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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. 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 log 10 IU/ml reduction from baseline) rate, safety and pharmacokinetics. 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 log 10 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. GSK3389404 showed an acceptable safety profile and target engagement, with dose-dependent reductions in HBsAg. However, no efficacious dosing regimen was identified. NCT03020745. 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. [Display omitted] • GSK3389404 is a GalNAc-conjugated antisense oligonucleotide targeting HBV pregenomic and mRNA transcripts. • GSK3389404 treatment for 12 weeks led to a dose-dependent reduction of HBsAg in patients with chronic HBV infection. • HBsAg reduction occurred in both HBeAg+/- patients, indicating the target site is away from the integration hotspot. • Only 3 of 56 patients had a >1.5 log IU/ml reduction in HBsAg and no HBsAg seroclearance was achieved. • GSK3389404 had an acceptable safety profile with no unexpected safety signals. [ABSTRACT FROM AUTHOR]