Discovery of RG7834: The First-in-Class Selective and Orally Available Small Molecule Hepatitis B Virus Expression Inhibitor with Novel Mechanism of Action

Han, Xingchun; Zhou, Chengang; Jiang, Min; Wang, Yongguang; Wang, Jianhua; Cheng, Z. H.; Wei, Min; Liu, Yongqiang; Liang, Chengzhen; Wang, Jianping; Wang, Zhanguo; Weikert, Robert J.; Lv, Wenzhe; Xie, Jianxun; Yu, Xin; Zhou, Xue; Luangsay, Souphalone; Shen, Hong C.; Mayweg, A.; Javanbakht, Hassan; Song, Yang

doi:10.1021/acs.jmedchem.8b01245

Cited by 54 publications

(47 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To investigate mechanisms of reducing HBsAg, we performed a genome-wide CRISPR screen resulting in the identification of several novel host factors required for HBsAg expression. Using this approach, we also interrogated the mechanism of a small molecule inhibitor of HBsAg expression (RG7834), which was recently shown to destabilize HBV transcripts through interactions with the non-canonical poly(A) RNA polymerases TENT4B (PAPD5) and TENT4A (PAPD7) (Han et al, 2018;Mueller et al, 2019;Mueller et al, 2018). Here we provide strong evidence that a newly implicated host factor, ZCCHC14, together with TENT4B and TENT4A, stabilizes HBsAg expression through HBV RNA tailing (nontemplated addition to the 3' terminus of the RNA).…”

Section: Introductionmentioning

confidence: 99%

“…For the HBV Rluc cell line, the Rluc reporter was inserted in HBV genotype B genome under internal S1/S2 promoters disrupting P polymerase. For the 4xSLα mutant, four mutations were introduced into the SLα region (ntd 1292-1321) of the HBV Rluc plasmid as previously described in.RG7834 and RO0321 were synthesized at Novartis based on the reported structures(Han et al, 2018;Mueller et al, 2019;Mueller et al, 2018). The EC50 value for RG7834 on intracellular HBsAg in Cas9 HepG2-HBV cell line was determined by a 16-point dose-response ranging from 0-10 µM.…”

mentioning

confidence: 99%

See 1 more Smart Citation

A genome-wide CRISPR screen identifies ZCCHC14 as a host factor required for hepatitis B surface antigen production

Hyrina

Jones

Chen

et al. 2019

Preprint

View full text Add to dashboard Cite

A hallmark of chronic hepatitis B virus (CHB) infection is the presence of high circulating levels of non-infectious small lipid HBV surface antigen (HBsAg) vesicles. Although rare, sustained HBsAg loss is the idealized endpoint of any CHB therapy. A novel small molecule RG7834 has been previously reported to inhibit HBsAg expression by targeting terminal nucleotidyltransferase protein 4A and 4B (TENT4A and TENT4B). In this study, we describe a genome-wide CRISPR screen to identify other potential novel host factors required for HBsAg expression and to gain further insights into the mechanism of RG7834. We report more than 60 genes involved in regulating HBsAg and identified novel factors involved in RG7834 activity, including a zinc finger CCHC-type containing 14 (ZCCHC14) protein. We show that ZCCHC14, together with TENT4A/B, stabilizes HBsAg expression through HBV RNA tailing, providing a potential new therapeutic target to achieve functional cure in CHB patients.

show abstract

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

A genome-wide CRISPR screen identifies ZCCHC14 as a host factor required for hepatitis B surface antigen production

Hyrina

Jones

Chen

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Specific blockage of the production of HBV DNA and viral antigens. 74,76,117 RG7834 (Roche) AB-452 (Arbutus) Core protein (Capsid) assembly modulators (CpAMs) NVR 3-778 (Novira, Janssen Pharmaceutica)…”

Section: Preclinicalmentioning

confidence: 99%

“…Recently, small molecules belonging to the dihydroquinolizinone series were shown to induce HBs mRNA degradation by targeting a post-transcriptional regulatory element, leading to a reduction of both viral antigens and viral DNA in vitro 74,75 and in a preclinical mouse model. 76 More data are needed to determine whether the decline in HBsAg production induced by these strategies can be sustained off treatment and if treatments that target HBsAg production alone might be sufficient to restore HBV-specific immunity, or if additional antiviral or immunomodulatory therapies are needed.…”

Section: Inhibition Of Gene Expressionmentioning

confidence: 99%

Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference‡

Cornberg

Lok

Terrault

et al. 2020

Journal of Hepatology

227

122

View full text Add to dashboard Cite

Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic HBV treatment endpoints to guide clinical trials aiming to 'cure' HBV. Agreement among the conference participants was reached on some key points. 'Functional' but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in > − 30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive or negative chronic hepatitis, who are treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV 'functional cure', the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.

show abstract

“…We recently reported a novel, orally available, small‐molecule HBV expression inhibitor, RG7834, that significantly reduces HBV DNA and HBsAg levels in both in vitro and in vivo models of chronic HBV infection. ( 13,14 ) Another group has also described a structurally similar molecule that reduces HBV expression levels. ( 15 ) RG7834 was shown to reduce viral messenger RNA and to accelerate RNA degradation by targeting the host proteins noncanonical poly(A) RNA polymerase‐associated domain‐containing protein 5 and 7 (PAPD5 and PAPD7).…”

mentioning

confidence: 99%

Efficacy of an Inhibitor of Hepatitis B Virus Expression in Combination With Entecavir and Interferon‐α in Woodchucks Chronically Infected With Woodchuck Hepatitis Virus

et al. 2020

Self Cite

View full text Add to dashboard Cite

RG7834 is a small-molecule inhibitor of hepatitis B virus (HBV) gene expression that significantly reduces the levels of hepatitis B surface antigen (HBsAg) and HBV DNA in a humanized liver HBV mouse model. In the current study, we evaluated the potency of RG7834 in the woodchuck model of chronic HBV infection, alone and in combination with entecavir (ETV) and/or woodchuck interferon-α (wIFN-α). RG7834 reduced woodchuck hepatitis virus (WHV) surface antigen (WHsAg) by a mean of 2.57 log 10 from baseline and WHV DNA by a mean of 1.71 log 10 . ETV + wIFN-α reduced WHsAg and WHV DNA by means of 2.40 log 10 and 6.70 log 10 , respectively. The combination of RG7834, ETV, and wIFN-α profoundly reduced WHsAg and WHV DNA levels by 5.00 log 10 and 7.46 log 10 , respectively. However, both viral parameters rebounded to baseline after treatment was stopped and no antibody response against WHsAg was observed. Effects on viral RNAs were mainly seen with the triple combination treatment, reducing both pregenomic RNA (pgRNA) and WHsAg RNA, whereas RG7834 mainly reduced WHsAg RNA and ETV mainly affected pgRNA. When WHsAg was reduced by the triple combination, peripheral blood mononuclear cells (PBMCs) proliferated significantly in response to viral antigens, but the cellular response was diminished after WHsAg returned to baseline levels during the off-treatment period. Consistent with this, Pearson correlation revealed a strong negative correlation between WHsAg levels and PBMC proliferation in response to peptides covering the entire WHsAg and WHV nucleocapsid antigen. Conclusion: A fast and robust reduction of WHsAg by combination therapy reduced WHV-specific immune dysfunction in the periphery. However, the magnitude and/or duration of the induced cellular response were not sufficient to achieve a sustained antiviral response. (Hepatology Communications 2020;4:916-931).

show abstract

Discovery of RG7834: The First-in-Class Selective and Orally Available Small Molecule Hepatitis B Virus Expression Inhibitor with Novel Mechanism of Action

Cited by 54 publications

References 17 publications

A genome-wide CRISPR screen identifies ZCCHC14 as a host factor required for hepatitis B surface antigen production

A genome-wide CRISPR screen identifies ZCCHC14 as a host factor required for hepatitis B surface antigen production

Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference‡

Efficacy of an Inhibitor of Hepatitis B Virus Expression in Combination With Entecavir and Interferon‐α in Woodchucks Chronically Infected With Woodchuck Hepatitis Virus

Contact Info

Product

Resources

About