Targeting the transcription factor GATA3 by the DNAzyme formulation SB012 in patients with moderately-to-severely active ulcerative colitis: a multicenter, randomized, placebo-controlled, phase 2a induction trial

Objective Augmented mucosal expression of the transcription factor GATA3 has been implicated in the pathogenesis of ulcerative colitis (UC). Here, we evaluated the efficacy and safety of SB012, an enema formulation of the DNAzyme hgd40 that specifically inactivates GATA3 messenger RNA, for induction therapy in patients with active UC. Design In this randomized, double-blind, placebo-controlled, multicenter, phase 2a study, patients with moderately-to-severely active UC were randomized to either receive SB012 enema (225 mg hgd40) or placebo once daily for 4 weeks. The primary endpoint was change in the Total Mayo Score at week 4 compared to baseline values in the SB012 versus placebo group. Results Patients were randomized 2:1 to the SB012 (n = 13) or placebo (n = 7) group. The treatment difference between the SB012 and placebo group was not statistically significant at week 4 (P = .286). In patients not treated with glucocorticoids, the Total Mayo score in the SB012 group improved on day 28 by −2.2 (P = .027; 95%CI: −4.1 to −0.3) compared to placebo, whereas no improvement was seen in patients using corticosteroids. Further, the median Total Mayo Score in the SB012 group dropped significantly from 9.0 (Q1-Q3 6.5-10) at baseline to 7.0 (4.0-8.5) at week 4 (P = .004), while there were no significant changes in the placebo group. Endoscopic improvement was reached by 17% (2/12) and 57% (4/7) in the SB012 and 17% (1/6) and 50% (3/6) in the placebo group at weeks 4 (P = 1.0) and 8 (P = 1.0), respectively. SB012 application was well tolerated. Conclusion Overall, topical application of the GATA3-specific DNAzyme formulation SB012 was well tolerated, but did not reach the defined primary endpoint of treatment difference at week 4 between the SB012 and placebo group in active moderate-to-severe UC patients, unless confounding by glucocorticoids was taken into account.