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.
作者: StephenW 时间: 2019-10-22 16:09
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。作者: newchinabok 时间: 2019-10-22 16:40
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作者: 齐欢畅 时间: 2019-10-23 22:07