Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy.

BACKGROUND & AIMS: Bepirovirsen, an antisense oligonucleotide targeting pregenomic and mRNA transcripts of HBV, has been conjugated to N-acetyl galactosamine (GSK3389404) to enhance hepatocyte delivery. This dose-finding study was the first to assess GSK3389404 for chronic HBV infection. METHODS: This phase IIa, randomised, double-blind, placebo-controlled, 2-part study was conducted in 22 centres in Asia (NCT03020745). Pharmacokinetic findings from Part 1 informed Part 2 dosing. In Part 2, patients with chronic hepatitis B on nucleos(t)ide analogue therapy were randomised 11:2 to GSK3389404 (30, 60, 120 mg weekly or 120 mg bi-weekly) or placebo until Day 85. Coprimary endpoints included HBsAg response (≥1.5 log10 IU/ml reduction from baseline) rate, safety and pharmacokinetics. RESULTS: Parts 1 and 2 included 12 (9 GSK3389404, 3 placebo) and 66 patients (56 GSK3389404, 10 placebo), respectively. In Part 2, one patient each in the 60 mg weekly, 120 mg weekly and 120 mg bi-weekly arms achieved a HBsAg response. HBsAg reductions were dose-dependent (Day 85: mean 0.34 [60 mg weekly] to 0.75 log10 IU/ml [120 mg weekly]) and occurred in hepatitis B e antigen-positive and -negative patients. No patient achieved HBsAg seroclearance. 43/56 (77%) GSK3389404- and 9/10 (90%) placebo-treated patients reported adverse events. No deaths were reported. Alanine aminotransferase flares (>2x upper limit of normal) occurred in 2 GSK3389404-treated patients (120 mg weekly, 120 mg bi-weekly); both were associated with decreased HBsAg, but neither was considered a responder. GSK3389404 plasma concentrations peaked 2-4 hours post dose; mean plasma half-life was 3-5 hours. CONCLUSIONS: GSK3389404 showed an acceptable safety profile and target engagement, with dose-dependent reductions in HBsAg. However, no efficacious dosing regimen was identified. CLINICAL TRIAL NUMBER: NCT03020745. LAY SUMMARY: Hepatitis B virus (HBV) can result in chronic HBV infection, which may ultimately lead to chronic liver disease, primary liver cancer and death; HBV proteins may prevent the immune system from successfully controlling the virus. GSK3389404 is an investigational agent that targets HBV RNA, resulting in reduced viral protein production. This study assessed the safety of GSK3389404 and its ability to reduce the viral proteins in patients with chronic HBV infection. GSK3389404 showed dose-dependent reduction in hepatitis B surface antigen, with an acceptable safety profile. While no clear optimal dose was identified, the findings from this study may help in the development of improved treatment options for patients with chronic HBV infections.

Hepatitis B infection among adults in the philippines: A national seroprevalence study.

AIM: To determine the prevalence of hepatitis B surface antigen (HBsAg) seropositivity among adult Filipinos. METHODS: Testing for HBsAg was performed on serum samples from persons aged ≥ 20 years old who participated in the National Nutrition and Health Survey (NNHeS) conducted in 2003. Information on age, sex, marital status, educational attainment, employment status, and income were collected. For this study, marital status was classified as never married or otherwise (i.e., married, divorced, separated, widowed); educational attainment was classified as high school graduate or below or at least some tertiary education; and employment status was classified as currently employed or currently unemployed. Annual income was divided into 4 quartiles in Philippine pesos (PhP): Q1, ≤ PhP 53064; Q2, PhP 53065-92192; Q3, PhP 92193-173387; and Q4, ≥ PhP 173388. Prevalence estimates were weighted so that they represented the general population. Social and demographic factors were correlated with HBsAg seropositivity. Multivariate analysis was used to determine independent predictors of HBsAg seropositivity. RESULTS: A total of 2150 randomly selected adults, 20 years and over, out of the 4753 adult participants of NNHeS were tested for HBsAg. The HBsAg seroprevalence was 16.7% (95%CI: 14.3%-19.1%), which corresponded to an estimated 7278968 persons infected with hepatitis B. There was no significant difference between males and females (17.5% vs 16.0%; P = 0.555). This corresponded to an estimated 3721775 men and 3557193 women infected with hepatitis B. The HBsAg seroprevalence peaked at age 20-39 years old, with declining prevalence in the older age groups. The only independent predictor of HBsAg seropositivity was the annual income, with persons in the highest income quartile being less likely to be HBsAg positive (age-adjusted OR = 0.51; 95%CI: 0.30-0.86) compared to subjects in the lowest income quartile. Sex, marital status, educational attainment, and employment status were not found to be independent predictors of HBsAg seropositivity. CONCLUSION: The high HBsAg seroprevalence among adults in the Philippines classifies the country as hyperendemic for HBV infection and appears unchanged over the last few decades.