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

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 log 10 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 log 10 IU/mL). A 25 mg JNJ-6379-treated patient had on-treatment enrichment of Y118F variant (HBV DNA decline 2.13 log 10 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.

Safety, pharmacokinetics, and antiviral activity of the capsid inhibitor AB‐506 from Phase 1 studies in healthy subjects and those with hepatitis B

“…Pre‐existing and emergent core protein variants associated with reduced susceptibility have been noted in other CI clinical programs, including T109M [ 13 ] and F23Y, T33N, I105T, and Y118F. [ 20 , 21 , 22 ]…”

Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731

“…A review of the available HBV sequence databases ( https://hbvdb.lyon.inserm.fr/HBVdb/ ) indicates that except for the Y38F variant (3.2%), none of the substitutions studied preexist as a natural polymorph in >1% of patient isolates ( Table 5 ). Currently, multiple classes of CIs are still in early-stage clinical development (phases 1 and 2) ( 23 , 24 ), and clinical baseline polymorphisms and on-treatment enrichment of substitutions reducing the in vitro activity of CIs are rare, with a few impacting the virological response ( 23 , 24 ). In the phase 1b study ABI-H0731-101(B), there was one HBeAg-negative patient who exhibited only a 1.0-log decline by day 28 on monotherapy, who was subsequently found to harbor a known CI-resistant variant (T109M) at baseline.…”

The Hepatitis B Virus Nucleocapsid—Dynamic Compartment for Infectious Virus Production and New Antiviral Target

“…Meanwhile, JNJ 6379 proceeded into 48 week phase 2 trials initially comprising monotherapy and several combination arms (JADE study NCT03361956). Different from the four-week treatment in phase 1 [ 247 ] drug-associated viral breakthrough was seen in some patients after 24 weeks of monotherapy but not in combination with a NUC [ 248 ]; the combination also achieved higher HBV suppression than NUC alone [ 229 ], especially in treatment-naïve HBeAg + CHB patients. Moreover, a higher fraction of these patients showed more pronounced (though still modest) reductions in HBsAg and HBeAg levels, often associated with flares of elevated serum alanine transaminase (ALT) levels, in line with liver inflammation.…”

“…Notably, natural polymorphisms have been found at HAP pocket positions by searches in HBV databases [ 261 ] and a large patient cohort [ 260 ], including Y118F and D29A, I105T/L/V and T114I/V but not T33N; the presence or absence of such baseline mutations may thus affect treatment outcome in patients, as seen by 20-fold reduced activity to AB-506 to Cp baseline mutant I105T [ 262 ]. In an early 28-day trial with JNJ-6379 half of the patients carried viruses with one or more potentially relevant mutations, including Y118F, I105T, T109M, and T019I, but their therapy response was not generally reduced, despite a detectable enrichment of the Y118F mutant [ 247 ]. Importantly, though, 24 week interim data from the JNJ-6379 monotherapy arm of the 48 week JADE study revealed viral breakthrough in several patients which correlated with baseline mutations Y118F and I105T and emergence of the T33N mutation [ 248 ].…”