LP7: SAFETY, TOLERABILITY, PHARMACOKINETICS (PK), AND ANTIVIRAL ACTIVITY OF THE CAPSID INHIBITOR (CI) AB-506 IN HEALTHY SUBJECTS (HS) AND CHRONIC HEPATITIS B (CHB) SUBJECTSMan-Fung Yuen1, Elina Berliba2, Wattana Sukeepaisarnjaroen3, Sang Hoon Ahn4, Tawesak Tanwandee5, Young-Suk LIM6, Yoon Jun Kim7, Kittiyod Poovorawan8, Pisit Tangkijvanich9, Henry Lik Yuen Chan10, Timothy Eley11, Joanne Brown11, Christopher Moore12, Amy C.H. Lee12, Jin Kim12, Emily P Thi12, Nagraj Mani12, Rene Rijnbrand12, Andrew Cole12, Michael J Sofia12, Gaston R. Picchio11, Karen Sims11 and Edward J. Gane13, (1)University of Hong Kong, Queen Mary Hospital, (2)Arensia Exploratory Medicine, (3)Gastroenterology, Khon Kaen University, Srinagarind Hospital, (4)Gastroenterology, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea, (5)Gastroenterology, Siriraj Hospital, (6)Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, (7)Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, (8)Tropical Medicine, Mahidol University, Hospital of Tropical Diseases, (9)Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, (10)Institute of Digestive Disease, Department of Medicine and Therapeutics, and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, (11)Clinical Development, Arbutus Biopharma, (12)Discovery, Arbutus Biopharma, (13)New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New ZealandBackground:AB-506 is an oral, class II, selective HBV CI for the treatment of CHB with activity against genotypes A-H and nucleos(t)ide resistant variantsin vitro. The objectives of this ongoing first-in -human study are to evaluate the safety, tolerability, PK, and antiviral activity of AB-506 in HS and HBV-DNA+ CHB subjects.Methods:In Part 1, 2 cohorts of HS were randomized 6:2 to receive single ascending doses of AB-506 from 30mg to 1000mg or placebo (PBO). In Part 2, 1 cohort of 12 HS was randomized 10:2 to receive AB[size=14.999999999999998px]-506 400mg or PBO once daily (QD) for 10 days. In Part 3, two cohorts of 12 non-cirrhotic, HBV DNA+ subjects were randomized 10:2 to receive AB-506 or PBO for 28 days at either 160mg or 400mg QD. Safety, tolerability, PK, immune markers, viral sequence and antiviral activity were assessed.Results:No serious adverse events (AEs) were observed in HS; most AEs were mild and considered unrelated to AB-5 06. No clinically significant abnormalities in laboratory tests, ECGs, or vital signs were noted. CHB subjects were aged 22-59 years and were mostly female, Asian and genotype C or D. HBV DNA and HBV RNA responses by dose and e-antigen status are shown in Table 1. There was no viral breakthrough on treatment. Baseline substitutions at positions Y38, I105, and T109 were noted in 5, 4 and 2 of the 24 subjects respectively; one subject with I105T had no response to treatment. There were no serious AEs; most AEs were mild. 6 subjects across both cohorts had transient, reversible ALT elevations (2 Grade 2, 4 Grade 4), with 2 subjects discontinuing study drug per protocol on Days 23 and 24. Bilirubin, albumin, and INR values remained normal in all subjects; none met drug-induced liver injury (DILI) criteria. All had declining HBV DNA levels of >2 log10 on treatment, and none had unusual AB-506 exposures. One subject has had persistent HBeAg (>2.6 log10) and HBsAg (>1.4 log10) declines from baseline 8 months-post flare and was the only subject with increases from baseline in interferon gamma (IFN[size=14.999999999999998px]-γ) and other T cell activation markers that preceded the ALT flare. The other Grade 4 flare subjects had accompanying increases in IP-10, but no changes in IFN[size=14.999999999999998px]-γ. A novel, longer duration (28 day) study of AB-506 in HS is ongoing.Conclusion:AB-506 was generally safe and well-tolerated and robust antiviral effects were observed in CHB subjects. The ALT flares observed in CHB subjects may be immune-mediated and may lead to beneficial declines in HBV markers.作者: StephenW 时间: 2019-10-22 16:28