JNJ-56136379单一疗法治疗慢性乙型肝炎感染患者28天的病毒学分

StephenW

Virology Analysis of Chronic Hepatitis B Infected Patients Treated for 28 Days With JNJ-56136379 Monotherapy
Thierry Verbinnen  1 , Moana Hodari  1 , Willem Talloen  1 , Jan Martin Berke  1 , David Blue  2 , Jeysen Yogaratnam  2   3 , Joris Vandenbossche  1 , Umesh Shukla  4 , Sandra De Meyer  1 , Oliver Lenz  1
Affiliations
Affiliations

    1
    Janssen Research & Development, Beerse, Belgium.
    2
    Janssen Biopharma Inc, South San Francisco, CA, USA.
    3
    Aligos Therapeutics, South San Francisco, CA, USA.
    4
    Janssen Pharmaceuticals Research & Development, Titusville, USA.

    PMID: 32579776 DOI: 10.1111/jvh.13351

Abstract

Four weeks of once-daily oral JNJ-56136379 (JNJ-6379; 25, 75, 150 or 250 mg), a class-N capsid assembly modulator (CAM-N), was well tolerated with potent antiviral activity in treatment-naïve, chronic hepatitis B e antigen-positive and -negative patients (NCT02662712). Hepatitis B virus (HBV) genome sequence analysis, using HBV DNA next-generation sequence (NGS) technology, was performed and impact of substitutions on efficacy was assessed. Analyses focused on HBV core protein amino acid (aa) positions associated with JNJ-6379 and/or other CAMs in-vitro resistance, and those within the CAM-binding pocket. 31/57 patients had ≥1 polymorphism at any of the core aa positions of interest, most frequently at positions 38 (32%), 105 (23%) and 109 (14%). None of these polymorphisms are known to reduce JNJ-6379 in-vitro activity (fold change [FC] in 50% effective concentration [EC50 ] <3.0).Two JNJ-6379-treated patients carried a Y118F baseline core polymorphism known to reduce JNJ-6379 activity in vitro (FC = 6.6) and had HBV DNA declines of 2.77 (75 mg) and 2.19 log10 IU/mL (150 mg) at end of treatment, respectively. One 75 mg JNJ-6379-treated patient had an emerging T109S substitution (FC = 1.8; HBV DNA decline 3.18 log10 IU/mL). A 25 mg JNJ-6379-treated patient had on-treatment enrichment of Y118F variant (HBV DNA decline 2.13 log10 IU/mL). In conclusion, baseline polymorphisms and enrichment of substitutions reducing JNJ-6379 in-vitro activity were rare, with no consistent impact on virological response during a 4 week phase 1b study. Emergence of resistance to longer treatments of JNJ-6379 will be evaluated in phase 2 studies.

Keywords: Hepatitis B virus; antiviral activity; capsid assembly modulator; phase 1b.

This article is protected by copyright. All rights reserved.

StephenW

JNJ-56136379单一疗法治疗慢性乙型肝炎感染患者28天的病毒学分析
Thierry Verbinnen 1，Moana Hodari 1，Willem Talloen 1，Jan Martin Berke 1，David Blue 2，Jeysen Yogaratnam 2 3，Joris Vandenbossche 1，Umesh Shukla 4，Sandra De Meyer 1，Oliver Lenz 1
隶属关系
隶属关系

    1个
    Janssen Research＆Development，比利时比尔。
    2
    美国加利福尼亚州南旧金山的简森生物制药公司。
    3
    Aligos Therapeutics，美国加利福尼亚州南旧金山。
    4
    美国蒂图斯维尔的Janssen Pharmaceuticals Research＆Development。

    PMID：32579776 DOI：10.1111 / jvh.13351

抽象

每天接受四周一次的口服NJ衣壳装配调节剂（CAM-N）JNJ-56136379（JNJ-6379; 25、75、150或250 mg），在未经治疗的情况下具有良好的抗病毒活性，慢性乙型肝炎e抗原阳性和阴性患者（NCT02662712）。使用HBV DNA下一代序列（NGS）技术进行了乙型肝炎病毒（HBV）基因组序列分析，并评估了替代对疗效的影响。分析的重点是与JNJ-6379和/或其他CAMs体外抗性相关的HBV核心蛋白氨基酸（aa）位置，以及与CAM结合口袋有关的位置。 31/57位患者在任何感兴趣的aa位置均具有≥1多态性，最常见的是在位置38（32％），105（23％）和109（14％）处。已知这些多态性均未降低JNJ-6379的体外活性（有效浓度50％时的倍数变化[FC] [EC50] <3.0）。两名接受JNJ-6379治疗的患者携带Y118F基线核心多态性，已知可降低JNJ -6379的体外活性（FC = 6.6），治疗结束时HBV DNA下降分别为2.77（75 mg）和2.19 log10 IU / mL（150 mg）。一名接受JNJ-6379治疗的75 mg患者出现了新出现的T109S替代（FC = 1.8； HBV DNA下降3.18 log10 IU / mL）。一名接受25 mg JNJ-6379治疗的患者接受治疗后的Y118F变异体富集（HBV DNA下降2.13 log10 IU / mL）。综上所述，基线多态性和降低JNJ-6379体外活性的取代基丰富很少见，并且在4周的1b期研究中对病毒学应答没有持续的影响。在第2期研究中将评估对JNJ-6379较长治疗的耐药性出现情况。

关键词：乙型肝炎病毒；抗病毒活性衣壳装配调节剂阶段1b。

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