Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy
Man‐Fung Yuen, Jeong Heo, Hiromitsu Kumada, Fumitaka Suzuki, Yoshiyuki Suzuki, Qing Xie, Jidong Jia, Yoshiyasu Karino, Jinlin Hou, Kazuaki Chayama, Michio Imamura, Judy Lao-Tan, Seng Gee Lim, Yasuhito Tanaka, Wen Xie, Jung‐Hwan Yoon, Zhongping Duan, Masayuki Kurosaki, Sung-Jae Park, Madalinee Eternity Labio, Rajneesh Kumar, Young-Oh Kweon, Hyung Joon Yim, Tao Yu, Jennifer Cremer, Robert C. Elston, Matt Davies, Sharon Baptiste‐Brown, Kelong Han, Fiona Campbell, Melanie Paff, Dickens Theodore
Abstract
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: IU/ml reduction from baseline) rate, safety and pharmacokinetics. RESULTS: 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.