vebicorvir (ABI-H0731) / Assembly Biosci, BeOne Medicines - LARVOL DELTA

A multiscale model of the action of a capsid assembly modulator for the treatment of chronic hepatitis B. (PubMed, PLoS Comput Biol) - "By fitting the model to participant data from a phase I trial of the first-generation CAM vebicorvir, we estimate the drug's dose-dependent effectiveness and identify the physiological mechanisms that drive the observed biphasic decline in HBV DNA and RNA, and mechanistic differences between HBeAg-positive and negative infection. Finally, we demonstrate analytically and numerically that the relative change of HBV RNA more accurately reflects the antiviral effectiveness of a CAM than the relative change in HBV DNA."

Journal • Fibrosis • Hepatitis B • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cancer • Oncology • Solid Tumor

Sustained off-treatment inhibition of HBV replication and HBsAg levels after long-term treatment with ABI-4334 in differentiated HepaRG cells and primary human hepatocytes (EASL 2025) - " Differentiated (d)HepaRG cells were treated from day 6 post-infection (pi) with 0.1 or 1 µM ABI-4334, 1 µM vebicorvir (VBR) or 1 µM lamivudine (3TC) for 1 month, followed by 1 month off- treatment monitoring... Durable HBsAg decreases and a lack of HBV rebound was observed after stopping long- term ABI-4334 treatment in both HepaRG cells and PHH, which could be ascribed to the depletion and/or functional inactivation of intracellular cccDNA pool in these experimental conditions."

Hepatitis B

A multiscale model of the action of a capsid assembly modulator for the treatment of chronic hepatitis B. (PubMed, bioRxiv) - "By fitting the model to participant data from a phase I trial of the first-generation CAM vebicorvir, we estimate the drug's dose-dependent effectiveness and identify the physiological mechanisms that drive the observed biphasic decline in HBV DNA and RNA, and mechanistic differences between HBeAg-positive and negative infection...We developed a multiscale model of the intracellular HBV lifecycle and extracellular dynamics using a time-since-infection structured partial differential equation. We fit the model to participant data from a recent phase I trial, performed a detailed parameter sensitivity analysis, identified key mechanisms driving viral response to first-generation CAM treatment, and demonstrated that HBV RNA is more sensitive than HBV DNA to changes in CAM efficacy, highlighting the potential role of HBV RNA as a biomarker for CAM effectiveness."

Journal • Fibrosis • Gastrointestinal Cancer • Hepatitis B • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cancer • Oncology • Solid Tumor

Long-term open-label vebicorvir for chronic HBV infection: Safety and off-treatment responses. (PubMed, JHEP Rep) - P2, P2a | "The results reported here will help researchers with the design and interpretation of future studies investigating core inhibitors as possible components of finite treatment regimens for patients with cHBV. It is possible that next-generation core inhibitors with enhanced potency may produce deeper and more durable antiviral activity than first-generation agents, including vebicorvir."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A Study Evaluating Treatment Regimens Containing Vebicorvir (ABI-H0731) in Participants With Chronic Hepatitis B Infection (clinicaltrials.gov) - P2 | N=65 | Terminated | Sponsor: Assembly Biosciences | Phase classification: P2a ➔ P2

Phase classification • Hepatitis B • Hepatology • Infectious Disease • Inflammation

PRELIMINARY OFF-TREATMENT RESPONSES FOLLOWING 48 WEEKS OF VEBICORVIR, NUCLEOS(T)IDE REVERSE TRANSCRIPTASE INHIBITOR, AND AB-729 COMBINATION IN VIROLOGICALLY SUPPRESSED PATIENTS WITH HEPATITIS B E ANTIGEN NEGATIVE CHRONIC HEPATITIS B: ANALYSIS FROM AN OPEN-LABEL PHASE 2 STUDY (AASLD 2023) - P2a | "Treatments were well tolerated. Available data indicate that adding VBR to AB-729+NrtI does not result in significantly greater on- or post-treatment improvements in markers of active HBV infection vs AB-729+NrtI."

Clinical • P2 data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

A Study Evaluating ABI-H0731-containing Regimens in Chinese Participants With Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2a | N=54 | Terminated | Sponsor: Assembly Biosciences | Completed ➔ Terminated; Study ABI-H0731-203 was terminated early by the study Sponsor for strategic reasons to prioritize research and development efforts on finite and curative HBV therapies.

Trial termination • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Vebicorvir, entecavir, and pegylated interferon in patients with hepatitis B e antigen positive chronic hepatitis B virus infection: findings from a phase 2, randomized open-label study in China (EASL-ILC 2023) - P2a | "Overall, the addition of IFN to VBR + ETV did not result in significantly greater declines in HBV parameters compared to the dual agent control arms and is unlikely to result in significant rates of functional cure following 24 wks of treatment."

Clinical • P2 data • Fibrosis • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Next generation core inhibitors ABI-H3733 and ABI-4334 have significantly improved potency and target coverage for both antiviral and cccDNA formation activities compared to first-generation core inhibitors (EASL-ILC 2023) - "Assembly Bio has two next generation CI candidates in Phase 1 clinical studies: ABI-H3733 (3733) and ABI-4334 (4334), which have improved potency against both MOAs compared to first-generation CIs including vebicorvir (VBR). Next generation CIs 3733 and 4334 have significantly improved coverage for both antiviral and cccDNA formation activities compared to first generation CIs. 3733 and 4334 are currently completing Phase 1b and Phase 1a studies, respectively."

A Study Evaluating Treatment Regimens Containing Vebicorvir (ABI-H0731) in Participants With Chronic Hepatitis B Infection (clinicaltrials.gov) - P2a | N=65 | Terminated | Sponsor: Assembly Biosciences | Trial completion date: Jan 2024 ➔ Mar 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jan 2024 ➔ Feb 2023; Sponsor decision

Trial completion date • Trial primary completion date • Trial termination • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A Study Evaluating ABI-H0731-containing Regimens in Chinese Participants With Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2a | N=54 | Completed | Sponsor: Assembly Biosciences | Active, not recruiting ➔ Completed | Trial completion date: Jun 2023 ➔ Dec 2022 | Trial primary completion date: Apr 2023 ➔ Dec 2022

Trial completion • Trial completion date • Trial primary completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation

EVALUATION OF THE VEBICORVIR, NRTI AND AB-729 COMBINATION IN VIROLOGICALLY SUPPRESSED PATIENTS WITH HBEAG NEGATIVE CHRONIC HEPATITIS B VIRUS INFECTION: INTERIM ANALYSIS FROM AN OPEN LABEL PHASE 2 STUDY (AASLD 2022) - P2a | "All regimens were safe and well tolerated. Interim data indicate that adding VBR to AB-729+NrtI does not result in greater on-treatment improvements in markers of active HBV infection as compared to AB-729+NrtI."

Clinical • Late-breaking abstract • P2 data • Hematological Disorders • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Novel Coronavirus Disease

Greater sequence diversity during early hepatitis B virus decline on vebicorvir plus entecavir is associated with a lower level of virus rebound following switch to entecavir monotherapy (EASL-ILC 2022) - P2, P2a | "Greater sequence diversity was observed during initial HBV DNA decline during HBV treatment among patients with lower rebound when VBR was DCed and ETV continued. The early differences in sequence diversity may reflect differences in HBV specific immune responses (also reflected in ALT levels) and viral load set points between these 2 groups, although the mechanism needs to be further defined."

Monotherapy • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Evaluation of the drug-drug interaction profile of vebicorvir, a first-generation hepatitis B core inhibitor: findings from phase 1 and phase 2a studies (EASL-ILC 2022) - P2a | "Parts 2 (N = 18) and 3 (N = 20) evaluated CYP3A4 and 2B6 inhibition/induction, respectively, using midazolam and bupropion...In Study 103 (Part 1), co-administration of VBR did not change the exposure of omeprazole, dextromethorphan, or repaglinide, suggesting VBR is not an inhibitor of CYPs 2C19, 2D6, or 2C8... The results in Phase 2a studies suggest no clinically significant DDI between VBR and NrtIs. Based on the Phase 1 study, VBR is aweak inhibitor of CYP2C9, but is not an inhibitor of CYP2C19, 2D6, or 2C8, and is not an inhibitor/inducer of CYP3A4 or 2B6. Overall, VBR shows a favorable DDI profile for use in combination treatments including NrtIs and other concomitant medications."

P1 data • P2a data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • CYP2C19 • CYP2C9 • CYP3A4

Deeper virologic suppression with the addition of vebicorvir, a first-generation hepatitis B core inhibitor, to entecavir correlates with reduced inflammation and fibrosis-4 index in treatment naïve patients with HBeAg positive chronic hepatitis B (EASL-ILC 2022) - P2a | "The addition of VBR to NrtI therapy provides deeper suppression of HBV DNA and pgRNA and more rapid normalization of ALT and AST than NrtI alone over 24 weeks of treatment. The deeper Figure: (abstract: SAT366) level of viral suppression and reduced inflammation is reflected in greater reductions in FIB-4 for VBR+ETV compared to ETV alone. In post hoc analyses, reductions in pgRNA, a marker for cccDNA replicative activity, and HBcrAg are associated with improvement in FIB-4 over 24 weeks of treatment."

Clinical • Fibrosis • Hepatitis B • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Inflammation

Evaluation of the disposition and mass balance recovery of vebicorvir, a first generation hepatitis B core inhibitor, in rats and humans (EASL-ILC 2022) - P1 | "Fecal excretion of unchanged drug is the primary route of VBR elimination in both rats and humans. VBR is the predominant component in the systemic circulation with low overall circulating metabolite-related radioactivity. VBR showed high liver loading in the rat indicating favourable distribution to the target organ for treatment of chronic HBV infection."

Preclinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection. (PubMed, J Hepatol) - P2a | "In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV with a favourable safety and tolerability profile."

Journal • Fibrosis • Hepatitis B • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Failure

A Study of Safety and Efficacy of ATI-2173 and Vebicorvir in Combination With Tenofovir Disoproxil Fumarate in Subjects With Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2a | N=2 | Terminated | Sponsor: Antios Therapeutics, Inc | N=10 ➔ 2 | Trial completion date: Feb 2023 ➔ May 2022 | Recruiting ➔ Terminated | Trial primary completion date: Feb 2023 ➔ May 2022; Sponsor stopped due to partner collaboration ending

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A Study of Safety and Efficacy of ATI-2173 and Vebicorvir in Combination With Tenofovir Disoproxil Fumarate in Subjects With Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2a | N=10 | Recruiting | Sponsor: Antios Therapeutics, Inc | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Efficacy and safety of vebicorvir administered in virologically-suppressed patients with chronic hepatitis B virus infection. (PubMed, J Hepatol) - P2a | "In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was evident by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone."

Journal • Dermatology • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Pruritus • Respiratory Diseases

A Study Evaluating Treatment Regimens Containing Vebicorvir (ABI-H0731) in Participants With Chronic Hepatitis B Infection (clinicaltrials.gov) - P2a | N=60 | Active, not recruiting | Sponsor: Assembly Biosciences | Recruiting ➔ Active, not recruiting | Trial completion date: Jul 2023 ➔ Jan 2024 | Trial primary completion date: Jul 2023 ➔ Jan 2024

Enrollment closed • Trial completion date • Trial primary completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A Study Evaluating ABI-H0731-containing Regimens in Chinese Participants With Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2a | N=60 | Active, not recruiting | Sponsor: Assembly Biosciences | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IFNA1

A Study of Safety and Efficacy of ATI-2173 and Vebicorvir in Combination With Tenofovir Disoproxil Fumarate in Subjects With Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2a | N=10 | Not yet recruiting | Sponsor: Antios Therapeutics, Inc

Combination therapy • New P2a trial • Hepatitis B • Hepatology • Infectious Disease • Inflammation

An automated microfluidic platform for the screening and characterization of novel hepatitis B virus capsid assembly modulators. (PubMed, Anal Methods) - "CAM-A compounds like BAY 41-4109 and GLS4 showed rapid kinetics, with assembly rates above 80% of the core protein after only a 7 second exposure to the compound, whereas CAM-N compounds like ABI-H0731 and JNJ-56136379 showed significantly slower kinetics. With this proof-of-concept study, we believe that this microfluidic system is a robust primary screening tool for HBV CAM drug discovery, especially for the hit finding and hit-to-lead optimization phases. In addition to EC values, this system gives valuable first information about the mode of action of novel CAM screening compounds."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Arbutus Reports Third Quarter 2021 Financial Results and Provides Corporate Update (Yahoo Finance) - "Enrollment is on-going in the Phase 2 proof-of-concept triple combination clinical trial evaluating AB-729, vebicorvir ('VBR'), Assembly’s lead HBV core inhibitor (capsid inhibitor), and an NA. Assembly is conducting this clinical trial and expecting initial data in 2022."

Enrollment status • P2 data • Hepatitis B • Infectious Disease