GSK3965193 for Hepatitis B

Recruiting at 13 trial locations

Overseen By EU GSK Clinical Trials Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: GlaxoSmithKline

Must be taking: Nucleoside analogs

Must not be taking: Immunosuppressants, Anticoagulants

Disqualifiers: HIV, Liver cirrhosis, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

84 Participants Needed

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. ^{1 2 3 4 5}

What 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. ^{6 7 8 9 10}

How 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. ^{2 5 8 11 12}

Research Team

GSK Clinical Trials

Principal Investigator

GlaxoSmithKline

Eligibility 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

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.

I have had chronic hepatitis B for at least 6 months.

Plasma or serum HBsAg concentration >100 IU/mL.

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

Treatment Details

Interventions

• Bepirovirsen
• GSK3965193

Trial Overview 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.

Participant Groups

Group I: Part 4 Cohort 8: GSK3965193 and bepirovirsen or placebo and bepirovirsen Experimental Treatment 3 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 bepirovirsen Experimental Treatment 1 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 placebo Experimental Treatment 2 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: GSK3965193 Experimental Treatment 1 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 placebo Experimental Treatment 2 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 placebo Experimental Treatment 2 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 placebo Experimental Treatment 2 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 placebo Experimental Treatment 2 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 placebo Experimental Treatment 2 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.

Who Is Running the Clinical Trial?

GlaxoSmithKline

Lead Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Findings from Research

Chronic hepatitis B virus (HBV) infection affects around 350 million people globally, and current treatments like nucleos/tide analogues and interferon alpha can prevent disease progression but do not cure the infection due to the persistence of viral DNA in infected cells.

To effectively eradicate HBV, future therapies will likely need to combine immune modulators, gene expression inhibitors, and drugs targeting the persistent cccDNA, as current treatments require lifelong management and do not eliminate the risk of liver cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New therapies for chronic hepatitis B. Bitton Alaluf, M., Shlomai, A.[2018]

Current treatments for chronic hepatitis B, including pegInterferon-alpha and nucleoside analogues, achieve high viral suppression (about 95%) but have low rates of HBeAg seroconversion (20-30%) and HBsAg loss (10%) after 5 years.

Research is focusing on new antiviral drugs targeting different steps in the HBV replication cycle, which could enhance treatment efficacy and reduce the risk of drug resistance and related complications like cirrhosis and liver cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are novel combination therapies needed for chronic hepatitis B? Zoulim, F.[2012]

Besifovir at doses of 90 mg and 150 mg daily showed similar effectiveness to entecavir 0.5 mg daily in suppressing HBV DNA in chronic hepatitis B patients after 48 weeks, with no significant differences in treatment outcomes.

The main side effect of besifovir was a decrease in serum L-carnitine levels in 94.1% of patients, which was manageable with carnitine supplementation, indicating a generally safe profile for the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IIb multicentred randomised trial of besifovir (LB80380) versus entecavir in Asian patients with chronic hepatitis B. Lai, CL., Ahn, SH., Lee, KS., et al.[2022]

The meeting highlighted that serious outcomes from hepatitis B virus (HBV) infection, such as liver failure and cancer, are closely linked to HBV DNA levels and liver enzyme levels, emphasizing the importance of monitoring these markers for effective disease management.

New oral treatments for chronic hepatitis B, like entecavir and pegylated interferons, have been approved, showing potent antiviral effects with reduced toxicity and resistance risk, while additional promising therapies are in advanced clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving outcomes for patients with chronic hepatitis B. Gish, RG.[2020]

In two phase 1 studies involving healthy participants and chronic hepatitis B patients, JNJ-73763989 was found to be generally safe and well tolerated, with all adverse events reported as mild to moderate.

The pharmacokinetics of JNJ-73763976 and JNJ-73763924 showed a dose-proportional increase in plasma concentrations, with a short half-life of 4-9 hours, and no significant differences in pharmacokinetics between Japanese and non-Japanese participants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Gane, E., Yuen, MF., Kakuda, TN., et al.[2022]

In a study of 45 chronic hepatitis B patients who had previously failed multiple nucleos(t)ide analogue treatments, the combination of Entecavir (ETV) and Adefovir (ADV) resulted in a high complete virologic response (CVR) rate of 97.8% after 24 months, indicating its efficacy as a rescue therapy.

The treatment was found to be safe, with no significant adverse events related to ETV and ADV therapy, making it a viable option for patients in regions where other treatments like tenofovir are unavailable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entecavir plus adefovir rescue therapy for chronic hepatitis B patients after multiple treatment failures in real-life practice. Xu, XH., Li, GL., Qin, Y., et al.[2021]

In a Phase 1b study involving 20 patients with chronic hepatitis B, JNJ-64530440 was well tolerated, with mild-to-moderate side effects reported in a minority of participants, indicating a favorable safety profile.

The treatment demonstrated significant antiviral activity, with substantial reductions in hepatitis B virus (HBV) DNA levels, achieving undetectable levels in several patients after 28 days of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Gane, EJ., Schwabe, C., Berliba, E., et al.[2022]

GSK3389404, a liver-targeted antisense oligonucleotide, was found to be safe in a phase 1 study with no serious adverse events reported among 42 healthy subjects, even with repeated dosing over 4 weeks.

The drug showed a predictable pharmacokinetic profile, with dose-proportional absorption and no accumulation in the body, indicating it is suitable for further testing in patients with chronic hepatitis B.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Han, K., Cremer, J., Elston, R., et al.[2020]

Bepirovirsen, an antisense oligonucleotide, showed promising results in reducing hepatitis B surface antigen (HBsAg) levels with a favorable safety profile after just 4 weeks of treatment in patients with chronic hepatitis B virus (HBV) infection.

The phase 2b B-Clear study enrolled 457 participants and aims to evaluate the long-term efficacy of bepirovirsen in achieving HBsAg and HBV DNA seroclearance after treatment, comparing results in patients receiving nucleos(t)ide analog therapy versus those not on therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B-Clear Phase 2b Study Design: Establishing the Efficacy and Safety of Bepirovirsen in Patients with Chronic Hepatitis B Virus Infection. Cremer, J., Elston, R., Campbell, FM., et al.[2023]

In a study of 419 nucleos(t)ide analogue-naive patients with chronic hepatitis B, both entecavir and tenofovir showed similar long-term efficacy in achieving virological response and HBeAg loss, indicating that either treatment can be effective for managing high HBV DNA levels.

However, tenofovir was associated with a higher risk of acute kidney injury compared to entecavir, suggesting that while both medications are effective, safety profiles differ, particularly regarding kidney health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Wu, IT., Hu, TH., Hung, CH., et al.[2018]

In a study involving 470 patients with chronic hepatitis B, the small interfering RNA JNJ-3989 showed a dose-dependent effect in helping patients meet stopping criteria for nucleos(t)ide analogues, indicating its potential efficacy in treatment.

While JNJ-3989 did not lead to complete HBsAg seroclearance, it resulted in significant reductions in HBsAg levels, which may enhance the liver's immune response and improve outcomes when combined with other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Yuen, MF., Asselah, T., Jacobson, IM., et al.[2023]

BAY 41-4109 effectively reduces HBV viral DNA in both the liver and plasma of HBV-transgenic mice, demonstrating dose-dependent antiviral activity comparable to the existing drug 3TC.

Unlike 3TC, BAY 41-4109 also reduces hepatitis B virus core antigen levels in the liver, suggesting it operates through a different mechanism of action, making it a promising new candidate for HBV treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model. Weber, O., Schlemmer, KH., Hartmann, E., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

New therapies for chronic hepatitis B. [2018]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Are novel combination therapies needed for chronic hepatitis B? [2012]

3. England pubmed.ncbi.nlm.nih.gov

Phase IIb multicentred randomised trial of besifovir (LB80380) versus entecavir in Asian patients with chronic hepatitis B. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Improving outcomes for patients with chronic hepatitis B. [2020]

5. England pubmed.ncbi.nlm.nih.gov

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]

6. England pubmed.ncbi.nlm.nih.gov

Entecavir plus adefovir rescue therapy for chronic hepatitis B patients after multiple treatment failures in real-life practice. [2021]

7. England pubmed.ncbi.nlm.nih.gov

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]

8. United States pubmed.ncbi.nlm.nih.gov

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]

9. United States pubmed.ncbi.nlm.nih.gov

B-Clear Phase 2b Study Design: Establishing the Efficacy and Safety of Bepirovirsen in Patients with Chronic Hepatitis B Virus Infection. [2023]

10. England pubmed.ncbi.nlm.nih.gov

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]

11. Netherlands pubmed.ncbi.nlm.nih.gov

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]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model. [2019]