Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy
Man-Fung Yuen 1 , Jeong Heo 2 , Hiromitsu Kumada 3 , Fumitaka Suzuki 3 , Yoshiyuki Suzuki 4 , Qing Xie 5 , Jidong Jia 6 , Yoshiyasu Karino 7 , Jinlin Hou 8 , Kazuaki Chayama 9 , Michio Imamura 10 , Judy Y Lao-Tan 11 , Seng Gee Lim 12 , Yasuhito Tanaka 13 , Wen Xie 14 , Jung-Hwan Yoon 15 , Zhongping Duan 16 , Masayuki Kurosaki 17 , Sung-Jae Park 18 , Madalinee Eternity Labio 19 , Rajneesh Kumar 20 , Young-Oh Kweon 21 , Hyung Joon Yim 22 , Yu Tao 23 , Jennifer Cremer 24 , Robert Elston 25 , Matt Davies 26 , Sharon Baptiste-Brown 27 , Kelong Han 27 , Fiona M Campbell 25 , Melanie Paff 27 , Dickens Theodore 24
Affiliations
PMID: 35714812 DOI: 10.1016/j.jhep.2022.05.031
Abstract
Background & aims: GSK3389404, an antisense oligonucleotide targeting hepatitis B virus (HBV) pregenomic and mRNA transcripts, is conjugated to N-acetyl galactosamine for enhanced hepatocyte delivery. This dose-finding study was the first to assess GSK3389404 in chronic HBV infection.
Methods: This Phase 2a, randomised, double-blind, placebo-controlled, 2-part study was conducted in 22 centres in Asia (NCT03020745). Pharmacokinetic (PK) 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 PK.
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 biweekly 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-treated and 9/10 (90%) placebo patients reported adverse events. No deaths were reported. Alanine aminotransferase flares (>2x upper limit of normal) occurred in two 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.