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Safety and efficacy of the oral TLR8 agonist selgantolimod in individuals with chronic hepatitis B under viral suppression

Published:October 28, 2022DOI:https://doi.org/10.1016/j.jhep.2022.09.027

      Highlights

      • Currently there is no finite cure for chronic hepatitis B virus (HBV) infection.
      • Combination therapy with immune modulators and other HBV-specific agents are being explored.
      • The immune modulator selgantolimod is an oral agonist of toll-like receptor 8 (TLR8).
      • Selgantolimod once-weekly was given to chronic HBV patients for 6 months.
      • Six months after treatment, a minority had serologic changes seen with durable cure.

      Abstract

      Background & Aims

      Selgantolimod (GS-9688) is a toll-like receptor 8 (TLR8) agonist that suppresses hepatitis B virus (HBV) in vitro. In a Phase 2 study, we evaluated safety and efficacy of weekly selgantolimod treatment in virally suppressed chronic HBV patients taking oral antiviral treatment.

      Methods

      Forty-eight patients were randomized in 2 cohorts (hepatitis B e antigen [HBeAg]-positive and -negative [n=24 each]) to receive oral selgantolimod 3 mg, 1.5 mg, or placebo (2:2:1) once weekly for 24 weeks while maintaining oral antivirals. Primary efficacy endpoint was percentage of patients with ≥1 log10 IU/mL decline in hepatitis B surface antigen (HBsAg) from baseline to week 24. Post-treatment, patients continued oral antivirals for 24 weeks.

      Results

      The primary endpoint was reached by one participant, who was HBeAg-negative and received selgantolimod 1.5 mg. In contrast with placebo-treated patients (n=9), only selgantolimod-treated patients (n=39 total) had HBsAg declines greater than 0.1 log10 IU/mL at weeks 24 (18%, 7/39) and 48 (26%, 10/39), HBsAg loss (5%, 2/39 through 48 weeks), or HBeAg loss (16%, 3/19 through 48 weeks). The most common adverse events in selgantolimod-treated groups were nausea (46%), upper respiratory tract infection (23%), and vomiting (23%). Gastrointestinal disorders were mostly mild and transient. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40, IFN-γ, and IL-1RA, as well as rapid redistribution of some circulating immune cell subsets.

      Conclusion

      Oral selgantolimod up to 3 mg once weekly for 24 weeks was generally safe and well tolerated and led to serologic changes associated with progression to durable cure in 2 individuals by week 48.

      Lay Summary

      Currently there are no cures for hepatitis B. The investigational drug selgantolimod is an immune stimulator that may have success with other agents to cure hepatitis B. Selgantolimod in combination with currently marketed antiviral treatment was followed by an immune response in a minority of persons with hepatitis B.

      ClinicalTrials.gov Identifier

      NCT03491553.

      Graphical abstract

      Keywords

      Abbreviations:

      AASLD (American Association for the Study of Liver Diseases), CCL (chemokine (C-C motif) ligand), CD (cluster of differentiation), CI (confidence interval), CV (coefficient of variation), FDR (false discovery rate), HBeAg (hepatitis B e antigen), HBsAg (hepatitis B virus surface antigen), HBV (hepatitis B virus), IFN (interferon), IL (interleukin), IL-1RA (interleukin-1 receptor antagonist), IQR (interquartile range), NK cells (natural-killer cells), OR (odds ratio), PBMC (peripheral blood mononuclear cell), SD (standard deviation), SF (superfamily), TNF (tumor necrosis factor), TNFSF (TNF superfamily), TLR (toll-like receptor), ULN (upper limit of normal)
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