GSK3965193 for Hepatitis B
Recruiting in Palo Alto (17 mi)
+12 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: GlaxoSmithKline
Must be taking: Nucleoside analogs
Must not be taking: Immunosuppressants, Anticoagulants
Disqualifiers: HIV, Liver cirrhosis, Cancer, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?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.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, participants in Parts 3 and 4 must be on stable NA therapy (like tenofovir or entecavir), so you may need to continue those medications.
What data supports the effectiveness of the drug GSK3965193 for treating Hepatitis B?
The research suggests that new treatments for Hepatitis B, like GSK3965193, may be more effective when combined with other drugs, as current therapies often require lifelong treatment and have limited success in completely curing the infection. Novel drugs targeting different steps in the virus's life cycle could improve treatment outcomes by reducing drug resistance and the risk of liver complications.
12345What safety data exists for GSK3965193 (Bepirovirsen) in humans?
Bepirovirsen, also known as GSK3965193, has been tested in humans and showed a favorable safety profile. In a study with healthy subjects, no serious adverse events were reported, and the most common side effect was mild injection site reactions, which resolved without stopping the treatment.
678910How is the drug GSK3965193 different from other treatments for hepatitis B?
GSK3965193 is unique because it is a liver-targeted treatment specifically designed to interfere with the hepatitis B virus, potentially offering a new approach compared to existing treatments that primarily focus on viral suppression. This novel mechanism could improve treatment outcomes by targeting different steps in the virus's life cycle.
2581112Eligibility Criteria
This trial is for healthy adults aged 18-55 and those with chronic hepatitis B aged 18-65, who are not pregnant or breastfeeding and use effective contraception. Participants must weigh at least 50 kg with a BMI of 18-32 kg/m^2. For parts involving patients with hepatitis, they must have been diagnosed over six months ago and be on stable antiviral therapy.Inclusion Criteria
I am between 18 and 55 years old.
I am between 18 and 65 years old.
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.
+7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment Part 1
Single ascending doses of GSK3965193 and placebo in healthy participants with a minimum of 7 days washout between dosing in each period
4 weeks
4 visits (in-person)
Treatment Part 2
Repeat doses of GSK3965193 or placebo in healthy participants, starting at least 3-fold below the highest dose completed in Part 1
4 weeks
Treatment Part 3
GSK3965193 to lower hepatitis B virus surface antigen in participants with chronic hepatitis B, with optional open label bepirovirsen for 24 weeks
24 weeks
Treatment Part 4
Combination therapy with GSK3965193 and bepirovirsen to evaluate safety and potential sustained virologic response in participants with chronic hepatitis B
Duration not specified
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study tests GSK3965193's safety, tolerability, and pharmacokinetics in healthy individuals (Parts 1 & 2) and its effect on lowering the hepatitis B surface antigen in infected participants (Part 3). Part 4 explores combining GSK3965193 with bepirovirsen to achieve sustained virologic response in those infected.
9Treatment groups
Experimental Treatment
Group I: Part 4 Cohort 8: GSK3965193 and bepirovirsen or placebo and bepirovirsenExperimental Treatment3 Interventions
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.
Group II: Part 3 Sub-Cohort 7: Open label bepirovirsenExperimental Treatment1 Intervention
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.
Group III: Part 3 Cohort 7: GSK3965193 or placeboExperimental Treatment2 Interventions
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.
Group IV: Part 2B Cohort 6: GSK3965193Experimental Treatment1 Intervention
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.
Group V: Part 2A Cohort 5: GSK3965193 or placeboExperimental Treatment2 Interventions
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.
Group VI: Part 2A Cohort 4: GSK3965193 or placeboExperimental Treatment2 Interventions
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.
Group VII: Part 2A Cohort 3: GSK3965193 or placeboExperimental Treatment2 Interventions
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.
Group VIII: Part 1 Cohort 2: GSK3965193 and placeboExperimental Treatment2 Interventions
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.
Group IX: Part 1 Cohort 1: GSK3965193 and placeboExperimental Treatment2 Interventions
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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
GSK Investigational SiteCalgary, Canada
GSK Investigational SiteOttawa, Canada
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Who Is Running the Clinical Trial?
GlaxoSmithKlineLead Sponsor
References
New therapies for chronic hepatitis B. [2018]Approximately 350 million people worldwide are chronically infected with hepatitis B virus (HBV), representing a significant public health challenge. Nucleos/tide analogues (NUCs) and interferon alpha (IFNα), the current standard of care for chronic infection, aim at preventing progression of the disease to cirrhosis, hepatocellular carcinoma (HCC) and death. However, in contrast to the case of hepatitis C virus infection, in which novel antiviral drugs cure the vast majority of treated patients, in regard to HBV, cure is rare due to the unusual persistence of viral DNA in the form of covalently closed circular DNA (cccDNA) within the nucleus of infected cells. Available therapies for HBV require lifelong treatment and surveillance, as reactivation frequently occurs following medication cessation and the occurrence of HCC is decreased but not eliminated, even after years of successful viral suppression. Progress has been made in the development of new therapeutics, and it is likely that only a combination of immune modulators, inhibitors of gene expression and replication and cccDNA-targeting drugs will eradicate chronic infection. This review aims to summarize the state of the art in HBV drug research highlighting those agents with the greatest potential for success based on in vitro as well as on data from clinical studies.
Are novel combination therapies needed for chronic hepatitis B? [2012]The treatment of chronic hepatitis B remains limited to monotherapy with pegInterferon-alpha or one of 5 different nucleoside analogues (NUC). While viral suppression can be achieved in approximately 95% of patients with new-generation NUCs, the rate of HBeAg seroconversion ranges from only 20% with NUCs to 30% with pegInterferon-alpha. HBsAg loss is achieved in only 10% of patients with both classes of drugs after a follow-up of 5years. Attempts to improve the response by administering two different NUCs or a combination of NUC and pegInterferon-alpha have been unsuccessful. This situation has led researchers to investigate a number of steps in the HBV replication cycle as potential targets for new antiviral drugs. Novel targets and compounds could readily be evaluated in in vitro and in vivo models of HBV infection. The addition of one or more new drugs to the current regimen should offer the prospect of markedly improving the response to therapy, reducing the future burden of drug resistance, cirrhosis and hepatocellular carcinoma.
Phase IIb multicentred randomised trial of besifovir (LB80380) versus entecavir in Asian patients with chronic hepatitis B. [2022]Besifovir (LB80380) is an acyclic nucleotide phosphonate effective in hepatitis B virus (HBV) DNA suppression for both treatment-naive and lamivudine-resistant chronic hepatitis B (CHB) patients in preliminary studies.
Improving outcomes for patients with chronic hepatitis B. [2020]A focused meeting on hepatitis B virus (HBV) infection was held at the United States National Institutes of Health in Washington, DC, in April 2006. This meeting focused on new and historical data and served as a review for basic scientists and clinicians, as well as representatives from the pharmaceutical industry. Understanding HBV disease must include up-to-date information concerning virology, immunology, animal models, natural history, prevalence, and transmission risk, as well as an understanding of the evolving therapies for this life-threatening infection. Serious outcomes such as advanced fibrosis, cirrhosis, liver failure and hepatocellular carcinoma from hepatitis B infection appear to be closely tied to both historical and current serum levels of HBV DNA, and elevated serum levels of liver enzymes. Decreasing risk events and vaccinating susceptible individuals are key steps in managing this global scourge. New oral treatments for patients withchronic hepatitis B infection characterized by more potent antiviral effects, less toxicity, and minimal or no risk of resistance were reviewed and emphasized. Entecavir and pegylated interferons have recently been approved for treatment of chronic hepatitis B. Further expansion of our information about lamivudine and adefovir were highlighted. Several other new anti-HBV agents are also in phase II or III clinical trials or have been submitted for licensing including LdT (telbivudine). The NIH review meeting is summarized in this review and new and emerging areas of information are highlighted.
JNJ-73763989 pharmacokinetics and safety: Liver-targeted siRNAs against hepatitis B virus, in Japanese and non-Japanese healthy adults, and combined with JNJ-56136379 and a nucleos(t)ide analogue in patients with chronic hepatitis B. [2022]JNJ-73763989 comprises two hepatitis B virus (HBV)-specific, liver-targeted N-galactosamine-conjugated short interfering RNA triggers, JNJ-73763976 and JNJ-73763924. JNJ-73763989 pharmacokinetics, safety and tolerability were assessed in two phase 1 studies: Japanese (NCT04002752), and non-Japanese healthy participants and chronic hepatitis B (CHB) patients also receiving the HBV capsid assembly modulator JNJ-56136379 and a nucleos(t)ide analogue (NA) (NCT03365947).
Entecavir plus adefovir rescue therapy for chronic hepatitis B patients after multiple treatment failures in real-life practice. [2021]To evaluate the efficacy and safety of Entecavir (ETV) plus adefovir (ADV) for chronic hepatitis B (CHB) patients after multiple nucleos(t)ide analogue (NAs) failure treatment.
Safety, antiviral activity and pharmacokinetics of JNJ-64530440, a novel capsid assembly modulator, as 4 week monotherapy in treatment-naive patients with chronic hepatitis B virus infection. [2022]We investigated JNJ-64530440 (a hepatitis B virus capsid assembly modulator) safety, antiviral activity and pharmacokinetics in patients with chronic hepatitis B (CHB) (Phase 1b, NCT03439488).
A Randomized, Double-Blind, Placebo-Controlled, First-Time-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects. [2020]GSK3389404 is a liver-targeted antisense oligonucleotide that inhibits synthesis of hepatitis B surface antigen and all other hepatitis B virus proteins. This first-in-human, randomized, double-blind, phase 1 study assessed the safety and pharmacokinetics of GSK3389404 administered subcutaneously (SC) in healthy subjects. Four single ascending-dose cohorts (10 mg, 30 mg, 60 mg, and 120 mg) and 3 multiple ascending-dose cohorts (30 mg, 60 mg, and 120 mg once weekly for 4 weeks) each comprised 6 subjects randomized to GSK3389404 and 2 subjects randomized to placebo. There were no serious adverse events (AEs) or withdrawals due to AEs. The safety profile did not worsen with repeated dosing. The most frequent treatment-related AEs were injection site reactions (19.0% [n = 8/42], frequency unrelated to dose levels); all were mild (Grade 1) and resolved without dose modification or discontinuation. GSK3389404 administered subcutaneously was readily absorbed with a time to maximum plasma concentration (Tmax ) of 1-4 hours and an elimination half-life of 3-6 hours in plasma. Plasma area under the concentration-time curve (AUC) and maximum observed concentration (Cmax ) were dose-proportional. Dose-normalized plasma AUC from time 0 to infinity averaged 69.9 ng·h/(mL·mg dose) across cohorts, and Cmax 9.5 ng/(mL·mg dose). Pharmacokinetic profiles and parameters were comparable between single and multiple dosing. No accumulation was observed with once-weekly dosing. The metabolite was undetectable in urine and plasma. In the pooled urine, GSK3389404 was estimated to account for <0.1% of the total dose. In summary, GSK3389404 dosing has been tested up to 120 mg for 4 weeks with an acceptable safety and pharmacokinetic profile, supporting further clinical investigation in patients with chronic hepatitis B.
B-Clear Phase 2b Study Design: Establishing the Efficacy and Safety of Bepirovirsen in Patients with Chronic Hepatitis B Virus Infection. [2023]Bepirovirsen (GSK3228836) is an antisense oligonucleotide that induced rapid and prolonged hepatitis B surface antigen (HBsAg) reduction with a favorable safety profile following 4 weeks of treatment in participants with chronic hepatitis B virus (HBV) infection. The objective of the phase 2b study B-Clear is to access the efficacy and safety of bepirovirsen in participants with chronic HBV infection.
Comparison of the efficacy and safety of entecavir and tenofovir in nucleos(t)ide analogue-naive chronic hepatitis B patients with high viraemia: a retrospective cohort study. [2018]Label="OBJECTIVES" NlmCategory="OBJECTIVE">The aims of this study are to compare the long-term efficacy and safety of entecavir and tenofovir in nucleos(t)ide analogue (NA)-naive patients with chronic hepatitis B (CHB) with high hepatitis B virus (HBV) DNA (> 6 log10 IU/mL).
Efficacy and safety of the siRNA JNJ-73763989 and the capsid assembly modulator JNJ-56136379 (bersacapavir) with nucleos(t)ide analogues for the treatment of chronic hepatitis B virus infection (REEF-1): a multicentre, double-blind, active-controlled, randomised, phase 2b trial. [2023]JNJ-73763989 (JNJ-3989), a small interfering RNA, targets all hepatitis B virus (HBV) RNAs, reducing all HBV proteins. JNJ-56136379 (JNJ-6379; also known as bersacapavir), a capsid assembly modulator, inhibits HBV replication. We aimed to evaluate the efficacy (ie, antiviral activity) and safety of these therapeutics in combination with nucleos(t)ide analogues in patients with chronic hepatitis B.
Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model. [2019]BAY 41-4109 is a member of a class of heteroaryl-pyrimidines that was recently identified as potent inhibitors of human hepatitis B virus (HBV) replication. We have investigated the antiviral activity of BAY 41-4109 (methyl (R)-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-pyrimidine-5-carboxylate) in HBV-transgenic mice (Tg [HBV1.3 fsX(-)3'5']). Bay 41-4109 was administered per os using different schedules (b.i.d. or t.i.d. for up to 28 days) and dosages ranging from 3 to 30 mg/kg. The compound reduced viral DNA in the liver and in the plasma dose-dependently with efficacy comparable to 3TC. In contrast to 3TC-treated mice, we found a reduction of cytoplasmic hepatitis B virus core antigen (HBcAg) in liver sections of BAY 41-4109-treated mice, which indicated a different mode of action. Pharmacokinetic studies in mice have shown rapid absorption, a bioavailability of 30% and dose-proportional plasma concentrations. We conclude that BAY 41-4109 is a new anti-HBV drug candidate.