AASLD2019[700]2a相，随机，双盲，定点控制 抗敏药（ISIS）的研

StephenW

PHASE 2a, RANDOMIZED, DOUBLE-BLIND, PLACEBOCONTROLLED
STUDY OF AN ANTISENSE INHIBITOR (ISIS
505358) IN TREATMENT-NAÏVE CHRONIC HEPATITIS B (CHB)
PATIENTS: SAFETY AND ANTIVIRAL EFFICACY
Man Fung Yuen, The University of Hong Kong, Hong Kong,
Jeong Heo, Medical Research Institute, Pusan National
University Hospital, Busan, Korea, Jeong-Won Jang,
Seoul St. Mary’s Hospital, the Catholic University of Korea,
Seoul, Republic of Korea, Jung-Hawn Yoon, Seoul National
University Hospital, Young-Oh Kweon, Kyungpook National
University Hospital, Sung-Jae Park, Inje University Busan
Paik Hospital, C. Frank Bennett, Ionis Pharmaceuticals Inc
and T. Jesse Kwoh, Ionis Pharmaceuticals Inc.
Background: Hepatitis B virus (HBV) surface antigen (HBsAg)
is suspected to play a major role in enabling and maintaining
persistent HBV infection. Ionis-HBVRx (ISIS 505358) is a 2´-
MOE modified antisense oligonucleotide (ASO) targeting
all HBV RNAs. It was selected for clinical study based on
its activity against HBsAg in non-clinical studies The safety
of the ASO was previously evaluated in healthy volunteers
The aim of the current study was to extend the safety and
tolerability evaluation to CHB patients and to assess the
antiviral activity of treatment given for 4 weeks Methods:
This study was conducted in treatment-naïve patients with
HBV DNA ≥2x103 IU/mL and HBsAg >50 IU/mL. Exclusion
criteria included: history or evidence of liver cirrhosis; coinfection
with HCV, HIV, or HDV; ALT or AST >5xULN, bilirubin
>1.1xULN, or serum creatinine >1.1xULN. Both HBeAg
positive and negative patients were eligible Treatment was
administered by subcutaneous injections on Days 1, 4, 8, 11,
15, and 22. The primary assessment for effect on HBV was
on Day 29 Thereafter, all patients received a 6-month course
of tenofovir Results: Treatments with placebo (n=6) and 150
mg (n=6) and 300 mg (n=12) ASO were studied Dose related
reductions of HBsAg and HBV DNA were observed. At 300
mg, HBsAg and HBV DNA mean ± SD log10 IU/mL changes
from baseline were -1 556±1 379 (p=0 001 vs placebo) and
-1 655±1 479 (p<0 001), respectively Three of these patients
had HBsAg and HBV DNA reductions >3.0 log10 IU/mL where
2 also had HBsAg and HBV DNA levels reduced to below
the lower limit of quantitation (LLoQ, 0.05 and 20 IU/mL,
respectively). HBsAg remained below LLoQ for at least 28
and 102 days post-ASO treatment All 3 patients were HBeAg
negative throughout. One SAE occurred in the study: post-
ASO treatment ALT flare to 781 U/L (24xULN) in a patient
with HBsAg and HBV DNA reductions to <LLoQ. A post-ASO
ALT flare to 479 U/L (15xULN) occurred in the other <LLoQ
patient. Otherwise, the AEs in >1 ASO patient and with higher
incidence than placebo patients were pyrexia (22%), injection
site (IS) pruritis (17%), and anemia, myalgia and IS pain
(11% each) Conclusion: Dose-related reductions of HBsAg
levels were observed with only 4-week ISIS 505358 treatment
indicating the ASO has significant inhibitory activity against
HBsAg and HBV DNA. The tolerability and safety were
acceptable for proceeding to longer treatment durations This
study was financially supported by GlaxoSmithKline.

StephenW

2a相，随机，双盲，定点控制
抗敏药（ISIS）的研究
505358）在未接受治疗的慢性乙型肝炎（CHB）中
患者：安全和抗病毒功效
香港大学文峰苑
郑浩，釜山国立医学研究所
韩国釜山大学医院张正元
韩国天主教大学首尔圣玛丽医院
大韩民国首尔，尹贞焕（Hung-Hawn Yoon），首尔国民
庆北国立大学杨幼权大学医院
釜山仁济大学成载公园大学医院
艾尼克斯制药公司C.弗兰克·贝内特·派克医院
和Ionis Pharmaceuticals Inc.的T. Jesse Kwoh。
背景：乙型肝炎病毒（HBV）表面抗原（HBsAg）
怀疑在启用和维护中起主要作用
持续性HBV感染。 Ionis-HBVRx（ISIS 505358）是2´-
MOE修饰的反义寡核苷酸（ASO）靶向
所有HBV RNA。它被选择用于临床研究基于
非临床研究中其对HBsAg的活性安全性
先前曾在健康志愿者中评估过ASO
当前研究的目的是扩展安全性和
对CHB患者的耐受性评估并评估
给予抗病毒活性治疗4周方法：
这项研究是针对未接受过治疗的初次患者
HBV DNA≥2x103IU / mL，HBsAg> 50 IU / mL。排除
标准包括：肝硬化病史或证据；共同感染
患有HCV，HIV或HDV； ALT或AST> 5xULN，胆红素
> 1.1xULN，或血清肌酐> 1.1xULN。两种HBeAg
阳性和阴性患者均符合条件
在第1、4、8、11天通过皮下注射给药
15和22。对HBV影响的主要评估是
此后的第29天，所有患者均接受了6个月的疗程
诺福韦治疗的结果：安慰剂（n = 6）和150的治疗
研究了mg（n = 6）和300 mg（n = 12）ASO剂量相关
观察到HBsAg和HBV DNA减少。在300
mg，HBsAg和HBV DNA平均值±SD log10 IU / mL变化
从基线开始为-1 556±1 379（相对于安慰剂，p = 0 001）和
-1 655±1 479（p <0 001），其中三名患者
HBsAg和HBV DNA减少> 3.0 log10 IU / mL，其中
2个患者的HBsAg和HBV DNA水平也降至以下
定量下限（LLoQ，0.05和20 IU / mL，
分别）。 HBsAg至少低于LLoQ至少28
ASO治疗后102天和3天均为HBeAg
整个负面。研究中发生了一种SAE：
ASO治疗患者的ALT爆发至781 U / L（24xULN）
HBsAg和HBV DNA降低至<LLoQ。后ASO
在另一<LLoQ中发生了ALT爆发到479 U / L（15xULN）
患者。否则，> 1名ASO患者和更高的AE
发生率高于安慰剂患者为发热（22％），注射
部位（IS）瘙痒（17％），以及贫血，肌痛和IS疼痛
（各占11％）结论：与剂量相关的HBsAg降低
ISIS 505358治疗仅4周即可观察到血脂水平
表明ASO对
HBsAg和HBV DNA。耐受性和安全性分别为
可以接受更长的治疗时间
葛兰素史克（GlaxoSmithKline）资助了这项研究。