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.

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.

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.

• Authors: Deepak M W Balak, Martijn B A van Doorn, Robert D Arbeit, Rianne Rijneveld, Erica Klaassen, Tim Sullivan, Julie Brevard, Hok Bing Thio, Errol P Prens, Jacobus Burggraaf, Robert Rissmann
• Journal: Clinical immunology (Orlando, Fla.) (Clin Immunol) Vol. 174 Pg. 63-72 (01 2017) ISSN: 1521-7035 [Electronic] United States
• PMID: 27876460 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

• Adult
• Double-Blind Method
• Female
• Humans
• Male
• Middle Aged
• Psoriasis (blood, drug therapy, pathology)
• Severity of Illness Index
• Skin (drug effects, pathology)
• Toll-Like Receptor 7 (antagonists & inhibitors)
• Toll-Like Receptor 8 (antagonists & inhibitors)
• Toll-Like Receptor 9 (antagonists & inhibitors)
• Treatment Outcome
• Young Adult
• beta-Defensins