title: 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: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  EudraCT 2013-000164-28 and Clinicaltrials.govNCT01899729.
authors.affiliation: Department of Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Deepak M W
authors.initials: DM
authors.lastname: Balak
authors.affiliation: Department of Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Martijn B A
authors.initials: MB
authors.lastname: van Doorn
authors.affiliation: Idera Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Arbeit
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Rianne
authors.initials: R
authors.lastname: Rijneveld
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Erica
authors.initials: E
authors.lastname: Klaassen
authors.affiliation: Idera Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Sullivan
authors.affiliation: Idera Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Brevard
authors.affiliation: Department of Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Hok Bing
authors.initials: HB
authors.lastname: Thio
authors.affiliation: Department of Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Errol P
authors.initials: EP
authors.lastname: Prens
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Jacobus
authors.initials: J
authors.lastname: Burggraaf
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands. Electronic address: rrissmann@chdr.nl.
authors.forename: Robert
authors.initials: R
authors.lastname: Rissmann
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D012720:Severity of Illness Index; D012867:Skin / Q000187:drug effects / Q000473:pathology; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors*; D051200:Toll-Like Receptor 8 / Q000037:antagonists & inhibitors*; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D055815:Young Adult; D023083:beta-Defensins
chemical_list: C106641:DEFB4A protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D023083:beta-Defensins
keywords: Drug-development; Endosomal toll-like receptors; Human beta-defensin-2; Immune-mediated inflammatory diseases; Oligonucleotide antagonist; Type 1 interferon signaling pathway