PMID- 33704806
OWN - NLM
STAT- MEDLINE
DCOM- 20220110
LR  - 20220110
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 74
IP  - 4
DP  - 2021 Oct
TI  - Safety, Pharmacokinetics, and Pharmacodynamics of the Oral TLR8 Agonist 
      Selgantolimod in Chronic Hepatitis B.
PG  - 1737-1749
LID - 10.1002/hep.31795 [doi]
AB  - BACKGROUND AND AIMS: In patients with chronic hepatitis B (CHB) infection, 
      activation of toll-like receptor 8 may induce antiviral immunity and drive 
      functional cure. Selgantolimod, a toll-like receptor 8 agonist, was evaluated in 
      patients with CHB who were virally suppressed on oral antiviral treatment or 
      viremic and not on oral antiviral treatment. APPROACH AND RESULTS: In this 
      phase 1b study, patients were randomized 4:1 to receive either selgantolimod or 
      placebo once weekly. Virally suppressed patients received either 1.5 mg (for 
      2 weeks) or 3 mg (for 2 weeks or 4 weeks). Viremic patients received 3 mg for 
      2 weeks. The primary endpoint was safety, as assessed by adverse events (AEs), 
      laboratory abnormalities, and vital sign examination. Pharmacokinetic and 
      pharmacodynamic parameters were assessed by plasma analysis. A total of 38 
      patients (28 virally suppressed, 10 viremic) were enrolled from six sites in 
      Australia, New Zealand, and South Korea. Twenty patients (53%) experienced an AE 
      and 32 (84%) had laboratory abnormalities, all of which were mild or moderate in 
      severity. The most common AEs were headache (32%), nausea (24%), and dizziness 
      (13%). With a half-life of 5 hours, no accumulation of selgantolimod was observed 
      with multiple dosing. Selgantolimod induced transient dose-dependent increases in 
      serum cytokines, including IL-12p40 and IL-1RA, which are important for the 
      expansion and activity of multiple T- cell subsets and innate immunity. 
      CONCLUSION: Selgantolimod was safe and well-tolerated in virally suppressed and 
      viremic patients with CHB and elicited cytokine responses consistent with target 
      engagement. Further studies with longer durations of selgantolimod treatment are 
      required to evaluate efficacy.
CI  - (c) 2021 by the American Association for the Study of Liver Diseases.
FAU - Gane, Edward J
AU  - Gane EJ
AD  - New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.
FAU - Kim, Hyung Joon
AU  - Kim HJ
AD  - Chung-Ang University Hospital, Seoul, South Korea.
FAU - Visvanathan, Kumar
AU  - Visvanathan K
AD  - St. Vincent's Hospital Melbourne and University of Melbourne, Fitzroy, VIC, 
      Australia.
FAU - Kim, Yoon Jun
AU  - Kim YJ
AD  - Seoul National University Hospital, Seoul, South Korea.
FAU - Nguyen, Anh-Hoa
AU  - Nguyen AH
AD  - Gilead Sciences, Inc, Foster City, CA.
FAU - Wallin, Jeffrey J
AU  - Wallin JJ
AD  - Gilead Sciences, Inc, Foster City, CA.
FAU - Chen, Diana Y
AU  - Chen DY
AD  - Gilead Sciences, Inc, Foster City, CA.
FAU - McDonald, Circe
AU  - McDonald C
AD  - Gilead Sciences, Inc, Foster City, CA.
FAU - Arora, Priyanka
AU  - Arora P
AD  - Gilead Sciences, Inc, Foster City, CA.
FAU - Tan, Susanna K
AU  - Tan SK
AD  - Gilead Sciences, Inc, Foster City, CA.
FAU - Gaggar, Anuj
AU  - Gaggar A
AD  - Gilead Sciences, Inc, Foster City, CA.
FAU - Roberts, Stuart K
AU  - Roberts SK
AD  - Alfred Hospital and Monash University, Melbourne, VIC, Australia.
FAU - Lim, Young-Suk
AU  - Lim YS
AUID- ORCID: 0000-0002-1544-577X
AD  - Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20210914
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Antiviral Agents)
RN  - 0 (Hexanols)
RN  - 0 (IL1RN protein, human)
RN  - 0 (Interleukin 1 Receptor Antagonist Protein)
RN  - 0 (Interleukin-12 Subunit p40)
RN  - 0 (Pyrimidines)
RN  - 0 (Toll-Like Receptor 8)
RN  - RM4GJT3SMQ (selgantolimod)
SB  - IM
MH  - Adult
MH  - Antiviral Agents/*therapeutic use
MH  - Dizziness/chemically induced
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Headache/chemically induced
MH  - Hepatitis B, Chronic/blood/*drug therapy
MH  - Hexanols/pharmacology/*therapeutic use
MH  - Humans
MH  - Interleukin 1 Receptor Antagonist Protein/blood
MH  - Interleukin-12 Subunit p40/blood
MH  - Male
MH  - Middle Aged
MH  - Nausea/chemically induced
MH  - Pyrimidines/pharmacology/*therapeutic use
MH  - Sustained Virologic Response
MH  - Toll-Like Receptor 8/*agonists
EDAT- 2021/03/12 06:00
MHDA- 2022/01/11 06:00
CRDT- 2021/03/11 13:00
PHST- 2021/02/04 00:00 [revised]
PHST- 2020/11/05 00:00 [received]
PHST- 2021/02/22 00:00 [accepted]
PHST- 2021/03/12 06:00 [pubmed]
PHST- 2022/01/11 06:00 [medline]
PHST- 2021/03/11 13:00 [entrez]
AID - 10.1002/hep.31795 [doi]
PST - ppublish
SO  - Hepatology. 2021 Oct;74(4):1737-1749. doi: 10.1002/hep.31795. Epub 2021 Sep 14.