Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial

Yuen, Man Fung; Agarwal, Kosh; Gane, Edward; Schwabe, Christian; Ahn, Sang Hoon; Kim, Dong Joon; Lim, Young Suk; Cheng, Wendy; Sievert, William; Visvanathan, Kumar; Ruby, Eric; Liaw, Sandy; Yan, Ran; Huang, Qi; Colonno, Richard J.; Lopatin, Uri

doi:10.1016/s2468-1253(19)30346-2

Cited by 87 publications

(89 citation statements)

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“…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.…”

Section: Resultsmentioning

confidence: 99%

“…This is underscored by several studies demonstrating that the inhibition of Cp perturbs biological processes such as viral capsid assembly, viral RNA encapsidation, viral DNA replication, HBV cccDNA establishment and transcription, as well as host immune responses to HBV infection ( 6 , 7 , 9 – 11 , 14 , 16 ). As a result, CIs have become a promising class of new anti-HBV therapeutics, with several candidates already in human clinical trials for the treatment of CHB patients ( 23 , 31 ). Here, we report the preclinical profiling of ABI-H0731, a novel and effective HBV CI currently in phase 2a human clinical trials ( 29 , 30 ).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it is anticipated that the clinical use of CIs will always be in combination with NrtI therapy in order to maintain an exceedingly high resistance barrier and prevent the enrichment of any CI-resistant variants with prolonged therapy. A preexisting T109M variant was discovered at baseline in a patient treated with ABI-H0731 in a phase 1b 28-day monotherapy clinical study ( 23 ). Although in vitro analysis showed that ABI-H0731 susceptibility was diminished >68-fold, this patient still exhibited a 1-log decline in viral load by day 28.…”

Section: Discussionmentioning

confidence: 99%

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

Huang

Yan

et al. 2020

Antimicrob Agents Chemother

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ABI-H0731, a first-generation Hepatitis B Virus (HBV) core protein inhibitor, has demonstrated effective antiviral activity in chronic hepatitis B (CHB) patients in a Phase 1b clinical trial and is currently being further evaluated in Phase 2 clinical trials. Here, we report the preclinical profile of ABI-H0731. In in vitro cell culture systems (HepG2 derived cell lines: HepAD38 and HepG2-NTCP and Primary Human Hepatocyte (PHH)), ABI-H0731 exhibited selective inhibition of HBV DNA replication (EC50 from 173 nM to 307 nM). Most importantly, ABI-H0731 suppressed cccDNA formation in two de novo infection models with EC50s from 1.84 μM to 7.3 μM. Mechanism of action (MOA) studies indicated ABI-H0731 is a direct-acting antiviral that targets HBV core protein, preventing HBV pregenomic RNA (pgRNA) encapsidation and subsequent DNA replication. The combination of ABI-H0731 with entecavir (ETV) appears to decrease viral DNA faster and deeper than nucleoside/nucleotide analogues (NrtI) therapy alone. In addition, ABI-H0731 disrupts incoming nucleocapsids, causing premature release of rcDNA before delivery to the nucleus and thus prevents new cccDNA formation. ABI-H0731 exhibits pan-genotypic activity and is additive to moderately synergistic when combined with a NrtI. In addition to potency and novel mechanism of action, ABI-H0731 possess drug-like properties and a preclinical pharmacokinetic profile supportive of once daily dosing in patients with CHB. Taken together, these data support the ongoing clinical development of ABI-H0731 as a treatment for HBV.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Huang

Yan

et al. 2020

Antimicrob Agents Chemother

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“…One patient each carried a T109M (+I105L) and T109T/I baseline polymorphism. The T109M substitution was described to reduce ABI‐H0731 (CAM‐N) in vitro activity by 150‐fold and led to suboptimal response to ABI‐H0731 in a phase 1 study, 21 while the T109I substitution reduced GLS4 (CAM‐A) in vitro activity 6.8‐fold and was observed in GLS4‐treated patients with viral breakthrough in a phase 2a study 22 . In line with the lack of in vitro resistance of these substitutions for JNJ‐6379 (FC of 1.2, 0.5 and 0.1 for T109M, I105L and T109L, respectively), both patients showed pronounced declines in HBV DNA of 3.18 and 3.38 log 10 IU/mL (patients #5 and #7, Figure 2E and 2C and Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, polymorphisms observed at these positions did not reduce JNJ‐6379 in vitro activity (FC ≤ 3.0) and had no impact on JNJ‐6379‐induced HBV DNA decline in this study. Recent analysis of antiviral activity in two phase 1 studies evaluating short‐term monotherapy with two other CAM‐Ns showed reduced and nonresponses in patients harbouring T109M and I105T polymorphisms, respectively 20,21 . Furthermore, T109I variants were observed in patients with viral breakthrough receiving 24‐week treatment with GLS4 (CAM‐A) monotherapy 22 .…”

Section: Discussionmentioning

confidence: 99%

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

Verbinnen

Hodari

Talloen

et al. 2020

Journal of Viral Hepatitis

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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.

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HBV RNA Profiles in Patients With Chronic Hepatitis B Under Different Disease Phases and Antiviral Therapy

et al. 2021

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Background and Aims Large‐scale comprehensive studies on HBV RNA in chronic hepatitis B are lacking. We aimed to study the HBV RNA profile and its correlation with other viral markers in patients with chronic hepatitis B who are treatment‐naïve and patients receiving nucleos(t)ide analogues (NA). Approach and Results Biomarkers, including HBV RNA and hepatitis B core‐related antigen (HBcrAg), were measured in 388 patients. Of these, 246 were treatment‐naïve and were categorized into HBeAg‐positive chronic infection (n = 41), HBeAg‐positive chronic hepatitis (n = 81), HBeAg‐negative chronic infection (n = 39), HBeAg‐negative chronic hepatitis (n = 66), and HBsAg seroclearance (n = 19). These biomarkers were also measured in 142 patients who were NA‐treated receiving tenofovir or entecavir at baseline, week 48, and week 96. The pattern of serum HBV RNA levels mirrored HBV DNA (1‐2 logs higher than HBV RNA) and HBcrAg in patients who were treatment‐naïve. HBV RNA correlated best with HBcrAg (r = 0.84) and to a lesser extent with HBV DNA (r = 0.737) (both P < 0.001). In patients with HBsAg seroclearance, 15.8% and 15.8% had detectable serum HBV RNA and HBcrAg, respectively. NA treatment reduced serum HBV RNA by 1.46 logs and 1.77 logs at weeks 48 and 96, respectively. At week 96 of NA therapy, only 19.1% patients who were tenofovir‐treated and 25.7% patients who were entecavir‐treated had unquantifiable HBV RNA (P > 0.05). In patients who were treated and had undetectable HBV DNA, 77.5% and 30% had quantifiable HBV RNA and HBcrAg, respectively. Conclusions HBV RNA showed distinct and corresponding profiles in patients with HBV in different disease phases. HBV RNA and HBcrAg could be used to monitor residual transcriptional activities in patients with HBsAg seroclearance. NA led to reduction of serum HBV RNA. Monitoring of viral activities can still be achieved in patients with undetectable HBV DNA by serum HBV RNA.

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Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial

Cited by 87 publications

References 12 publications

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

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

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

HBV RNA Profiles in Patients With Chronic Hepatitis B Under Different Disease Phases and Antiviral Therapy

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