title: Clinical Effects of a Topically Applied Toll-like Receptor 9 Agonist in Active Moderate-to-Severe Ulcerative Colitis.
abstract: OBJECTIVE
  Toll-like receptors [TLRs] are potential drug targets for immunomodulation. We determined the safety and efficacy of the TLR-9 agonist DNA-based immunomodulatory sequence 0150 [DIMS0150] in ulcerative colitis [UC] patients refractory to standard therapy.
  
  
  METHODS
  In this randomized, double-blind, placebo-controlled trial, 131 patients with moderate-to-severe active UC were randomized to receive two single doses of the oligonucleotide DIMS0150 [30 mg] or placebo administered topically during lower GI endoscopy at baseline and Week 4. The primary endpoint was clinical remission, defined as Clinical Activity Index [CAI] ≤4, at Week 12. Secondary endpoints included mucosal healing and symptomatic remission of key patient-reported outcomes [absence of blood in stool and weekly stool frequency <35].
  
  
  RESULTS
  There was no statistical significant difference between the groups in the induction of clinical remission at Week 12, with 44.4% in the DIMS0150 group vs. 46.5% in the placebo group. However, the proportion of patients who achieved symptomatic remission was 32.1% in the DIMS0150 group vs. 14.0% in the placebo group at Week 4 [p = 0.020], and 44.4% vs. 27.9% at Week 8 [p = 0.061]. More patients on DIMS0150 compared with those on placebo had mucosal healing [34.6% vs. 18.6%; p = 0.09] and histological improvement regarding the Geboes score [30.9% vs. 9.3%; p = 0.0073] at Week 4. Significantly more patients on DIMS0150 were in clinical remission with mucosal healing at Week 4: 21% vs. 4.7% in the placebo group [p = 0.02]. DIMS0150 was well tolerated, and no safety signals compared with placebo were evident.
  
  
  CONCLUSIONS
  Therapy with the topically applied TLR-9 agonist DIMS0150 is a promising and well-tolerated novel therapeutic option for treatment-refractory, chronic active UC patients, warranting further clinical trials.
authors.affiliation: Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Raja
authors.initials: R
authors.lastname: Atreya
authors.affiliation: Gastroenterology, University College London Hospital, London, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Bloom
authors.affiliation: Internal Medicine Department/Gastroenterology Division, Catholic University of Rome, Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Scaldaferri
authors.affiliation: Internal Medicine Department/Gastroenterology Division, Catholic University of Rome, Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Gerardi
authors.affiliation: InDex Pharmaceuticals, Tomtebodavägen 23A, 171 77 Stockholm, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Admyre
authors.affiliation: InDex Pharmaceuticals, Tomtebodavägen 23A, 171 77 Stockholm, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Karlsson
authors.affiliation: InDex Pharmaceuticals, Tomtebodavägen 23A, 171 77 Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Knittel
authors.affiliation: JK Biostatistics AB, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Kowalski
authors.affiliation: Clinical Centre Isacre Lighthouse, IBD Clinical and Research Centre, Prague, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Lukas
authors.affiliation: Stockholm Gastro Center, Sophiahemmet, Stockholm, Sweden.|Department of Medicine, Karolinska Institutet, Solna, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Löfberg
authors.affiliation: Gastroenterology, Lyon-Sud Hospital, Hospices Civils de Lyon, Pierre-Bénite, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Nancey
authors.affiliation: NZOZ Vivamed, Warsaw, Poland.
authors.forename: Robert
authors.initials: R
authors.lastname: Petryka
authors.affiliation: Central Clinical Hospital Ministry of Interior in Warsaw, Warsaw, Poland.|Jan Kochanowski University, Kielce, Poland.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Rydzewska
authors.affiliation: Pannonia Maganorvosi Centrum, Budapest, Hungary.
authors.forename: Robert
authors.initials: R
authors.lastname: Schnabel
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Seidler
authors.affiliation: Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.affiliation: Department of Gastroenterology, Nottingham Digestive Diseases Centre, Nottingham University Hospitals, Nottingham, UK cj.hawkey@nottingham.ac.uk.
authors.forename: Christopher
authors.initials: C
authors.lastname: Hawkey
mesh_terms: D000287:Administration, Topical; D000328:Adult; D000368:Aged; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D003106:Colon / Q000187:drug effects; D004247:DNA / Q000008:administration & dosage / Q000627:therapeutic use*; D004311:Double-Blind Method; D004724:Endoscopy / Q000379:methods; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D055815:Young Adult
chemical_list: C582905:DIMS0150; D007155:Immunologic Factors; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D004247:DNA
keywords: Toll-like receptors; therapy; ulcerative colitis