Virology analysis of chronic hepatitis B virus–infected patients treated for 28 days with JNJ‐56136379 monotherapy.

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. [ABSTRACT FROM AUTHOR]