BACKGROUND AND AIMS: 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.

Central Clinical Hospital Ministry of Interior in Warsaw Warsaw Poland

Clinical Centre Isacre Lighthouse IBD Clinical and Research Centre Prague Czech Republic

Department of Gastroenterology Hepatology and Endocrinology Hannover Medical School Hannover Germany

Department of Gastroenterology Nottingham Digestive Diseases Centre Nottingham University Hospitals Nottingham UK

Department of Medicine Karolinska Institutet Solna Sweden

Gastroenterology Lyon Sud Hospital Hospices Civils de Lyon Pierre Bénite France

Gastroenterology University College London Hospital London UK

InDex Pharmaceuticals Tomtebodavägen 23A 171 77 Stockholm Sweden

Internal Medicine Department Gastroenterology Division Catholic University of Rome Rome Italy

Jan Kochanowski University Kielce Poland

JK Biostatistics AB Stockholm Sweden

Medical Clinic 1 Friedrich Alexander University Erlangen Nürnberg Erlangen Germany

NZOZ Vivamed Warsaw Poland

Pannonia Maganorvosi Centrum Budapest Hungary

Stockholm Gastro Center Sophiahemmet Stockholm Sweden

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