AASLD2019[695]多剂量治疗12周后的结果 慢性乙型肝炎（CHB）患者

StephenW

695
RESULTS AFTER 12 WEEKS TREATMENT OF MULTIPLE DOSES
OF GSK3389404 IN CHRONIC HEPATITIS B (CHB) SUBJECTS
ON STABLE NUCLEOS(T)IDE THERAPY IN A PHASE 2a
DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY
Man-Fung Yuen1, Jeong Heo2, Hiromitsu Kumada3, Fumitaka
Suzuki4, Yoshiyuki Suzuki3, Qing Xie5, Jidong Jia6, Yoshiyasu
Karino7, Jinlin Hou8, Kazuaki Chayama9, Michio Imamura10,
Judy y. lao-Tan11, Seng Gee Lim12, Yasuhito Tanaka13, Wen
Xie14, Jung-Hwan Yoon15, Zhongping Duan16, Masayuki
Kurosaki17, Sung-Jae Park18, Eternity Labio19, Rajneesh
Kumar20, Young-Oh Kweon21, Hyung Joon Yim22, Jennifer
Cremer23, Robert Elston23, Shuguang Chen23, Matt Davies23,
Sharon Baptiste-Brown23, Kelong Han23, Fiona m. Campbell23,
Melanie Paff23 and Dickens Theodore23, (1)University of
Hong Kong, Queen Mary Hospital, (2)Department of Internal
Medicine, College of Medicine, Pusan National University,
Busan, Korea, (3)Hepatology, Toranomon Hospital, (4)
Hepatology, Toranomon Hospital Kajigaya, (5)Ruijin Hospital,
(6)Beijing Friendship Hospital, (7)Hokkaido P.W.F.a.C.
Sapporo-Kosei General Hospital, (8)Department of Infectious
Diseases , Nanfang Hospital, Southern Medical University,
(9)Research Center for Hepatology and Gastroenterology,
Hiroshima University, Hiroshima, Japan, (10)Hiroshima
University Hospital, (11)Cebu Doctors University Hospital, (12)
National University Health System, Singapore, (13)Nagoya
City University Hospital, (14)Center of Liver Diseases, Beijing
Ditan Hospital, Capital Medical University, (15)Department
of Internal Medicine and Liver Research Institute, Seoul
National University Hospital, (16)Beijing Youan Hospital, (17)
Musashino Red Cross Hospital, (18)Inje University Busan Paik
Hospital, (19)Makati Medical Center, (20)Singapore General
Hospital, (21)Kyungpook National University Hospital, (22)
Korea University Ansan Hospital, (23)Glaxosmithkline
Background: GSK3389404 (GSK404) is a 2nd generation,
liver targeted antisense oligonucleotide A Phase 2a study
was conducted in CHB patients on stable nucleos(t)ide
therapy to assess the safety, tolerability, and pharmacokinetic
(PK) profile of GSK404, and to identify one or more efficacious
dose(s) and dosing regimen(s) Methods: 66 subjects
(demographics in table) were randomized to either placebo,
GSK404 30 mg weekly (wk), 60 mg wk, 120 mg bi-weekly
(BW), 120 mg wk subcutaneous injections for 12 weeks.
The primary objectives were to assess the safety, tolerability,
and PK profile of GSK404 and to identify efficacious dose(s)
and dosing regimen(s). GSK financially sponsored the study
[NCT03020745]. Results: Efficacy: Dose-dependent HBsAg
declines occurred in both HBeAg positive and negative
subjects with mean HBsAg declines of 0 02 log IU/mL in
placebo, 0 13 log IU/mL in 30 mg wk, 0 34 log IU/mL in 60 mg
wk, 0.44 log Iu/mL in 120 mg BW, and 0.75 log IU/mL in 120 mg
wk treatment arms by Day 85 Three subjects, from the 60 mg
wk, 120 mg BW, and 120 mg wk treatment arms, had HBsAg
1 54 log reduction (Day 85), 2 36 log (Day 92), and 2 72 log
(Day 85) without ALT elevation >2X ULN, respectively. Two
subjects had ALT >2xULN with HBsAg decline, 0.37 log IU/
mL [ALT 182 U/L; baseline 19 U/L] and 1.45 log IU/mL decline
[ALT 113 U/L; baseline 39 U/L]. No subjects had undetectable
HBsAg levels at end of treatment Safety: Overall, GSK404
had an acceptable safety profile. There was 1 SAE of
renal colic (120 mg GSK404 BW) considered unrelated to
treatment and 1 withdrawal due to pruritis, rash (Grade 1
[mild] on neck; 120 mg BW) considered treatment-related.
The most frequently reported AE was injection site reactions
Most AEs were Grade 1 or Grade 2 (moderate) with no clear
relationship to dose Platelets showed dose-dependent
declines that plateaued on treatment and started to recover
after dose completion No bleeding events were reported Two
placebo subjects had Grade 4 (potentially life-threatening) lab
abnormality of creatine kinase increase attributed to physical
activity PK: GSK404 had a Tmax at 2-4 hours post dose with
mean t1/2 of 3-5 hours across dose levels No accumulation
of plasma concentrations was observed with repeat dosing
Conclusion: GSK404 had an acceptable safety profile and
showed target engagement with dose-dependent declines in
mean HBsAg The Phase 2a study is ongoing with subjects in
an optional post-treatment period.

StephenW

695
多剂量治疗12周后的结果
慢性乙型肝炎（CHB）患者中GSK3389404的表达
在第2a阶段进行稳定的核苷（T）疗法
双盲，地点控制的研究
袁文峰1，郑赫2，广田弘光3，富高
铃木4，吉幸铃木3，清谢5，冀东佳6，吉安
Karino7，Jinlin Hou8，Kazuaki Chayama9，Imamura Michio10，
朱迪老坛11，成吉林12，田中靖人13，温
谢14，尹Jung焕15，段中平16，正月
Kurosaki17，Sung-Jae Park18，Eternal Labio19，Rajneesh
Kumar20，Young-Oh Kweon21，Henung Joon Yim22，Jennifer
Cremer23，Robert Elston23，Shuguang Chen23，Matt Davies23，
莎朗·巴蒂斯特·布朗（Sharon Baptiste-Brown）23，科隆·汉（Kelong Han）23，菲奥娜（Fiona）坎贝尔23，
Melanie Paff23和Dickens Theodore23，（1）
香港玛丽医院（2）内科
釜山国立大学医学院医学部
韩国釜山（3）虎之门医院肝病（4）
龟岛虎之门医院肝病，（5）瑞金医院，
（6）北京友谊医院，（7）北海道P.W.F.a.C.
札幌市科生综合医院（8）传染科
南方医科大学附属南方医院疾病科
（9）肝肠胃病研究中心
日本广岛广岛大学（10）广岛
大学医院（11）宿雾博士大学医院（12）
国立大学卫生系统，新加坡，（13）名古屋
北京大学城市大学医院（14）肝病中心
首都医科大学附属地坛医院（15）
首尔内科学与肝脏研究所
国立大学医院（16）北京佑安医院（17）
武藏野红十字会医院（18）仁济大学釜山白
医院（19）马卡蒂医疗中心（20）新加坡
医院，（21）庆北国立大学医院，（22）
高丽大学安山医院，（23）
背景：GSK3389404（GSK404）是第二代产品，
肝脏靶向反义寡核苷酸A 2a期研究
是在CHB患者中使用稳定的核苷酸（t）进行的
评估安全性，耐受性和药代动力学的疗法
（PK）配置文件，以识别一种或多种有效药物
剂量和给药方案方法：66名受试者
（表中的人口统计数据）随机分配给任一安慰剂，
GSK404每周30 mg，每周60 mg，每两周120 mg
（BW），120 mg wk皮下注射，持续12周。
主要目标是评估安全性，耐受性，
和GSK404的PK曲线，以鉴定有效剂量
和给药方案。 GSK资助了这项研究
[NCT03020745]。结果：功效：剂量依赖性HBsAg
HBeAg阳性和阴性均下降
HBsAg平均下降为0 02 log IU / mL的受试者
安慰剂，每周30 mg，0 13 log IU / mL，60 mg，0 34 log IU / mL
wk，在120 mg BW中为0.44 log Iu / mL，在120 mg中为0.75 log IU / mL
第85天的wk治疗臂三位受试者，从60毫克开始
周，体重120毫克体重和治疗周120毫克，均患有HBsAg
1 54 log减少（第85天），2 36 log（第92天）和2 72 log
（第85天），而ALT却没有升高> 2倍ULN。二
受试者的ALT> 2xULN，HBsAg下降，0.37 log IU /
毫升[ALT 182 U / L;基线19 U / L]和1.45 log IU / mL下降
[ALT 113 U / L；基线39 U / L]。没有受试者被发现
治疗结束时的HBsAg水平安全性：总体，GSK404
具有可接受的安全性。共有1个SAE
肾绞痛（120 mg GSK404 BW）被认为与
治疗和因瘙痒，皮疹而停药1次（1级
脖子上的120 mg BW）被视为与治疗有关。
报道最频繁的AE是注射部位反应
大多数不良事件为1级或2级（中度），不清楚
与剂量的关系血小板表现出剂量依赖性
下降至治疗水平并开始恢复
服药完成后未报告出血事件2
安慰剂受试者接受了4级（可能威胁生命）的实验室
肌酸激酶异常的增加归因于身体
活性PK：GSK404在给药后2-4小时具有Tmax，
整个剂量水平3-5小时的平均t1 / 2无累积
重复给药观察到血浆浓度
结论：GSK404具有可接受的安全性，并且
显示目标参与度与剂量依赖性下降有关
平均HBsAg 2a期研究正在进行中
可选的后处理期。