LP4：在慢性乙型肝炎（CHB）中进行基于RNA干扰[RNAi]的三联疗

StephenW

LP4: FIRST CLINICAL EXPERIENCE WITH RNA INTERFERENCE [RNAi]-BASED TRIPLE COMBINATION THERAPY IN CHRONIC HEPATITIS B (CHB): JNJ-73763989 (JNJ-3989), JNJ-56136379 (JNJ-6379) AND A NUCLEOS(T)IDE ANALOGUE (NA)Man-Fung Yuen1, Stephen Locarnini2, Bruce Given3, Thomas Schluep3, James Hamilton3, Michael Biermer4, Ronald Kalmeijer5, Maria Beumont-Mauviel5, Oliver Lenz4, Gavin Cloherty6, Kathy Jackson2, Carlo Ferrari7, Ching Lung Lai1, Kevin Sze-Hang Liu1, Lung Yi Mak1, Danny Ka Ho Wong1, Wai Pan To1, Kwan-Lung Ko1 and Robert G. Gish8, (1)The University of Hong Kong, (2)Victorian Infectious Disease Reference  Laboratory,  (3)Arrowhead  Pharmaceuticals,  (4)Janssen  Pharmaceuticals  BV,  (5)Janssen  R&D,  (6)Abbott  Diagnostics,  (7)University of Parma, (8)Hepatitis B FoundationBackground:JNJ-3989 (RNAi) silences HBV RNA transcripts from integrated HBV DNA and episomal cccDNA. JNJ-6379 (novel class N capsid assembly modulator [CAM-N]; normal empty capsids) blocks HBV viral replication and de novo cccDNA formation in preclinical models, and reduced HBV DNA and RNA in CHB patients (pts) (AASLD 2018). AROHBV1001 showed that 3 monthly JNJ-3989 doses (100–400mg) with a NA: achieved >1 log10 HBsAg reductions; reduced all measurable viral products; was well tolerated (EASL 2019). Combining agents with different modes of action may lead to additive/synergistic antiviral effects, possibly increasing functional cure rates after finite treatment. To help design longer term studies, a cohort was added to explore triple combination therapy of JNJ-3989, JNJ[size=14.999999999999998px]-6379 and a NA.Methods:HBeAg +ve or -ve, NA-experienced (regardless of HBV DNA level) or -naïve CHB pts were enrolled. 12 pts received  3  JNJ-3989  doses  (200mg  subcutaneously,  days  [D]  1,  29  and  57)  +  oral  JNJ-6379  250mg  once  daily  for  12  wks.  Pts  started/continued NA on D1 and continued beyond JNJ-6379 dosing. Assessments included safety, qHBsAg, qHBeAg, qHBV DNA, qHBV RNA and qHBcrAg levels. Planned follow-up is 1 yr with continued NA treatment.Results:All pts were Asian; median age 46 (34–67) yrs; 8 males; HBeAg 4 +ve 8 –ve; 7 NA-experienced. All pts had 3 JNJ-3989 doses and 84 days of JNJ-6379; follow-up was 17–64 days. No    deaths,    discontinuations,    seriousor    severe    adverse    events    (AEs)    or    clinically    significant    findings    on    vital    signs/ECG/hematology/chemistry  were  reported.  Two  AEs  (mild  respiratory  infection,  not  related)  were  reported.  The  only  notable laboratory findings were grade 1 transient isolated ALT elevations (n=5, 57–118 U/L), possibly therapeutic response flares. HBsAg levels declined during treatment (Fig). Mean HBsAg (SE) log10 reductions were 1.4 (0.12) on D85 (n=12) and 1.8 (0.11) in 7 pts with D113 data. In pts with >1000 IU/mL HBV DNA on D1 (n=6, 3.7–7.7 log10 IU/mL), all had a rapid decline in DNA. 9 pts had quantifiable HBV RNA (D1, 1.75–7.5 log10 IU/mL); 6 were <limit of quantification by D29. Pts positive (D1) for HBeAg (n=4) and HBcrAg (n=8) all had reductions in these parameters.Conclusion:This is the first study to investigate the safety and efficacy of a triple combination of a RNAi (JNJ-3989), a CAM-N (JNJ-6739) and a NA in CHB pts. This combination was well tolerated and pts achieved robust reductions in HBsAg as well as other measurable viral parameters.

StephenW

LP4：在慢性乙型肝炎（CHB）中进行基于RNA干扰[RNAi]的三联疗法的首次临床经验：JNJ-73763989（JNJ-3989），JNJ-56136379（JNJ-6379）和一个核（T）IDE模拟物（ NA）Man-Fung Yuen1，Stephen Locarnini2，Bruce Given3，Thomas Schluep3，James Hamilton3，Michael Biermer4，Ronald Kalmeijer5，Maria Beumont-Mauviel5，Oliver Lenz4，Gavin Cloherty6，Kathy Jackson2，Carlo Ferrari7，Chung Lung1，Kevin Sze-Hang Liu1，Longyi Mak1，Danny Ka Ho Wong1，Wai Pan To1，Kwan-Lung Ko1和Robert G. Gish8，（1）香港大学，（2）维多利亚州传染病参考实验室，（3）Arrowhead Pharmaceuticals，（ 4）詹森制药公司（5）詹森研发（6）Abbott Diagnostics（7）帕尔马大学（8）乙型肝炎基金会背景：JNJ-3989（RNAi）使整合的HBV DNA和游离cccDNA的HBV RNA转录沉默。 JNJ-6379（新型N类衣壳装配调节剂[CAM-N];正常空衣壳）可在临床前模型中阻断HBV病毒复制和从头cccDNA形成，并降低CHB患者的HBV DNA和RNA（pts）（AASLD 2018）。 AROHBV1001表明，JNJ-3989的3个月每月剂量（100-400mg），且NA：HBsAg减少超过1 log10。减少了所有可测量的病毒产品；耐受性良好（EASL 2019）。具有不同作用方式的组合剂可能导致加性/协同抗病毒作用，可能在有限治疗后提高功能治愈率。为了帮助设计长期研究，增加了一个队列来研究JNJ-3989，JNJ-6379和NA的三联疗法。方法：HBeAg + ve或-ve，NA经验（无论HBV DNA水平如何）或-naive已注册CHB积分。 12名患者接受3次JNJ-3989剂量（皮下200mg，在[D] 1、29和57天）+口服JNJ-6379 250mg，每天一次，连续12周。点开始/继续在D1上不适用，并继续超过JNJ-6379剂量。评估包括安全性，qHBsAg，qHBeAg，qHBV DNA，qHBV RNA和qHBcrAg水平。计划的随访时间为1年，并持续进行NA治疗。中位年龄46（34-67）岁； 8名男性； HBeAg 4 + ve 8 –ve;有7位NA经验。所有患者均接受3次JNJ-3989剂量和84天JNJ-6379；随访17-64天。没有关于生命体征/ ECG /血液学/化学方面的死亡，停药，严重或严重不良事件（AE）或临床上重要发现的报道。据报道有两种不良事件（轻度呼吸道感染，无关）。唯一值得注意的实验室检查结果是1级暂时性孤立性ALT升高（n = 5，57-118 U / L），可能是治疗反应性发作。治疗期间HBsAg水平下降（图）。在D113数据下，D85（n = 12）的平均HBsAg（SE）log10降低为1.4（0.12），而7分则为1.8（0.11）。在D1上HBV DNA> 1000 IU / mL的患者（n = 6，3.7–7.7 log10 IU / mL），所有患者的DNA均迅速下降。 9例可量化的HBV RNA（D1，1.75-7.5 log10 IU / mL）； 6是＜通过D29的定量极限。 HBeAg（n = 4）和HBcrAg（n = 8）的Pts阳性（D1）均降低了这些参数。结论：这是首次研究三联RNAi（JNJ-3989）的安全性和有效性），CAM-N（JNJ-6739）和NA的CHB点数。这种组合具有良好的耐受性，pts可使HBsAg以及其他可测量的病毒参数显着降低。

newchinabok

很遗憾，没有毛用，只降低，不根治

天上飞鱼

至少明确了三联疗法短期内无法转阴，就看二期最终数据了

dxd2017

请教各位：
一直打下去表抗会不会继续降低？
如果效果不好，箭头的股票为什么一直涨？

平凡之路123

回复 newchinabok 的帖子

文章里说结论了？不是刚开始实验吗。

傻狍子7号

这个意思是第85天表面抗原降低1.4log，第113天降低1.8log吗？

傻狍子7号

回复 傻狍子7号 的帖子

HBsAg levels declined during treatment (Fig). Mean HBsAg (SE) log10 reductions were 1.4 (0.12) on D85 (n=12) and 1.8 (0.11) in 7 pts with D113 data

齐欢畅

不错