3:1 to receive repeat doses either GSK3965193 (Dose Y) 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<br>* GSK3965193 will be administered<br>Drug: Placebo to match GSK3965193<br>* Placebo to match GSK3965193 will be administered<br>|
| Experimental: Part 2A Cohort 5: GSK3965193 or placebo<br>Healthy participants will be randomized 3:1 to receive repeat doses either GSK3965193 (Dose Z) 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<br>* GSK3965193 will be administered<br>Drug: Placebo to match GSK3965193<br>* Placebo to match GSK3965193 will be administered<br>|
| Experimental: Part 2B Cohort 6: GSK3965193<br>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<br>* GSK3965193 will be administered<br>|
| Experimental: Part 3 Cohort 7: GSK3965193 or placebo<br>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<br>* GSK3965193 will be administered<br>Drug: Placebo to match GSK3965193<br>* Placebo to match GSK3965193 will be administered<br>|
| Experimental: Part 4 Cohort 8: GSK3965193 and bepirovirsen or placebo and bepirovirsen<br>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<br>* GSK3965193 will be administered<br>Drug: Placebo to match GSK3965193<br>* Placebo to match GSK3965193 will be administered<br>Drug: Bepirovirsen<br>* Bepirovirsen will be administered<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 and 2B: Number of participants with clinically significant changes in laboratory parameters |  | Up to 2 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 6 weeks | 
| 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 85 days | 
| Part 4: Number of participants with AEs, SAEs, and withdrawals due to AEs |  | Up to 36 weeks | 
| Part 3: Number of participants with clinically significant changes in laboratory parameters and vital signs |  | Up to 85 days | 
| Part 3: Number of participants with clinically significant changes in cardiac parameters (ECG) |  | Up to 36 days | 
| Part 4: Number of participants with clinically significant changes in laboratory parameters and vital signs |  | Up to 36 weeks | 
| Part 4: Number of participants with clinically significant changes in cardiac parameters (ECG) |  | Up to 13 weeks | 
| Part 3: Number of participants with clinically significant nerve changes |  | Up to 85 days | 
| Part 4: Number of participants with clinically significant nerve changes |  | Up to 13 weeks | 
| Part 3: Change from Baseline in HBsAg levels |  | Baseline and up to 6 weeks | 
| Part 4 : Number of participants achieving sustained virologic response |  | Up to 36 weeks | 
| Parts 1 and 2B: Number of participants with. adverse events (AEs), serious adverse events. (SAEs), and withdrawals due to AEs |  | Up to 14 days | 
| Parts 1 and 2B: Number of participants with. clinically significant changes in laboratory. parameters |  | Up to 2 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 2A: T1/2 of GSK3965193 following repeat. dose administration |  | Up to 17 days | 
| Part 3: Number of participants with clinically. significant changes in laboratory parameters and vital signs |  | Up to 85 days | 
| Part 3: Number of participants with clinically. significant changes in cardiac parameters (ECG) |  | Up to 36 days | 
| Part 4: Number of participants with clinically. significant changes in laboratory parameters and vital signs |  | Up to 36 weeks | 
| Part 4: Number of participants with clinically. significant changes in cardiac parameters (ECG) |  | Up to 13 weeks | 
| Part 3: Number of participants with clinically. significant nerve changes |  | Up to 85 days | 
| Part 4: Number of participants with clinically. significant nerve changes |  | Up to 13 weeks | 
| Part 3: Maximum reduction of serum HBsAg levels from Baseline |  | Baseline and up to 6 weeks | 
| Part 4: Number of participants achieving. sustained virologic response |  | Up to 36 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2B: AUC(0-inf) of GSK3965193 following single dose administration |  | Up to 5 days | 
| Part 2B: Cmax of GSK3965193 following single dose administration |  | Up to 5 days | 
| Part 3: AUC(0-tau) of GSK3965193 following repeat dose administration |  | Up to 29 days | 
| Part 3: Cmax of GSK3965193 following repeat dose administration |  | Up to 29 days | 
| Part 3: Tmax of GSK3965193 following repeat dose administration |  | Up to 29 days | 
| Part 3: T1/2 of GSK3965193 following repeat dose administration |  | Up to 29 days | 
| Part 3: Change from Baseline in HBsAg levels (greater than or equal to [>=] 0.5 times log international units per milliliters [IU/mL]) |  | Baseline and up to 85 days | 
| Part 4: Number of participants with HBsAg loss |  | Up to 36 weeks | 
| 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 29 days | 
| Part 3: Tmax of GSK3965193 following repeat. dose administration |  | Up to 29 days | 
| Part 3: T1/2 of GSK3965193 following repeat. dose administration |  | Up to 29 days | 
| Part 3: Change from baseline in serum HBsAg levels from baseline. (greater than or equal to [≥] 0.5 times log. international units per milliliters [IU/mL]) |  | Baseline and up to 85 days | 
| Number of participants with HBsAg loss |  | Up to 36 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bepirovirsen, Chronic hepatitis B, First-time-in-human, GSK3965193