study of gsk3965193 in healthy participants and participants living with chronic hepatitis b infection

Conditions: Hepatitis B

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.


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.

Keywords: bepirovirsen chronic hepatitis b first-time-in-human gsk3965193