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。