AASLD2020[856]慢性乙型肝炎病毒序列分析 （CHB）接受CAPSID大会

StephenW

856
VIRAL SEQUENCE ANALYSIS OF CHRONIC HEPATITIS B
(CHB) PATIENTS TREATED WITH THE CAPSID ASSEMBLY
MODULATOR (CAM-N) JNJ-56136379 (JNJ-6379) AS
MONOTHERAPY IN THE ONGOING JADE PHASE 2a STUDY
Thierry Verbinnen1,2, Willem Talloen2,3, Umesh Shukla4, Joris
J. Vandenbossche5, Michael Biermer1, Maria Beumont-
Mauviel6,7, Sandra De Meyer1 and Oliver Lenz1, (1)Janssen
Pharmaceutica NV, (2)Janssen Pharmaceutica NV, Beerse,
Belgium, (3)Janssen Research & Development, Janssen
Pharmaceutica NV, Beerse, Belgium, (4)Infectious Diseases
and Vaccines, Janssen, (5)Janssen Pharmaceuticals BV,
Beerse, Belgium, (6)Janssen R&D, Titusville, USA, (7)
Janssen R&D
Background: JNJ-6379 is a CAM-N currently in phase 2
clinical development Previous in vitro analysis showed that
single amino acid (aa) substitutions in HBV core protein can
lead to reduced susceptibility to CAMs In an ongoing phase
2a study (NCT03361956), CHB patients received JNJ-6379 at
doses of 75mg QD or 250mg QD as monotherapy (open label)
or in combination with TDF/ETV (placebo-controlled) In the
75mg and 250mg JNJ-6379 monotherapy arms (N=28 and 32
respectively), viral breakthroughs (VBT; confirmed >1log10 IU/
mL increase in HBV DNA from nadir) were observed in 5 and
1 patient, respectively, which led to discontinuation of JNJ-
6379 monotherapy treatment arms Here we present the viral
sequencing analysis of patients treated with monotherapy
Methods: HBV DNA was extracted from serum and HBV
genome was sequenced using next generation sequencing
(NGS). Baseline aa polymorphisms were defined as changes
versus the universal HBV reference sequence (sequence
read frequency >15%). Emerging mutations were defined
as aa changes compared to baseline sequence (frequency
<1% at baseline and ≥15% post-baseline). Results: In the 5
patients in the 75mg arm, VBT was associated with emerging
T33N core protein mutation (JNJ-6379 in vitro fold change
in EC50 value [FC] of 85) Except for one VBT patient (GTE),
who had baseline polymorphism Y118F (FC=6 6) and
showed HBV DNA increase from Week 4 onwards, all other
VBT patients had profound HBV DNA declines until Week 12
One additional 75mg treated patient had unconfirmed VBT at
Week 32 and emerging F23Y mutation (FC=5 2) One 250mg
treated patient had a non-response with <1log10 IU/mL decline
in HBV DNA at Week 4 and subsequently experienced VBT
at Week 8 This patient (GT-E) had no emerging mutations at
core protein positions of interest and carried I105T baseline
polymorphism (FC of 2 7) Eight additional monotherapy
treated patients did not meet VBT criteria but had a shallow
second phase of their HBV DNA profile and had emerging
T33N (N=7) or F23Y (N=1) mutation One patient with VBT and
emerging T33N showed ALT flare at time of VBT, JNJ-6379
was switched to TDF and had subsequent profound HBsAg
and HBV DNA decline Conclusion: JNJ-6379 monotherapy
resulted in VBT which was associated with the selection of
JNJ-6379 resistant variants ETV/TDF treatment (either as
switch [75mg arm] or add-on [250mg arm], respectively])
was initiated in all monotherapy patients and resulted in HBV
DNA declines No VBT was observed during JNJ-6379+NA
combination therapy.

StephenW

856
慢性乙型肝炎病毒序列分析
（CHB）接受CAPSID大会治疗的患者
调制器（CAM-N）JNJ-56136379（JNJ-6379）AS
正在进行的玉石阶段2a研究中的单刀治疗
Thierry Verbinnen1,2，Willem Talloen2,3，Umesh Shukla4，Joris
J.Vandenbossche5，Michael Biermer1，Maria Beumont-
Mauviel6,7，Sandra De Meyer1和Oliver Lenz1（1）詹森
Pharmaceutica NV，（2）Jansen Pharmaceutica NV，Beerse，
比利时（3）詹森研究与发展，詹森
Pharmaceutica NV，比利时比尔，（4）传染病
和疫苗，扬森（5）詹森制药有限公司，
比利时比尔斯（6）詹森研发（美国Titusville）（7）
简森研发
背景：JNJ-6379是目前处于第2阶段的CAM-N
临床发展先前的体外分析表明
HBV核心蛋白中的单个氨基酸（aa）替代可以
导致对CAM的敏感性降低
2a研究（NCT03361956），CHB患者在2007年接受了JNJ-6379
单一治疗剂量为75mg QD或250mg QD（开放标签）
或与TDF / ETV（安慰剂控制）结合使用
75mg和250mg JNJ-6379单药治疗臂（N = 28和32
），病毒突破（VBT；已确认> 1log10 IU /
在5和5中观察到从最低点开始的HBV DNA的毫升增加）
分别导致1名患者中断了JNJ-
6379单药治疗臂这里我们展示病毒
单药治疗患者的测序分析
方法：从血清和乙肝病毒中提取乙肝病毒DNA
使用下一代测序对基因组进行测序
（NGS）。基线氨基酸多态性定义为变化
与通用HBV参考序列（序列
读取频率> 15％）。定义了新兴突变
与基线序列相比（频率变化）
基线<1％，基线后≥15％）。结果：在5
75mg组患者，VBT与新兴
T33N核心蛋白突变（JNJ-6379体外倍数变化
EC50值[FC]为85）除了一名VBT患者（GTE），
具有基线多态性Y118F（FC = 6 6）和
从第4周开始显示HBV DNA增加
直到第12周，VBT患者的HBV DNA下降严重
另有75mg治疗的患者未确诊VBT
第32周和新出现的F23Y突变（FC = 5 2）一250mg
治疗的患者无反应，下降<1log10 IU / mL
在第4周接受HBV DNA检测，随后经历VBT
在第8周时，该患者（GT-E）在
感兴趣的核心蛋白位置和携带的I105T基线
多态性（FC of 2 7）八种单药治疗
治疗的患者不符合VBT标准，但病情较轻
他们的HBV DNA谱图的第二阶段已经出现
T33N（N = 7）或F23Y（N = 1）突变1例VBT和
新兴的T33N在VBT时显示ALT耀斑，JNJ-6379
改用TDF并随后出现严重的HBsAg
和HBV DNA下降结论：JNJ-6379单一疗法
导致VBT与选择
JNJ-6379耐药变体ETV / TDF处理（可以作为
分别切换[75mg手臂]或附加[250mg手臂]]）
在所有单一疗法患者中开始使用，并导致HBV
DNA下降JNJ-6379 + NA期间未观察到VBT
联合疗法。