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721
CHARACTERIZATION OF CYTOKINE RESPONSE TO TOLL-LIKE
RECEPTOR 8 AGONIST SELGANTOLIMOD (SLGN) IN VIREMIC
AND VIRALLY SUPPRESSED CHRONIC HEPATITIS B (CHB)
PATIENTS
Diana Chen1, Circe McDonald1, Susanna Tan1, Jenny Yang1,
Edward J. Gane2, Harry L.A. Janssen3, Shyam Kottilil4, Lydia
Tang5, Carla S. Coffin6, Sang Hoon Ahn7, Hyung Joon Kim8,
Yoon Jun Kim9, Young-Suk Lim10, Wan-Long Chuang11, Jia-
Horng Kao12, Cheng-Hao Tseng13, Anuj Gaggar14 and Jeffrey
Wallin15, (1)Gilead Sciences, Inc, Foster City, California, USA,
(2)Auckland Clinical Studies, Auckland, New Zealand, (3)
Toronto Centre for Liver Disease, University Health Network,
(4)Division of Clinical Care and Research, Institute of
Human Virology, University of Maryland School of Medicine,
Baltimore, MD, United States, (5)Division of Clinical Care and
Research, Institute of Human Virology, University of Maryland
School of Medicine, Baltimore, MD, USA, (6)Gastroenterology
& Hepatology, University of Calgary, (7)Yonsei Liver Center,
Severance Hospital, Seoul, Republic of Korea, (8)Chung-Ang
University College of Medicine, Seoul, Republic of Korea,
(9)Department of Internal Medicine and Liver Research
Institute, Seoul National University Hospital, Seoul, Republic
of Korea, (10)Department of Gastroenterology, Liver
Center, Asan Medical Center, University of Ulsan College
of Medicine, Seoul, Republic of Korea, (11)Hepatobiliary
Division, Department of Internal Medicine, Kaohsiung
Medical University Hospital, Kaohsiung, Taiwan, (12)Division
of Gastroenterology, Department of Internal Medicine,
National Taiwan University Hospital, Taipei, Taiwan, (13)
Gastroenterology and Hepatology, E-DA Cancer Hospital,
Kaohsiung, Taiwan, (14)Gilead Sciences, Inc, Foster City,
CA, USA, (15)Gilead Sciences, Inc., Foster City, CA, USA
Background: SLGN is an oral selective small molecule
agonist of TLR8 that has been shown to be safe and well tolerated
in CHB patients Here we evaluate serum cytokine
and chemokine response to SLGN treatment in viremic and
virally suppressed patients on oral antivirals and identify
factors that may correlate with cytokine response to SLGN
Methods: Viremic and virally suppressed patients were
randomized (2:2:1) to receive once weekly SLGN doses of
1 5 mg, 3 mg or placebo for 24 doses Blood samples were
collected at baseline and on-treatment and evaluated for
serum cytokine and chemokine levels Differences in baseline
cytokine expression between viremic status as well as
differences in cytokine concentration ratios between baseline
and on- treatment time points were determined by Bonferroni
adjusted Wilcoxon test Generalized linear model regression
analyses were conducted to determine factors which correlate
with cytokine response to SLGN treatment Results: In both
viremic and virally suppressed patients, SLGN induced a
dose-dependent increase of circulating antiviral cytokines
such as IL-12p40, IL-12p70, IFNg and IL-1RA as well as
chemokines important for leukocyte trafficking. Levels of most
cytokine and chemokines peaked at 4 hours post-dose and
returned to near baseline by 24 hours post-dose, with the
notable exceptions of SAA1 and CRP which displayed peak
response at 24 hours post-dose A subset of these cytokines
including IL-12p40, IL-1RA, CCL4, ICAM-1 and IL-8 were also
significantly higher at baseline in viremic compared to virally
suppressed subjects (p < 1x10-2), suggesting viremic patients
were in a higher immune active state However, baseline
expression of these cytokines did not correlate with magnitude
of response to SLGN except for CCL4, where higher baseline
CCL4 correlated with a higher CCL4 response to both 1 5mg
and 3 0mg SLGN treatments (p < 1x10-14, p < 1x10-3) For
Th1 cytokines IFNg and IL-18, baseline cytokine levels did
not differ by viremic status but did correlate with response to
3 0mg SLGN treatment (p < 4x10-2, p < 1x10-5) These effects
were consistent in separate models controlling for age, sex,
and race as well as ALT levels at baseline and post-treatment
time points Conclusion: Immune response to SLGN was
generally similar between viremic and virally suppressed CHB
patients CCL4, IFNg, and IL-18 cytokine response to SLGN
may be influenced by baseline expression. |
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发表于 2020-10-21 16:52
