EASL2019 GS-12 inarigivir的上升剂量队列研究 - 一种新的RIG I激动

StephenW

GS-12
Ascending dose cohort study of inarigivir - A novel RIG I agonist in
chronic HBV patients: Final results of the ACHIEVE trial
Man-Fung Yuen1, Chi-Yi Chen2, Chun-Jen Liu3, RachelWen-Juei Jeng4,
Magdy Elkhashab5, Carla Coffin6, Won Kim7, Susan Greenbloom8,
Alnoor Ramji9, Young-Suk Lim10, Yoon Jun Kim11, Scott Fung12,
Dong Joon Kim13, JeongWon Jang14, Kwan Sik Lee15, Nezam Afdhal16,
Radhakrishnan Iyer16, Chelsea Macfarlane16, Kathy Jackson17,
Stephen Locarnini17, Henry Chan18. 1University of Hong Kong, Queen
Marys Hospital, Hong Kong, Hong Kong; 2Chia-Yi Christian Hospital,
Chia-Yi City, Taiwan; 3National Taiwan University Hospital, Taipei,
Taiwan; 4Chang Gung Memorial Hospital, New Taipei City, Taiwan;
5Toronto Liver Centre, Toronto, Canada; 6University of Calgary, Calgary,
Canada; 7Borame Medical Center, Seoul, Korea, Rep. of South; 8Toronto
Digestive Disease Associates, Vaughn, Canada; 9Gastrointestinal
Institute, Vancouver; 10University of Ulsan College of Medicine, Asan
Medical Center, Seoul, Korea, Rep. of South; 11Seoul National University
Hospital, Seoul, Korea, Rep. of South; 12Toronto General Hospital, United
Health Network, Toronto, Canada; 13Hallym University Chuncheon
Sacred Heart Hospital, Seoul, Korea, Rep. of South; 14The Catholic
University of Korea, Seoul St. Mary’s Hospital, Seoul, Korea, Rep. of South;
15Gangnam Severance Hospital, Yonsei University Health System, Seoul,
Korea, Dem. People’s Rep. of; 16Spring Bank Pharmaceuticals, Hopkinton,
United States; 17VIDRL, Melbourne, Australia; 18Chinese University of
Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
Email: [email protected]
Background and Aims: Inarigivir, an oral dinucleotide RIG-I agonist
has demonstrated anti-viral activity against HBV via a combination of
activation of innate immunity and a DAA effect as a Non Nucleotide
reverse transcriptase inhibitor (NNRTI). We report here the final
results of the ACHIEVE trial, an ascending dose cohort study of 12
weeks of inarigivir followed by a switch to 12 weeks of tenofovir
(TDF) 300 mg daily in treatment naïve HBV patients.
Method: 80 patients were randomized to inarigivir (25,50,100 and
200 mg) daily or placebo in a 4:1 ratio for 12 weeks and then all
patients were switched to TDF. Primary endpoints were safety and
efficacy measured by reduction in HBV DNA atweek 12 from baseline.
Secondary endpoints included HBV RNA, quantitative HBsAg,
peripheral serum cytokines and change in ALT.
Results: Patient demographics are given in the table. Primary
endpoint of HBV DNA reduction was achieved in a dose dependent
fashion for both HBeAg positive and negative patients with a
maximal reduction of 3.26 log10 in the 200 mg dose. HBV RNA
paralleled HBV DNA reductions, with greater reduction in HBeAgnegative patients. Quantitative HBsAg response with a predefined
threshold of a >0.5 log10 reduction at either week 12 or week 24 was
seen in 22% of patients with a mean reduction of 0.8 log10 and a
maximal reduction of 1.4 log10. Unlike HBV DNA, HBsAg decline was
not dose dependent and indicates the potential importance of the
host response to inarigivir. Tolerability of treatment was good with 1
unrelated SAE of knee pain and 1 grade 3 non-sustained laboratory
abnormality of hypertriglyceridemia. ALT flares (>200 IU) were seen
in 6 treated patients (10%) and 4 placebo patients (25%) and 1 patient
required dose discontinuation for ALT > 400 IU. No significant
increases in bilirubin or INR were seen.
Pbo E+ ve,Pbo E− ve,Epos 25mg, Eneg 25mg,Epos 50mg,Eneg 50mg,Epos 100mg,Eneg 100mg,Epos 200 mg,Eneg200mg
n 8 8 9 7 11 5 13 4 8 7
Age 35 48 37 43 36 47 34 46 42 52
M: F 7:1 5: 3 5:5 3:3 9:2 5:0 7:6 3:1 4:4 2:5
ALT 85 53 82 75 75 65 75 90 54 73
HBVDNA 7.6 4 4.75 7.86 5.69 7.79 4.55 8.20 5.95 7.88 4.95
GTA ,1,, 1
GTB 2 6 4 3 3 4 4 3 2 5
GTC 6 1 5 1 7 1 8 1 6 2
GTD ,,,2 ,1 ,,1

Conclusion: The ACHIEVE trial confirms the safety and anti-viral
efficacy of inarigivir up to 200 mg daily and further studies at doses of
up to 400 mg daily in combination with TDF or added to NUC
suppressed patients are underway.

StephenW

GS-12
inarigivir的上升剂量队列研究 - 一种新的RIG I激动剂
慢性HBV患者：ACHIEVE试验的最终结果
Man-Fung Yuen1，陈志毅2，刘春仁3，RachelWen-Juei Jeng4，
Magdy Elkhashab5，Carla Coffin6，赢得Kim7，Susan Greenbloom8，
Alnoor Ramji9，Young-Suk Lim10，Yoon Jun Kim11，Scott Fung12，
Dong Joon Kim13，JeongWon Jang14，Kwan Sik Lee15，Nezam Afdhal16，
Radhakrishnan Iyer16，Chelsea Macfarlane16，Kathy Jackson17，
Stephen Locarnini17，Henry Chan18。 1香港大学，女王
香港香港玛丽医院; 2基督教基督医院，
台湾嘉义市; 3台北大学医院，台北，
台湾;台湾新北市4Chang Gung纪念医院;
5多伦多加拿大多伦多肝脏中心; 6卡尔加里卡尔加里大学，
加拿大; 7Borame医疗中心，韩国首尔，南方代表; 8Toronto
Digestive Disease Associates，Vaughn，Canada; 9Gastrointestinal
温哥华研究所; 10阿山蔚山大学医学院
医疗中心，韩国首尔，南方代表; 11首尔国立大学
医院，韩国首尔，南方代表; 12联合总部医院
健康网络，加拿大多伦多; 13Hallym University Chuncheon
圣心医院，韩国首尔，南方代表; 14天主教徒
韩国大学，首尔圣玛丽医院，韩国首尔，南方代表;
首尔延世大学卫生系统15号，南京Severance医院，
韩国，民主党人民代表; 16斯普林班克药业，霍普金顿，
美国; 17VIDRL，澳大利亚墨尔本; 18中国大学
香港沙田威尔斯亲王医院香港
电子邮件：[email protected]
背景和目的：Inarigivir，一种口服二核苷酸RIG-I激动剂
通过结合使用可以证明抗HBV的抗病毒活性
激活先天免疫和作为非核苷酸的DAA效应
逆转录酶抑制剂（NNRTI）。我们在这里报告决赛
ACHIEVE试验的结果，12的递增剂量队列研究
几周的inarigivir，然后转换为12周的替诺福韦
（TDF）每日300毫克治疗初治HBV患者。
方法：将80例患者随机分入inarigivir（25,50,100和20）
每日200mg）或安慰剂，比例为4：1，持续12周，然后全部
患者转为TDF。主要终点是安全和
通过每周12次从基线降低HBV DNA来测量功效。
次要终点包括HBV RNA，定量HBsAg，
外周血清细胞因子和ALT的变化。
结果：患者人口统计学在表中给出。主
HBV DNA减少的终点以剂量依赖性实现
HBeAg阳性和阴性患者的时尚
200mg剂量的最大减少3.26log10。 HBV RNA
与HBV DNA平行减少平行，HBeAg阴性患者减少更多。具有预定义的定量HBsAg响应
在第12周或第24周时降低> 0.5 log10的阈值为
在22％的患者中观察到平均减少0.8 log10和a
最大减少1.4 log10。与HBV DNA不同，HBsAg下降了
不依赖于剂量，表明了潜在的重要性
主持人对inarigivir的回应。 1的治疗耐受性良好
膝关节疼痛SAE和1级3级非持续性实验室无关
高甘油三酯血症的异常。发现ALT耀斑（> 200 IU）
6名接受治疗的患者（10％）和4名安慰剂患者（25％）和1名患者
ALT> 400 IU所需剂量中断。没有意义
观察到胆红素或INR增加。
Pbo E.
+ ve
Pbo E.
-  ve
史诗
25
毫克
Eneg
25
毫克
史诗
50
毫克
Eneg
50
毫克
史诗
100
毫克
Eneg
100
毫克
史诗
200
毫克
Eneg
200
毫克
n 8 8 9 7 11 5 13 4 8 7
年龄35 48 37 43 36 47 34 46 42 52
M：F 7：1 5：3 5：5 3：3 9：2 5：0 7：6 3：1 4：4 2：5
ALT 85 53 82 75 75 65 75 90 54 73
HBVDNA 7.6 4 4.75 7.86 5.69 7.79 4.55 8.20 5.95 7.88 4.95
GTA 1 1
GTB 2 6 4 3 3 4 4 3 2 5
GTC 6 1 5 1 7 1 8 1 6 2
GTD 2 1 1
结论：ACHIEVE试验证实了安全性和抗病毒性
每日200克的inarigiv的功效和剂量的进一步研究
每日最多400毫克与TDF组合或添加到NUC
抑制患者正在进行中。