Safety, pharmacokinetics and pharmacodynamics of a topical SYK inhibitor in cutaneous lupus erythematosus: A double-blind Phase Ib study.
SYK Kinase
cutaneous lupus erythematosus
interferons
pharmacology
safety
Journal
Experimental dermatology
ISSN: 1600-0625
Titre abrégé: Exp Dermatol
Pays: Denmark
ID NLM: 9301549
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
revised:
05
11
2020
received:
11
12
2019
accepted:
23
11
2020
pubmed:
19
12
2020
medline:
5
4
2022
entrez:
18
12
2020
Statut:
ppublish
Résumé
The immunoregulator spleen tyrosine kinase (SYK) is upregulated in cutaneous lupus erythematosus (CLE). This double-blind, multicentre, Phase Ib study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy of the selective SYK inhibitor GSK2646264 in active CLE lesions. Two lesions from each participant (n = 11) were each randomized to topical application of 1% (w/w) GSK2646264 or placebo for 28 days; all participants received GSK2646264 and placebo. The primary endpoint was safety and tolerability of GSK2646264, assessed by adverse event incidence and a skin tolerability test. Secondary endpoints included change from baseline in clinical activity and mRNA expression of interferon-related genes in skin biopsies. Levels of several immune cell markers were evaluated over time. Eight (73%) participants experienced ≥ 1 adverse event (all mild in intensity), and maximal dermal response was similar for GSK2646264 and placebo. The expression of several interferon-related genes, including CXCL10 and OAS1, showed modest decreases from baseline after 28 days of treatment with GSK2646264 compared with placebo. Similar findings were observed for CD3 + T cell and CD11c + dendritic cell levels; however, overall clinical activity remained unchanged with GSK2646264 vs. placebo. Further studies are warranted to assess SYK inhibitors as potential treatment for CLE.
Identifiants
pubmed: 33336508
doi: 10.1111/exd.14253
pmc: PMC8596667
doi:
Substances chimiques
GSK2646264
0
Pyridines
0
SYK protein, human
EC 2.7.10.2
Syk Kinase
EC 2.7.10.2
Banques de données
ClinicalTrials.gov
['NCT02927457']
Types de publication
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1686-1692Informations de copyright
© 2020 Glaxo Group Limited. Experimental Dermatology published by John Wiley & Sons Ltd.
Références
Lupus. 2017 Feb;26(2):115-118
pubmed: 27687023
Br J Dermatol. 2010 Jul;163(1):83-92
pubmed: 20394621
Int J Womens Dermatol. 2018 Apr 13;4(3):152-158
pubmed: 30175217
Br J Pharmacol. 2019 Apr;176(8):1135-1142
pubmed: 30735243
Bioorg Med Chem Lett. 2018 Nov 15;28(21):3458-3462
pubmed: 30249354
Nat Rev Immunol. 2010 Jun;10(6):387-402
pubmed: 20467426
Exp Dermatol. 2021 Nov;30(11):1686-1692
pubmed: 33336508
Int J Mol Sci. 2014 Jan 06;15(1):545-59
pubmed: 24398980
Pathology. 2008 Dec;40(7):682-93
pubmed: 18728929
Br J Dermatol. 2012 May;166(5):971-5
pubmed: 22242767
Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3175-3180
pubmed: 28270605
J Exp Med. 2010 Dec 20;207(13):2931-42
pubmed: 21115693
Arthritis Rheum. 2010 Jul;62(7):2086-92
pubmed: 20222110
Exp Dermatol. 2016 May;25(5):375-9
pubmed: 26910509
Best Pract Res Clin Rheumatol. 2013 Jun;27(3):391-404
pubmed: 24238695
Front Immunol. 2013 Sep 20;4:290
pubmed: 24062752