TLR7 agonist RO7020531 versus placebo in healthy volunteers and patients with chronic hepatitis B virus infection: a randomised, observer-blind, placebo-controlled, phase 1 trial

Yuen, Man‐Fung; Balabanska, R.; Cottreel, Emmanuelle; Chen, Ethan; Duan, Dan; Jiang, Qiudi; Patil, Avinash; Triyatni, Miriam; Upmanyu, Ruchi; Zhu, Yibing; Canducci, Filippo; Gane, Edward

doi:10.1016/s1473-3099(22)00727-7

Cited by 10 publications

(6 citation statements)

References 28 publications

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“…Furthermore, results of this study were obtained in healthy individuals, and whether similar responses will be observed in CHB patients remains to be determined. Of note, other oral TLR7 agonists such as vesatolimod 61 and RO7020531 43 demonstrate comparable ISG responses between healthy volunteers and CHB patients. At the doses tested, ISG activation without cytokine (e.g., IFN-α) induction was observed in CHB patients.…”

Section: Discussionmentioning

confidence: 93%

“…39 Several immunotherapies have been tested in humans, including TLR7 agonists, [40][41][42] and have been shown to induce type I IFN response (measured by induction of ISG15, MX1, OAS1, as well as MHC class I and TRIM genes families, inducing activation of HBV-specific T cells and NK cells in pre-clinical models. 11,43,44 Immune cell phenotyping revealed induction of molecules associated with immune cell activation in cell types that may be activated by JNJ-4964 directly (e.g., CD86 on B cells) or indirectly (e.g., CD69 and CD134 on NK cells; in particular, CD56 dim NK cells). These changes correlated well with C max and with fold changes of ISG15, CXCL10, and IFN-α.…”

Section: Discussionmentioning

confidence: 99%

“…39 Several immunotherapies have been tested in humans, including TLR7 agonists, 40–42 and have been shown to induce type I IFN response (measured by induction of ISG15 , MX1 , OAS1 , as well as MHC class I and TRIM genes families, inducing activation of HBV-specific T cells and NK cells in pre-clinical models. 11,43,44…”

Section: Discussionmentioning

confidence: 99%

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A single, oral dose of the TLR7 agonist JNJ-64794964 induces transcriptomic and phenotypic changes in peripheral immune cells in healthy adults

et al. 2023

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Background Chronic hepatitis B (CHB) is responsible for major disease burden worldwide. However, the number of available therapies is limited; cure remains an elusive goal. JNJ-64794964 (JNJ-4964) is an oral toll-like receptor-7 (TLR7) agonist being evaluated for the treatment of CHB. Here, we investigated the capacity of JNJ-4964 to induce transcriptomic and immune cell changes in peripheral blood in healthy volunteers. Methods Peripheral blood was collected in the JNJ-4964 first-in-human phase 1 trial at multiple time points to assess transcriptomics and changes in frequency and phenotype of peripheral-blood mononuclear cells. Correlation of changes to JNJ-4964 exposure (Cmax) and changes in cytokine levels (C-X-C motif chemokine ligand 10 [CXCL10] and interferon alpha [IFN-α]) were evaluated. Results Fifty-nine genes, mainly interferon-stimulated genes, were up-regulated between 6 hours and 5 days after JNJ-4964 administration. JNJ-4964 increased frequencies of CD69, CD134, CD137, and/or CD253-expressing natural killer (NK) cells, indicative of NK cell activation. These changes correlated with Cmax, increase of CXCL10, and induction of IFN-α and were observed at IFN-α levels that are associated with no/acceptable flu-like adverse events. JNJ-4964 administration resulted in increased frequencies of CD86-expressing B cells, indicative of B-cell activation. These changes were predominantly observed at high IFN-α levels, which are associated with flu-like adverse events. Conclusions JNJ-4964 administration led to changes in transcriptional profiles and immune cell activation phenotype, particularly for NK cells and B cells. Together, these changes could represent a set of biomarkers for the characterization of the immune response in CHB patients receiving TLR7 agonists.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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A single, oral dose of the TLR7 agonist JNJ-64794964 induces transcriptomic and phenotypic changes in peripheral immune cells in healthy adults

et al. 2023

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“…Similarly, a phase 1 clinical trial of TLR7 agonist RG7854 demonstrated that treatment with this agonist increased the expression of various genes, including IFN-γ, ISG15, and IP10, in previously untreated and previously treated NA patients. Nevertheless, the reduction in HBsAg was modest, with an average decrease of 0.14 log 10 IU/mL (170 mg dose group) and a maximum decrease of 0.4 log 10 IU/mL in NA-treated patients ( Yuen et al., 2023a ).…”

Section: Strategies To Accelerate Cccdna Decaymentioning

confidence: 94%

Classifying hepatitis B therapies with insights from covalently closed circular DNA dynamics

Hu,

Huang

2024

Virologica Sinica

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“…RO7020531, an agonist for toll-like receptor7 (TLR7), has been trialed across a dosage spectrum of 3–170 mg. The safety profile of RO7020531 is favorable, indicating that it is well-tolerated in HBV patients [ 77 ]. The activation of toll-like receptor 8 (TLR8) contributes to the functional cure of HBV infection.…”

Section: Hbv Therapymentioning

confidence: 99%

Hepatitis B: Model Systems and Therapeutic Approaches

Yu,

Gao,

Zhang

et al. 2024

Journal of Immunology Research

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Hepatitis B virus (HBV) infection is a major global health issue and ranks among the top causes of liver cirrhosis and hepatocellular carcinoma. Although current antiviral medications, including nucleot(s)ide analogs and interferons, could inhibit the replication of HBV and alleviate the disease, HBV cannot be fully eradicated. The development of cellular and animal models for HBV infection plays an important role in exploring effective anti-HBV medicine. During the past decades, advancements in several cell culture systems, such as HepG2.2.15, HepAD38, HepaRG, hepatocyte-like cells, and primary human hepatocytes, have propelled the research in inhibiting HBV replication and expression and thus enriched our comprehension of the viral life cycle and enhancing antiviral drug evaluation efficacy. Mouse models, in particular, have emerged as the most extensively studied HBV animal models. Additionally, the present landscape of HBV therapeutics research now encompasses a comprehensive assessment of the virus’s life cycle, targeting numerous facets and employing a variety of immunomodulatory approaches, including entry inhibitors, strategies aimed at cccDNA, RNA interference technologies, toll-like receptor agonists, and, notably, traditional Chinese medicine (TCM). This review describes the attributes and limitations of existing HBV model systems and surveys novel advancements in HBV treatment modalities, which will offer deeper insights toward discovering potentially efficacious pharmaceutical interventions.

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TLR7 agonist RO7020531 versus placebo in healthy volunteers and patients with chronic hepatitis B virus infection: a randomised, observer-blind, placebo-controlled, phase 1 trial

Cited by 10 publications

References 28 publications

A single, oral dose of the TLR7 agonist JNJ-64794964 induces transcriptomic and phenotypic changes in peripheral immune cells in healthy adults

A single, oral dose of the TLR7 agonist JNJ-64794964 induces transcriptomic and phenotypic changes in peripheral immune cells in healthy adults

Classifying hepatitis B therapies with insights from covalently closed circular DNA dynamics

Hepatitis B: Model Systems and Therapeutic Approaches

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