Evaluating GSK3965193 in Healthy Individuals and Those with Chronic Hepatitis B

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 study is testing a new drug called GSK3965193 to see if it is safe and effective for lowering the hepatitis B virus in people with chronic hepatitis B, while also checking its effects in healthy individuals.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 84 (estimated)
• Ages: 18 Years to 65 Years
• Sex: All
• Sponsor: GlaxoSmithKline (Industry-sponsored)
• Drugs / interventions: radiation, prednisone
• Locations: 16 sites (Calgary, Alberta and 15 other locations)
• Trial ID: NCT05330455 on ClinicalTrials.gov

What this trial studies

This Phase 1/2a study aims to assess the safety, tolerability, and pharmacokinetics of GSK3965193 in healthy participants and its effectiveness in lowering hepatitis B virus surface antigen in individuals with chronic hepatitis B infection. The study consists of multiple parts, with the first two focusing on healthy participants receiving single and repeat doses, while the latter parts involve participants with chronic hepatitis B receiving GSK3965193 and potentially bepirovirsen. The study will also evaluate the safety of the combination therapy. This is a first-time-in-human study, making it crucial for understanding the drug's effects.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 to 65 with chronic hepatitis B infection or healthy individuals aged 18 to 55.

Not a fit: Patients who are not living with chronic hepatitis B or those outside the specified age range may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to improved treatment options for patients with chronic hepatitis B.

How similar studies have performed: Other studies have shown promise in similar approaches, but this specific combination and methodology is novel.

Eligibility criteria

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.

Where this trial is running

Calgary, Alberta and 15 other locations

• GSK Investigational Site — Calgary, Alberta, Canada (Recruiting)
• GSK Investigational Site — Ottawa, Ontario, Canada (Recruiting)
• GSK Investigational Site — Grenoble Cedex 9, France (Recruiting)
• GSK Investigational Site — Lyon, France (Recruiting)
• GSK Investigational Site — Nantes cedex 1, France (Recruiting)
• GSK Investigational Site — Rennes, France (Recruiting)
• GSK Investigational Site — Milano, Italy (Recruiting)
• GSK Investigational Site — Monza MB, Italy (Recruiting)
• GSK Investigational Site — Daegu, Korea, Republic of (Recruiting)
• GSK Investigational Site — Pusan, Korea, Republic of (Recruiting)
• GSK Investigational Site — Seoul, Korea, Republic of (Recruiting)
• GSK Investigational Site — Bangkok, Thailand (Recruiting)
• GSK Investigational Site — Cambridge, United Kingdom (Completed)
• GSK Investigational Site — London, United Kingdom (Recruiting)
• GSK Investigational Site — London, United Kingdom (Recruiting)
• GSK Investigational Site — London, United Kingdom (Recruiting)

Study contacts

• Study coordinator: US GSK Clinical Trials Call Center

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