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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 hepatitis B e antigen-negative patients (NCT02662712). Hepatitis B virus (HBV) genome sequence analysis, using HBV DNA next-generation sequence technology, was performed, and impact of substitutions on efficacy was assessed. Analyses focused on HBV core protein amino acid 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 amino acid 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 <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 the end of treatment. 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.
摘要：
每日口服JNJ-56136379（JNJ-6379;25、75、150或250mg）四周，N类衣壳组装调制器(CAM-N)，在治疗中具有良好的耐受性，具有有效的抗病毒活性，慢性乙型肝炎e抗原阳性和乙型肝炎e抗原阴性患者（NCT02662712）。乙型肝炎病毒（HBV）基因组序列分析，使用HBVDNA下一代序列技术，被执行，并评估了替代对疗效的影响.分析集中在与JNJ-6379和/或其他CAM的体外抗性相关的HBV核心蛋白氨基酸位置，以及CAM绑定袋中的那些。31/57患者在任何感兴趣的核心氨基酸位置具有≥1个多态性，最常见的位置是38(32%)，105（23%）和109（14%）。已知这些多态性均未降低JNJ-6379的体外活性(50%有效浓度下的倍数变化[FC]<3.0)。两名JNJ-6379治疗的患者携带Y118F基线核心多态性，已知在体外降低JNJ-6379活性（FC=6.6），并在治疗结束时HBVDNA下降2.77（75mg）和2.19log10IU/mL（150mg）。一名75mgJNJ-6379治疗的患者出现了T109S替代（FC=1.8;HBVDNA下降3.18log10IU/mL）。25毫克JNJ-6379治疗的患者在治疗富集Y118F变异（HBVDNA下降2.13log10IU/mL）。总之,基线多态性和富集取代降低JNJ-6379的体外活性是罕见的，在为期4周的1b期研究中，对病毒学应答没有一致的影响。将在2期研究中评估对JNJ-6379的更长治疗的抗性的出现。
