IMO-8400, a toll-like receptor 7, 8, and 9 antagonist, demonstrates clinical activity in a phase 2a, randomized, placebo-controlled trial in patients with moderate-to-severe plaque psoriasis

Bibliographische Detailangaben
Veröffentlicht in:	Clinical immunology (Orlando, Fla.). - 1999. - 174(2017) vom: 01. Jan., Seite 63-72
1. Verfasser:	Balak, Deepak M W (VerfasserIn)
Weitere Verfasser:	van Doorn, Martijn B A, Arbeit, Robert D, Rijneveld, Rianne, Klaassen, Erica, Sullivan, Tim, Brevard, Julie, Thio, Hok Bing, Prens, Errol P, Burggraaf, Jacobus, Rissmann, Robert
Format:	Online-Aufsatz
Sprache:	English
Veröffentlicht:	2017
Zugriff auf das übergeordnete Werk:	Clinical immunology (Orlando, Fla.)
Schlagworte:	Clinical Trial, Phase II Journal Article Randomized Controlled Trial Research Support, Non-U.S. Gov't Drug-development Endosomal toll-like receptors Human beta-defensin-2 Immune-mediated inflammatory diseases Oligonucleotide antagonist Type 1 interferon signaling pathway mehr... DEFB4A protein, human TLR7 protein, human TLR8 protein, human TLR9 protein, human Toll-Like Receptor 7 Toll-Like Receptor 8 Toll-Like Receptor 9 beta-Defensins

Beschreibung
Zusammenfassung:	Copyright © 2016 Elsevier Inc. All rights reserved. BACKGROUND: Aberrant toll-like receptors (TLRs) 7, 8, and 9 activation by self-nucleic acids is implicated in immune-mediated inflammatory diseases (IMIDs) such as psoriasis. In preclinical IMID models, blocking TLR-activation reduced disease severity. IMO-8400 is a first-in-class, oligonucleotide-based antagonist of TLRs 7, 8, and 9. We evaluated the short-term safety and proof-of-concept for efficacy of IMO-8400 in a first-in-patient phase 2 trial METHODS: Forty-six psoriasis patients were randomly assigned to IMO-8400 in four dose levels or placebo for 12weeks. Post-treatment follow-up was seven weeks. Primary outcome was incidence of adverse events. Secondary, exploratory outcomes included changes in psoriasis area and severity index (PASI) RESULTS: IMO-8400 across all dose levels did not cause any serious or severe adverse events. The most common treatment-related adverse events were dose-dependent injection-site reactions. All IMO-8400 groups showed clinical improvement, but a clear dose-response relationship and statistically significant differences with placebo were not observed (P=0.26). Eleven (38%) of 29 subjects on IMO-8400 achieved ≥50% PASI-reduction, compared to 1 (11%) of 9 subjects on placebo. Five (17%) and 2 (7%) IMO-8400-treated subjects achieved PASI-75 and PASI-90, respectively, compared to none on placebo CONCLUSIONS: Short-term IMO-8400-treatment was well tolerated and reduced psoriasis severity. These findings warrant further investigation of endosomal TLR-antagonism as a therapeutic approach in psoriasis and other TLR-mediated IMIDs TRIAL REGISTRATION: EudraCT 2013-000164-28 and Clinicaltrials.govNCT01899729
Beschreibung:	Date Completed 13.06.2017 Date Revised 06.02.2018 published: Print-Electronic ClinicalTrials.gov: NCT01899729 EudraCT: 2013-000164-28 Citation Status MEDLINE
ISSN:	1521-7035
DOI:	10.1016/j.clim.2016.09.015