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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.
- Source :
-
Clinical immunology (Orlando, Fla.) [Clin Immunol] 2017 Jan; Vol. 174, pp. 63-72. Date of Electronic Publication: 2016 Nov 20. - Publication Year :
- 2017
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Abstract
- 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.<br />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).<br />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.<br />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.<br />Trial Registration: EudraCT 2013-000164-28 and Clinicaltrials.govNCT01899729.<br /> (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Subjects :
- Adult
Double-Blind Method
Female
Humans
Male
Middle Aged
Psoriasis blood
Psoriasis pathology
Severity of Illness Index
Skin drug effects
Skin pathology
Treatment Outcome
Young Adult
beta-Defensins
Psoriasis drug therapy
Toll-Like Receptor 7 antagonists & inhibitors
Toll-Like Receptor 8 antagonists & inhibitors
Toll-Like Receptor 9 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1521-7035
- Volume :
- 174
- Database :
- MEDLINE
- Journal :
- Clinical immunology (Orlando, Fla.)
- Publication Type :
- Academic Journal
- Accession number :
- 27876460
- Full Text :
- https://doi.org/10.1016/j.clim.2016.09.015