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456
Pharmacodynamic Response to Oral
Administration of the Selective Toll-like
Receptor 8 Agonist GS-9688 in Healthy
Volunteers
Ethan Grant1, Adarsh Joshi2, Natarajan Ayithan3, Stephane
Daffis4, Jacky Woo5, Tina Lam6, Richard L Mackman7, Simon
Fletcher4, Anuj Gaggar8, Audrey H. Lau9, Shyamasundaran
Kottilil10 and Bhawna Poonia11, (1)Biomarker Sciences, Gilead
Sciences, Inc., (2)Biostatistics, Gilead Sciences, Inc., (3)
Division of Clinical Care and Research, Institute of Human
Virology, University of Maryland School of Medicine, (4)
Virology, Gilead Sciences, Inc., (5)Gilead Sciences, Inc., (6)
Biomarker Operations, Gilead Sciences, Inc., (7)Medicinal
Chemistry, Gilead Sciences, Inc., (8)Gilead Sciences, Inc,
Foster City, California, USA, (9)Clinical Research, Gilead
Sciences, Inc., (10)Division of Clinical Care and Research,
Institute of Human Virology, University of Maryland School
of Medicine, Baltimore, MD 21201, (11)Division of Clinical
Care and Research, Institute of Human Virology, Institute of
Human Virology, University of Maryland School of Medicine,
Baltimore, MD 21201
Background: GS-9688 is an oral selective small molecule
agonist of toll-like receptor 8 (TLR8) currently in clinical
development for the treatment of chronic hepatitis B (CHB).
A single ascending dose Phase 1a study (GS-US-389-2021)
in healthy volunteers demonstrated that oral GS-9688
induced a dose-dependent increase in serum IL-12p40 and
IL-1RA. Here we describe an extensive evaluation of the
pharmacodynamic (PD) response in this study. Methods:
Healthy volunteers (n=11 placebo; n=12 per GS-9688 group)
received a single oral dose of GS-9688 (placebo, 0.5 mg, 1.5
mg, 3 mg or 5 mg). Serum and peripheral blood mononuclear
cells (PBMC) samples were collected at baseline and at
various times after GS-9688 dosing. Serum levels of 89
different proteins were analyzed by high sensitivity ELISA
and multiplexed Luminex panels. PBMCs were analyzed by
flow cytometry. Results: Oral GS-9688 induced a statistically
significant and dose-dependent increase in serum levels of
immunomodulatory (e.g. IL-12p70) and antiviral (e.g. IFN-g
and TNF-a) cytokines, as well as a variety of chemokines
and acute phase proteins (Table 1). Cytokine and chemokine
levels peaked 2–4 hours post-dose, and returned to near
baseline by 24 hours post-dose. Induction of acute phase
proteins C-reactive protein (CRP) and serum amyloid A (SAA)
displayed slower kinetics, with highest levels measured 24
hours post-dose. In addition to these soluble factors, oral GS-
9688 increased the frequency of NK and mucosal associated
invariant T (MAIT) cells expressing the early activation marker
CD69. Conclusion: Oral GS-9688 induced serum levels of
immunomodulatory and antiviral cytokines, and activated NK
and MAIT cells in the periphery. GS-9688 also induced acute
phase proteins, consistent with activation of intrahepatic
cells, as well as chemokines (e.g. CXCL9, CXCL10) with
the potential to induce trafficking of activated T cells and NK
cells into the liver. Together, these data support further clinical
development of GS-9688 in CHB patients. |
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