P0942 Orismilast for the treatment of moderate to severe Ulcerative Colitis: Analysis of preliminary data from UCORIS, a phase 2a, open-label, single-arm exploratory clinical trial
Authors: Velte Honoré T , Bendtsen F , Seidelin J B , Burisch J ,   Copenhagen IBD Center
Published: January 2025

Abstract

Background
Existing medications aim to induce and maintain remission in Ulcerative Colitis (UC), yet 30-55% of UC patients remain refractory in the induction phase, underscoring an unmet need for novel treatments1. Orismilast, an oral B/D selective phosphodiesterase-4 (PDE4) inhibitor, is currently in development for the treatment of atopic dermatitis, psoriasis, and hidradenitis suppurativa. PDE4 receptors have also been shown to be upregulated in UC2. This study (the UCORIS study) aims to explore the efficacy and safety of orismilast to guide future studies.

Methods
The UCORIS study is an ongoing phase 2a, open-label, single-arm exploratory clinical study assessing the efficacy and safety of orismilast in patients with moderate to severe UC. Patients with a UC diagnosis currently on stable 5-ASA treatment and experiencing moderate-severe disease activity (defined as a MAYO endoscopic subscore of 2 or 3) were eligible for inclusion. Orismilast was administered twice daily for 12 weeks, with investigators allowed to individualize the dose based on body weight, treatment response and side effects. Responding patients could extend treatment to a total duration of 52 weeks. The primary endpoint was clinical remission based on the total Mayo score at week 12, defined as 2 points or lower with no individual sub-score above 1.

Results
To date, nine patients have been enrolled in the study. Four patients have completed the initial 12-week trial period. Among these, one patient reached the primary endpoint, achieving remission with a total Mayo score of 0, a SCCAI &lt;2 and a f-calprotectin &lt;15. The remaining three patients who completed treatment did not achieve remission.
Five patients discontinued treatment prematurely: three due to lack of efficacy and two due to adverse effects (headache and nausea). The two patients who discontinued due to adverse effects did achieve remission after six weeks of treatment, as indicated by a partial Mayo score of 0, a SCCAI &lt; 2, and an f-calprotectin level &lt; 15.
The most common adverse events were nausea (67%), dizziness (22%), and headache (22%), aligning with previous findings.

Conclusion
In this preliminary analysis, 1 patient (14%) achieved the primary endpoint of clinical remission after 12 weeks of treatment with orismilast, defined as a total Mayo score of 2 or lower, with no individual sub-score exceeding 1. Across all patients included in the study, 3 out of 9 (33%) achieved remission following treatment with orismilast; however, two of these three patients discontinued treatment due to adverse events (headache and nausea). In conclusion, these preliminary data suggest that orismilast shows potential as a treatment for UC, with one patient reaching the primary endpoint and two others achieving remission.

References
1.Zhao M, Sall Jensen M, Knudsen T, et al. Trends in the use of biologicals and their treatment outcomes among patients with inflammatory bowel diseases – a Danish nationwide cohort study. Aliment Pharmacol Ther. 2022;55(5):541-557. doi:10.1111/apt.16723
2.Li H, Zhang Y, Liu M, et al. Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal homeostasis. Acta Pharm Sin B. 2022;12(1):228-245. doi:10.1016/j.apsb.2021.04.007