DOP055 Luminal application of a GATA3-specific DNAzyme ameliorates mucosal inflammation in a randomised trial with active ulcerative colitis patients

Abstract

Background: The transcription factor GATA-3 has been identified to play a central role in Th2-dependent immune pathways and is overexpressed in the mucosa of ulcerative colitis (UC) patients. We investigated the efficacy and safety of SB012, an enema formulation of a novel GATA-3 specific DNAzyme that specifically binds and inactivates GATA-3 messenger RNA (mRNA) in patients with active UC. Methods: In this randomised, double-blind, placebo-controlled, multi-centre, parallel-group, phase 2a clinical trial, 20 patients with moderate-to-severe UC (Mayo Score ≥6; endoscopic subscore of the sigmoid ≥2) were randomised to receive 225 mg SB012 enema (n = 13) or placebo (n = 7) once daily for a 28-day period. The primary efficacy variable was the change in disease activity (Mayo Score) after 28 days of treatment. Clinical and endoscopic disease activity was further assessed at day 56. Endoscopy was centrally read in the study. Furthermore, a panel of biomarkers was evaluated by gene expression profiling in collected colon biopsies. This study is registered with EudraCT-Nr. 2013-004599-36. Results: In the SB012 treated patients, the Mayo Score dropped from 8.4 ± 1.7 (n = 13) at baseline to 6.5 ± 2.6 (n = 13) at day 28 (p = 0.004), and 5.0 ± 3.5 (n = 7) at day 56 (p = 0.016). In the placebo group, the Mayo Score was 10.0 ± 2.1 (n = 6) at baseline, and 9.0 ± 1.3 (n = 6) at day 28 (not significant; ns), and 9.0 ± 1.4 (n = 2) at day 56 (ns). At day 28, there was a statistically significant improvement in the Mayo Score in the SB012 compared with the placebo group (p = 0.044). Clinical remission was reached by 0.0% (0/12) at day 28 and 42.9% (3/7) at day 56 of the SB012-treated patients, compared with 0.0% (0/6) at day 28 and 0.0% (0/2) at day 56 of the placebo-treated patients. Clinical response at day 28 occurred in 41.7% (5/12) at day 28 and 42.9% (3/7) at day 56 in the SB012 vs. 0.0% (0/6) and 0.0% (0/2) in the placebo group. Mucosal healing rates were 16.7% (2/12) at day 28 and 57.1% (4/7) at day 58 in the SB012, compared with 0.0% (0/6) and 0.0% (0/2) in the placebo treated group. The two-item PRO (PRO2) consisting of rectal bleeding= 0 and stool frequency ≤1 (and at least one point decrease from baseline), combined with an endoscopy subscore ≤1, was reached by 8.3% (1/12) at day 28 and 42.9% (3/7) at day 56 of the SB012 compared with 0.0% (0/6) and 0.0% (0/2) of the placebo treated patients. SB012 was well tolerated and no safety signals compared with placebo were evident. Conclusions: Topical application of the GATA3-specific DNAzyme SB012 was well tolerated and lead to marked clinical and endoscopic improvement in patients with active ulcerative colitis. Therefore, blockade of GATA-3 might represent a unique therapeutic approach for the treatment of ulcerative colitis patients.