LP7：健康受试者（HS）和慢性乙型肝炎（CHB）受试者中速效抑

StephenW

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.

StephenW

LP7：健康受试者（HS）和慢性乙型肝炎（CHB）受试者中速效抑制剂（CI）AB-506的安全性，耐受性，药代动力学（PK）和抗病毒活性Ahn4，Tawesak Tanwandee5，Young-Suk LIM6，Yoon Jun Kim7，Kittiyod Poovorawan8，Pisit Tangkijvanich9，Henry Lik Yuen Chan10，Timothy Eley11，Joanne Brown11，Christopher Moore12，Amy CH Lee12，Jim Kim12，Emily P Thi12，Nagraj Mani12，Rene Rijnbrand12，Andrew Cole12，Michael J Sofia12，Gaston R.Picchio11，Karen Sims11和Edward J.Gane13，（1）香港大学，玛丽医院，（2） Arensia探索医学，（3）孔敬大学斯利那加林德医院消化内科，（4）延世大学医学院，大韩民国首尔遣散医院，消化内科，（5）Siriraj医院消化内科，（6）阿桑，消化内科大韩民国首尔蔚山医学院大学医学中心，（7）首尔国立大学医院内科和肝脏研究所，（8）玛希顿大学，热带病医院，热带医学，（9）朱拉隆功大学医学院肝炎和肝癌卓越研究中心，（10）药物与治疗学系消化疾病研究所，国家重点实验室f香港中文大学消化系统疾病，（11）临床开发，Arbutus生物制药，（12）Discovery，Arbutus生物制药，（13）新西兰奥克兰市医院新西兰肝移植单位，新西兰奥克兰，背景：AB -506是一种口服II类选择性HBV CI，用于体外治疗具有抗AH和基因型抗核苷酸变异的CHB。这项正在进行的首次人体研究的目的是评估AB-506在HS和HBV-DNA + CHB受试者中的安全性，耐受性，PK和抗病毒活性。方法：在第1部分中，将2组HS随机分配6 ：2接受30mg至1000mg的单次递增剂量的AB-506或安慰剂（PBO）。在第2部分中，将1组12 HS随机分配10：2，以接受每日一次（QD）10天的AB-506 400mg或PBO。在第3部分中，将12个非肝硬化HBV DNA +受试者的两个队列按10：2随机分配，以160mg或400mg QD接受AB-506或PBO治疗28天。结果：HS未观察到严重的不良事件（AEs）。大多数AE轻微，被认为与AB-5 06无关。在实验室检查，ECG或生命体征中未发现临床上明显的异常。 CHB受试者年龄在22-59岁之间，主要为女性，亚洲人和C型或D型基因型。表1显示了按剂量和电子抗原状况的HBV DNA和HBV RNA反应。治疗无病毒突破。分别在24名受试者中的5名，4名和2名中注意到了Y38，I105和T109位置的基线替代；一位患有I105T的受试者对治疗无反应。没有严重的不良事件；大多数AE轻微。两个队列中的6名受试者均出现短暂，可逆的ALT升高（2级，2级，4级4级），其中2名受试者在第23和24天时根据方案中止研究药物。所有受试者的胆红素，白蛋白和INR值均保持正常；没有一个符合药物诱发的肝损伤（DILI）标准。治疗后所有患者的HBV DNA水平均下降> 2 log10，且没有人暴露于异常的AB-506。一个受试者在耀斑后8个月持续存在HBeAg（> 2.6 log10）和HBsAg（> 1.4 log10）持续下降，是唯一一个干扰素γ（IFN-γ）和其他T细胞活化标志物比基线增加的受试者在ALT爆发之前。其他4级耀斑受试者伴随IP-10升高，但IFN-γ无变化。正在进行关于HS中AB-506的新的，持续时间较长（28天）的研究。结论：AB-506通常是安全且耐受性良好的，在CHB受试者中观察到了强大的抗病毒作用。在CHB受试者中观察到的ALT爆发可能是免疫介导的，并可能导致HBV标志物的有益下降。