Safety, pharmacokinetics, and antiviral activity of the capsid inhibitor AB-506 from Phase 1 studies in healthy subjects and those with hepatitis B
Man-Fung Yuen 1 , Elina Berliba 2 , Wattana Sukeepaisarnjaroen 3 , Sang Hoon Ahn 4 , Tawesak Tanwandee 5 , Young-Suk Lim 6 , Yoon Jun Kim 7 , Kittiyod Poovorawan 8 , Pisit Tangkijvanich 9 , Christian Schwabe 10 , Timothy Eley 11 , Joanne Brown 11 , Amy C H Lee 12 , Emily P Thi 12 , Bhavna Paratala 12 , Nagraj Mani 12 , Michael J Sofia 12 , Gaston Picchio 11 , Karen D Sims 11 , Edward J Gane 13
Affiliations
Affiliations
1
Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
2
Arensia Exploratory Medicine, Chisinau, Moldova.
3
Department of Medicine, Khon Kaen University, Srinagarind Hospital, Khon Kaen, Thailand.
4
Department of Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea.
5
Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
6
Department of Gastroenterology, Asan Medical Center, Seoul, Republic of Korea.
7
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
8
Faculty of Tropical Medicine, Hospital for Tropical Diseases, Mahidol University, Bangkok, Thailand.
9
Center of Excellence in Hepatitis and Liver Cancer, Chulalongkorn University, Bangkok, Thailand.
10
New Zealand Clinical Research, Auckland, New Zealand.
11
Clinical Development, Arbutus Biopharma, Warminster, Pennsylvania, USA.
12
Discovery, Arbutus Biopharma, Warminster, Pennsylvania, USA.
13
Department of Medicine, University of Auckland, Auckland, New Zealand.
PMID: 36194181 DOI: 10.1002/hep4.2095
Abstract
AB-506 is a potent, pan-genotypic small molecule capsid inhibitor that inhibits hepatitis B virus (HBV) pregenomic RNA encapsidation. We assessed the safety, pharmacokinetics, and antiviral activity of AB-506 in two randomized, double-blinded Phase 1 studies in healthy subjects (HS) and subjects with chronic HBV infection (CHB). Single ascending and multiple doses of AB-506 or placebo (30-1000 mg or 400 mg daily for 10 days) were assessed in HS. AB-506 or placebo was assessed at either 160 mg or 400 mg daily for 28 days in subjects with CHB. A second follow-up study examined AB-506 or placebo at 400 mg daily for 28 days in 14 Caucasian and 14 East-Asian HS. Twenty-eight days of AB-506 at 160 mg and 400 mg produced mean HBV-DNA declines from baseline of 2.1 log10 IU/ml and 2.8 log10 IU/ml, respectively. Four subjects with CHB (all Asian) had Grade 4 alanine aminotransferase (ALT) elevations (2 at each dose) as HBV DNA was declining; three events led to treatment discontinuation. In the second follow-up study, 2 Asian HS had serious transaminitis events leading to treatment and study termination. No subjects had bilirubin elevations or signs of hepatic decompensation. Conclusion: AB-506 demonstrated mean HBV-DNA declines of >2 log10 ; however, transient but severe ALT flares were observed in 4 Asian subjects with CHB. In the follow-up study in HS, 2 additional Asian HS had Grade 4 flares, suggesting that AB-506 hepatotoxicity contributed to the ALT elevations. The AB-506 development program was terminated because of these findings.