| Reference | 1. J Hepatol. 2017 Dec 13. pii: S0168-8278(17)32489-3. doi:
10.1016/j.jhep.2017.12.007. [Epub ahead of print]
<br>
Toll-Like Receptor 7 Agonist GS-9620 Induces Prolonged Inhibition of HBV via a
Type I Interferon-Dependent Mechanism.
<br>
Niu C(1), Li L(1), Daffis S(1), Lucifora J(2), Bonnin M(2), Maadadi S(2), Salas
E(1), Chu R(1), Ramos H(1), Livingston CM(1), Beran RK(1), Garg AV(1), Balsitis
S(1), Durantel D(2), Zoulim F(3), Delaney WE 4th(1), Fletcher SP(4).
<br>
Author information: <br>
(1)Gilead Sciences, Inc, Foster City, CA, USA.
(2)INSERM 1052, Université Claude Bernard Lyon 1, CNRS 5286, Centre Léon Bérard,
Centre de Recherche en Cancérologie de Lyon, Lyon 69003, France.
(3)INSERM 1052, Université Claude Bernard Lyon 1, CNRS 5286, Centre Léon Bérard,
Centre de Recherche en Cancérologie de Lyon, Lyon 69003, France; Hospices Civils
de Lyon (HCL), 69002 Lyon, France; Institut Universitaire de France (IUF), 75005
Paris, France.
(4)Gilead Sciences, Inc, Foster City, CA, USA. Electronic address:
[email protected].
<br>
BACKGROUND & AIMS: GS-9620, an oral agonist of toll-like receptor 7 (TLR7), is in
clinical development for the treatment of chronic hepatitis B (CHB). GS-9620 was
previously shown to induce prolonged suppression of serum viral DNA and antigens
in the woodchuck and chimpanzee models of CHB. Here we investigated the molecular
mechanisms that contribute to the antiviral response to GS-9620 using in vitro
models of hepatitis B virus (HBV) infection.<br>
METHODS: Cryopreserved primary human hepatocytes (PHH) and differentiated HepaRG
(dHepaRG) cells were infected with HBV and treated with GS-9620, conditioned
media from human peripheral blood mononuclear cells (PBMCs) treated with GS-9620
(GS-9620 conditioned media; GS-9620-CM), or other innate immune stimuli. The
antiviral and transcriptional response to these agents was determined.<br>
RESULTS: GS-9620 had no antiviral activity in HBV-infected PHH, consistent with
low level TLR7 mRNA expression in human hepatocytes. In contrast, GS-9620-CM
induced prolonged reduction of HBV DNA, RNA, and antigen levels in PHH and
dHepaRG cells via a type I interferon (IFN)-dependent mechanism. GS-9620-CM did
not reduce cccDNA levels in either cell type. Transcriptional profiling
demonstrated that GS-9620-CM strongly induced various HBV restriction factors –
although not APOBEC3A or the Smc5/6 complex – and indicated that established HBV
infection does not modulate innate immune sensing or signaling in cryopreserved
PHH. GS-9620-CM also induced expression of immunoproteasome subunits and enhanced
presentation of an immunodominant viral peptide in HBV-infected PHH.
CONCLUSIONS: Type I IFN induced by GS-9620 durably suppressed HBV in human
hepatocytes without reducing cccDNA levels. Moreover, HBV antigen presentation
was enhanced, suggesting additional components of the TLR7-induced immune
response played a role in the antiviral response to GS-9620 in animal models of
CHB.<br>
LAY SUMMARY: GS-9620 is a drug in clinical trials for the treatment of chronic
hepatitis B virus (HBV) infection. GS-9620 has previously been shown to suppress
HBV in various animal models, but the underlying antiviral mechanisms were not
completely understood. In this study, we determined that GS-9620 does not
directly activate antiviral pathways in human liver cells, but can induce
prolonged suppression of HBV via induction of an antiviral cytokine called
interferon. However, interferon did not destroy the HBV genome, suggesting that
other parts of the immune response (e.g. activation of immune cells that kill
infected cells) also play an important role in the antiviral response to GS-9620.
<br>
2. J Hepatol. 2015 Aug;63(2):320-8. doi: 10.1016/j.jhep.2015.02.037. Epub 2015 Feb
27.
<br>
The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis
B virus infection.
<br>
Gane EJ(1), Lim YS(2), Gordon SC(3), Visvanathan K(4), Sicard E(5), Fedorak
RN(6), Roberts S(7), Massetto B(8), Ye Z(8), Pflanz S(8), Garrison KL(8), Gaggar
A(8), Mani Subramanian G(8), McHutchison JG(8), Kottilil S(9), Freilich B(10),
Coffin CS(11), Cheng W(12), Kim YJ(13).
<br>
Author information: <br>
(1)New Zealand Liver Transplant Unit, Auckland City Hospital and University of
Auckland, Auckland, New Zealand. Electronic address: [email protected].
(2)Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic
of Korea.
(3)Henry Ford Health Systems, Detroit, MI, USA.
(4)The University of Melbourne, Parkville, Victoria, Australia.
(5)Algorithme Pharma, Montréal, Canada.
(6)University of Alberta, Edmonton, Alberta, Canada.
(7)Alfred Health, Victoria, Australia.
(8)Gilead Sciences, Inc., Foster City, CA, USA.
(9)National Institutes of Health, Department of Health and Human Services,
Bethesda, MD, USA.
(10)Kansas City Gastroenterology and Hepatology, Kansas City, MO, USA.
(11)University of Calgary, Calgary, Albert, Canada.
(12)Royal Perth Hospital, Perth, Australia.
(13)Seoul National University College of Medicine, Seoul, Republic of Korea.
<br>
BACKGROUND & AIMS: GS-9620 is an oral agonist of toll-like receptor 7, a
pattern-recognition receptor whose activation results in innate and adaptive
immune stimulation. We evaluated the safety, pharmacokinetics, and
pharmacodynamics of GS-9620 in patients with chronic hepatitis B.
METHODS: In two double-blind, phase 1b trials of identical design, 49
treatment-naïve and 51 virologically suppressed patients were randomized 5:1 to
receive GS-9620 (at doses of 0.3mg, 1mg, 2mg, 4mg) or placebo as a single dose or
as two doses seven days apart. Pharmacodynamic assessment included evaluation of
peripheral mRNA expression of interferon-stimulated gene 15 (ISG15), serum
interferon gamma-induced protein 10 and serum interferon (IFN)-alpha.
RESULTS: Overall, 74% of patients were male and 75% were HBeAg negative at
baseline. No subject discontinued treatment due to adverse events. Fifty-eight
percent experienced ⩾1 adverse event, all of which were mild to moderate in
severity. The most common adverse event was headache. No clinically significant
changes in HBsAg or HBV DNA levels were observed. Overall, a transient
dose-dependent induction of peripheral ISG15 gene expression was observed peaking
within 48 hours of dosing followed by return to baseline levels within seven
days. Higher GS-9620 dose, HBeAg positive status, and low HBsAg level at baseline
were independently associated with greater probability of ISG15 response. Most
patients (88%) did not show detectable levels of serum IFN-alpha at any time
point.<br>
CONCLUSIONS: Oral GS-9620 was safe, well tolerated, and associated with induction
of peripheral ISG15 production in the absence of significant systemic IFN-alpha
levels or related symptoms.
<br>
3. Antivir Ther. 2013;18(3):409-18. doi: 10.3851/IMP2548. Epub 2013 Feb 15.
<br>
Safety, pharmacokinetics and pharmacodynamics of GS-9620, an oral Toll-like
receptor 7 agonist.
<br>
Lopatin U(1), Wolfgang G, Tumas D, Frey CR, Ohmstede C, Hesselgesser J, Kearney
B, Moorehead L, Subramanian GM, McHutchison JG.
<br>
Author information: <br>
(1)Gilead Sciences, Foster City, CA, USA.
<br>
BACKGROUND: GS-9620 is a novel oral agonist of Toll-like receptor 7 (TLR7) in
development for the treatment of chronic viral hepatitis. TLR7 is a highly
conserved innate immune receptor expressed primarily on plasmacytoid dendritic
cells and B lymphocytes. The aim of this double-blind, placebo-controlled, single
ascending-dose study was to investigate the safety, tolerability,
pharmacokinetics and pharmacodynamics of GS-9620 in healthy volunteers.
METHODS: In total, 75 healthy volunteers (8 subjects in each of the 10 cohorts; 5
subjects participated in two cohorts) were randomized (6:2) to receive a single
dose of GS-9620 (0.3, 1, 2, 4, 6, 8 or 12 mg) or placebo.
RESULTS: GS-9620 was well-absorbed and well-tolerated in oral doses up to 12 mg.
Minimal treatment-related adverse events were seen at doses up to 8 mg. Serum
interferon (IFN)-α was only detected in subjects who received 8 or 12 mg doses,
and the adverse event profile at 8 and 12 mg doses was generally consistent with
that associated with IFN-α exposure (flu-like symptoms), consistent with the
mechanism of TLR7 agonism. All adverse events resolved within 72 h. Induction of
chemokines/cytokines and IFN-stimulated genes were seen at GS-9620 doses ≥ 2 mg,
well below doses that induced serum IFN-α or led to clinical adverse events.
CONCLUSIONS: GS-9620 demonstrates safety and pharmacodynamic activity at doses up
to 12 mg. Pharmacodynamic activity is seen before adverse events, suggesting the
potential for induction of an antiviral response without systemic adverse events
in subjects with chronic viral hepatitis.
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