Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B

Janssen, Harry L.A.; Brunetto, Maurizia Rossana; Kim, Yoon Jun; Ferrari, Carlo; Massetto, Benedetta; Nguyen, Anh H.; Joshi, Adarsh; Woo, Jacky; Lau, Audrey H.; Gaggar, Anuj; Subramanian, G. Mani; Yoshida, Eric M.; Ahn, Sang Hoon; Tsai, Naoky; Fung, Scott; Gane, Edward

doi:10.1016/j.jhep.2017.10.027

Cited by 160 publications

(150 citation statements)

References 34 publications

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“…Disappointingly in humans, oral TLR7 ligands thus far have not achieved any beneficial effect, despite that treatment was well tolerated (Gane et al, 2015;Janssen et al, 2017). It is not clear why clinical benefit in CHB patients was lacking, but impaired patient TLR7 responses could have contributed.…”

Section: Discussionmentioning

confidence: 99%

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

et al. 2018

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A B S T R A C TTLR7 agonists are of high interest for the treatment of cancer, auto-immunity and chronic viral infections. They are known to activate plasmacytoid dendritic cells (pDCs) to produce high amounts of Type I Interferon (IFN) and to facilitate T and B cell responses, the latter with the help of maturation markers such as CD40, CD80 and CD86. The TLR7 single nucleotide polymorphism (SNP) rs179008 (GLn11Leu), sex and chronic viral infection have all been reported to influence pDC IFN production. It is unknown, however, whether these factors also influence pDC phenotypic maturation and thereby IFN-independent pDC functions. Furthermore, it is unclear whether SNP rs179008 influences HBV susceptibility and/or clearance.Here we investigated whether the SNP rs179008, sex and HBV infection affected phenotypic maturation of pDCs from 38 healthy individuals and 28 chronic HBV patients. In addition, we assessed SNP prevalence in a large cohort of healthy individuals (n = 231) and chronic HBV patients (n = 1054).Consistent with previous reports, the rs179008 variant allele was largely absent in Asians and more prevalent in Caucasians. Among Caucasians, the SNP was equally prevalent in healthy and chronically infected males. The SNP was, however, significantly more prevalent in healthy females than in those with chronic HBV infection (42 versus 28%), suggesting that in females it may offer protection from chronic infection. Ex vivo experiments demonstrated that induction of the co-stimulatory molecules CD40 and CD86 by TLR7 ligands, but not TLR9 ligands, was augmented in pDCs from healthy SNP-carrying females. Furthermore, CD80 and CD86 upregulation was more pronounced in females independent of the SNP. Lastly, our data suggested that chronic HBV infection impairs pDC maturation. These findings provide insight into factors determining TLR7 responses, which is important for further clinical development of TLR7-based therapies.

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Section: Discussionmentioning

confidence: 99%

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

et al. 2018

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“…GS‐9620, an oral agonist of toll‐like receptor 7, induced a decline in serum HBV DNA and HBsAg levels as well as hepatic HBV DNA in HBV‐infected chimpanzees . Similar effects were also observed in woodchucks but not in humans . The discrepancies between results in animal models and humans highlight the importance of testing new therapies in humans at an early stage in drug development.…”

Section: Immune Response To Hbv and Implications For Immune Modulatormentioning

confidence: 90%

Hepatitis B cure: From discovery to regulatory approval

et al. 2017

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The majority of persons currently treated for chronic hepatitis B require long-term or lifelong therapy. New inhibitors of hepatitis B virus entry, replication, assembly or secretion, and immune-modulatory therapies are in development. The introduction of these novel compounds for chronic hepatitis B necessitates a standardized appraisal of the efficacy and safety of these treatments, and definitions of new or additional endpoints to inform clinical trials. To move the field forward, and to expedite the pathway from discovery to regulatory approval, a workshop with key stake holders was held in September 2016 to develop a consensus on treatment endpoints to guide the design of clinical trials aimed at hepatitis B cure. The consensus reached was that a complete sterilizing cure i.e. viral eradication from the host is unlikely to be feasible. Instead, a functional cure characterized by sustained loss of HBsAg with or without anti-HBs seroconversion, which is associated with improved clinical outcomes, in a higher proportion of patients than is currently achieved with existing treatments is a feasible goal. Development of standardized assays for novel biomarkers towards better defining HBV cure should occur in parallel with development of novel antiviral and immune modulatory therapies such that approval of new treatments can be linked to the approval of new diagnostic assays used to measure efficacy or to predict response. Combination of antiviral and immune modulatory therapies will likely be needed to achieve functional HBV cure. Limited proof-of-concept monotherapy studies to evaluate safety and antiviral activity should be conducted prior to proceeding to combination therapies. The safety of any new curative therapies will be paramount given the excellent safety of currently approved nucleos(t)ide analogues.

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“…Vesatolimod targets liver and/or gut‐associated TLR7‐expressing plasmacytoid dendritic cells (DC) for on‐target, pre‐systemic induction of local IFNα expression with minimal systemic exposure and induces activation of the TLR7 pathway, enhancing HBV‐specific cytotoxic T‐cell activation . In a previous Phase 2 study in virally suppressed chronic HBV patients administered 1‐, 2‐ or 4‐mg vesatolimod doses for different treatment durations up to 12 weeks, no change in HBsAg decline was observed . In this companion Phase 2, double‐blind, randomized, placebo (PBO)‐controlled study, the safety and efficacy of vesatolimod was assessed in viremic CHB patients not on oral antiviral therapy.…”

Section: Introductionmentioning

confidence: 88%

Safety and efficacy of vesatolimod (GS‐9620) in patients with chronic hepatitis B who are not currently on antiviral treatment

Agarwal

Ahn

Elkhashab

et al. 2018

Journal of Viral Hepatitis

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Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline.

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Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B

Cited by 160 publications

References 34 publications

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

Hepatitis B cure: From discovery to regulatory approval

Safety and efficacy of vesatolimod (GS‐9620) in patients with chronic hepatitis B who are not currently on antiviral treatment

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