Safety, pharmacokinetics, and antiviral activity of RO7049389, a core protein allosteric modulator, in patients with chronic hepatitis B virus infection: a multicentre, randomised, placebo-controlled, phase 1 trial

Yuen, Man‐Fung; Zhou, Xue; Gane, Edward; Schwabe, Christian; Tanwandee, Tawesak; Feng, Sheng; Jin, Yuyan; Triyatni, Miriam; Lemenuel‐Diot, Annabelle; Cosson, Valérie; Zou, Xue; Kazma, Rémi; Bo, Qingyan

doi:10.1016/s2468-1253(21)00176-x

Cited by 47 publications

(39 citation statements)

References 21 publications

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“…However, no significant changes in HBsAg were registered whereas viral rebound was observed after the end of treatment. In this study, only mild or moderate adverse events were observed with the most frequent events being ALT and AST increase in chronic HBV patients but not in healthy volunteers [ 72 ].…”

Section: Cam Molecules In Preclinical and Clinical Developmentmentioning

confidence: 99%

“…Interestingly, RO7049389 treatments causes a strong HBV DNA decrease as well as HBsAg and HBeAg loss in murine AAV-HBV-based models [ 71 ]. Recently, in a double-blind phase 1 study, RO7049389 was tested in chronic HBV patients and demonstrated potent antiviral activity with a maximum HBV DNA and RNA reduction (3.33 log 10 IU/mL and 2.77 log 10 IU/mL, respectively) in patients following the oral administration of 400 mg of the drug twice a day [ 72 ]. However, no significant changes in HBsAg were registered whereas viral rebound was observed after the end of treatment.…”

Section: Cam Molecules In Preclinical and Clinical Developmentmentioning

confidence: 99%

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Capsid Assembly Modulators as Antiviral Agents against HBV: Molecular Mechanisms and Clinical Perspectives

Taverniti

Ligat

Debing³

et al. 2022

JCM

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Despite a preventive vaccine being available, more than 250 million people suffer from chronic hepatitis B virus (HBV) infection, a major cause of liver disease and HCC. HBV infects human hepatocytes where it establishes its genome, the cccDNA with chromosomal features. Therapies controlling HBV replication exist; however, they are not sufficient to eradicate HBV cccDNA, the main cause for HBV persistence in patients. Core protein is the building block of HBV nucleocapsid. This viral protein modulates almost every step of the HBV life cycle; hence, it represents an attractive target for the development of new antiviral therapies. Capsid assembly modulators (CAM) bind to core dimers and perturb the proper nucleocapsid assembly. The potent antiviral activity of CAM has been demonstrated in cell-based and in vivo models. Moreover, several CAMs have entered clinical development. The aim of this review is to summarize the mechanism of action (MoA) and the advancements in the clinical development of CAMs and in the characterization of their mod of action.

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Section: Cam Molecules In Preclinical and Clinical Developmentmentioning

confidence: 99%

Section: Cam Molecules In Preclinical and Clinical Developmentmentioning

confidence: 99%

Capsid Assembly Modulators as Antiviral Agents against HBV: Molecular Mechanisms and Clinical Perspectives

Taverniti

Ligat

Debing³

et al. 2022

JCM

View full text Add to dashboard Cite

show abstract

“…In a humanized mouse model, oral administration of RO7049389 reduced serum HBV DNA significantly, as well as HBsAg and HBeAg levels [115]. Notably, treatment of CHB patients with 200 or 400 mg RO7049389 twice a day for four weeks reduced mean HBV DNA levels by 2.44 and 3.33 log IU/mL, respectively, in a phase I clinical study (NCT02952924) [116]. A phase 2 trial evaluating the antiviral efficacy and safety of this compound in multiple combinations with NUCs, siRNA (RO7445482), a TLR7 modulator (RO7020531) or pegylated IFN is underway (NCT04225715).…”

Section: Ro7049389mentioning

confidence: 99%

Current Progress in the Development of Hepatitis B Virus Capsid Assembly Modulators: Chemical Structure, Mode-of-Action and Efficacy

Kim

Lee

et al. 2021

Molecules

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Hepatitis B virus (HBV) is a major causative agent of human hepatitis. Its viral genome comprises partially double-stranded DNA, which is complexed with viral polymerase within an icosahedral capsid consisting of a dimeric core protein. Here, we describe the effects of capsid assembly modulators (CAMs) on the geometric or kinetic disruption of capsid construction and the virus life cycle. We highlight classical, early-generation CAMs such as heteroaryldihydropyrimidines, phenylpropenamides or sulfamoylbenzamides, and focus on the chemical structure and antiviral efficacy of recently identified non-classical CAMs, which consist of carboxamides, aryl ureas, bithiazoles, hydrazones, benzylpyridazinones, pyrimidines, quinolines, dyes, and antimicrobial compounds. We summarize the therapeutic efficacy of four representative classical compounds with data from clinical phase 1 studies in chronic HBV patients. Most of these compounds are in phase 2 trials, either as monotherapy or in combination with approved nucleos(t)ides drugs or other immunostimulatory molecules. As followers of the early CAMs, the therapeutic efficacy of several non-classical CAMs has been evaluated in humanized mouse models of HBV infection. It is expected that these next-generation HBV CAMs will be promising candidates for a series of extended human clinical trials.

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“…RO7049389 is a small oral molecule recently evaluated in a multi-centre, randomised placebo-controlled phase I study. Treatment with RO7049389 led to a 2.7–3.2 and 2.1–2.5 log 10 decline in median HBV DNA and HBV RNA, respectively [ 59–61 ]. There was, however, no change in HBsAg levels and viral rebound to pre-treatment level was observed post-treatment.…”

Section: Novel Direct-acting-antivirals (Daas)mentioning

confidence: 99%

Novel therapeutic strategies for chronic hepatitis B

2022

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The last few years have seen a resurgence of activity in the hepatitis B drug pipeline, with many compounds in various stages of development. This review aims to provide a comprehensive overview of the latest advances in therapeutics for chronic hepatitis B (CHB). We will discuss the broad spectrum of direct-acting antivirals in clinical development, including capsids inhibitors, siRNA, HBsAg and polymerase inhibitors. In addition, host-targeted therapies (HTT) will be extensively reviewed, focusing on the latest progress in immunotherapeutics such as toll-like receptors and RIG-1 agonists, therapeutic vaccines and immune checkpoints modulators. A growing number of HTT in pre-clinical development directly target the key to HBV persistence, namely the covalently closed circular DNA (cccDNA) and hold great promise for HBV cure. This exciting area of HBV research will be highlighted, and molecules such as cyclophilins inhibitors, APOBEC3 deaminases and epigenetic modifiers will be discussed.

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Safety, pharmacokinetics, and antiviral activity of RO7049389, a core protein allosteric modulator, in patients with chronic hepatitis B virus infection: a multicentre, randomised, placebo-controlled, phase 1 trial

Cited by 47 publications

References 21 publications

Capsid Assembly Modulators as Antiviral Agents against HBV: Molecular Mechanisms and Clinical Perspectives

Capsid Assembly Modulators as Antiviral Agents against HBV: Molecular Mechanisms and Clinical Perspectives

Current Progress in the Development of Hepatitis B Virus Capsid Assembly Modulators: Chemical Structure, Mode-of-Action and Efficacy

Novel therapeutic strategies for chronic hepatitis B

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