Introduction
Existing treatments aim to induce and maintain remission in Ulcerative Colitis (UC); however, 30–55% of patients remain refractory during the induction phase, highlighting an unmet need for novel therapeutic options(1). Phosphodiesterase-4 (PDE4) is a cyclic adenosine monophosphate (cAMP)-specific enzyme expressed by immune and inflammatory cells. Abnormal expression of PDE4 and dysregulated signal transduction have been reported in colonic biopsies from patients with UC (2,3). Orismilast is an oral, B/D-selective PDE4 inhibitor with a modified-release formulation.
Aims & Methods
This study (the UCORIS study) was a 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 UC currently on stable 5-ASA treatment and experiencing moderate-severe disease activity (defined as a Mayo endoscopic sub score 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.
A last-observation-carried-forward (LOCF) approach was applied to early discontinuers when com-paring to those who completed treatment. No hypothesis testing was performed due to the small sample size. The primary endpoint was clinical remission at week 12, defined as a total Mayo score of 2 or lower, with no individual sub score exceeding 1.
Results
10 patients were included in the study. Six participants discontinued the study prematurely - three due to lack of efficacy and three due to adverse events. Clinical remission at week 12 was achieved by one patient, who continued orismilast for 50 weeks, maintaining endoscopic remission.
In the completed trial group, mean Total Mayo Score decreased from 9.75 to 5.25 (Δ– 4.50, [95% CI: -4.17;13.17], p=0.20), and Partial Mayo Score from 7.25 to 3.75 (Δ –3.5, [95% CI: -2.66;9.66], p=0.17). In the early determination group, Partial Mayo Score declined from 5.83 to 4.17 (Δ–1.66, [95% CI: -2.46;5.79], p=0.35); follow-up Total Mayo Scores were unavailable. Faecal calprotectin levels showed modest reductions in both groups.
A total of 75 adverse events (AEs) were recorded. Of these, 48 were mild (68%), consistent with previous findings(4). The most common ADRs were nausea (15% of AEs; 8 patients (80%)), abdominal pain (12%; 5 patients (50%)), dizziness (5%; 2 patients (20%)), and headache (4%; 2 patients (20%)). Three serious AEs occurred in one patient but did not result in discontinuation. None of the serious AEs were considered related to orismilast. The overall safety profile aligned with known effects of PDE4 inhibitors(4–6), although the frequency of nausea was higher, potentially reflecting overlap with underlying disease symptoms.
Conclusion
Orismilast demonstrated reductions in both Total and Partial Mayo scores among patients who completed the trial, and a reduction in Partial Mayo score among those who discontinued early. Although only one patient, who completed the full 12-week regimen, achieved both clinical and endoscopic response, three out of ten patients achieved remission based on Partial Mayo score, faecal calprotectin, and SCCAI. Adverse drug reactions were common; although none were severe, nausea had a notable impact on daily life. Effective management of this adverse event may be essential to improving tolerability and supporting the therapeutic potential of orismilast in the treatment of ulcerative colitis.
References
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3. 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 Jan 1;12(1):228–45.
4. Silverberg JI, Eichenfield LF, et al. Orismilast, a PDE4B/D inhibitor, in moderate-to-severe atopic dermatitis: Efficacy and safety from a multicenter, randomized, placebo-controlled, phase 2b dose-ranging study (ADESOS). Br J Dermatol [Internet]. 2025 Jan 7;
5. Warren RB, French LE, et al. Orismilast in moderate-to-severe psoriasis: Efficacy and safety from a 16-week, randomized, double-blinded, placebo-controlled, dose-finding, and phase 2b trial (IASOS). J Am Acad Dermatol. 2024 Mar 1;90(3):494–503.
6. Frederiksen CG, Sedeh FB, et al. Orismilast for the treatment of mild to severe hidradenitis suppurativa: Week 16 data from OSIRIS, a Phase 2a, open-label, single-centre, single-arm, dose-finding clinical trial. Journal of the European Academy of Dermatology and Venereology. 2024 May 1;38(5):920–30.
Disclosure
TVH: No disclosures
JBS: Research grants from Takeda and Johnson and Johnson, national coordinator of studies from AbbVie, Arena Pharmaceuticals, Ely Lilly, and Boehringer Ingelheim.
JB: Dr. Burisch reports grants from AbbVie, Janssen-Cilag, MSD, Takeda, Tillots Pharma, Bristol Myers Squibb, and Novo Nordisk Foundation; personal fees from AbbVie, Janssen-Cilag, Celgene, MSD, Pfizer, Takeda, Tillots Pharma, Bristol Myers Squibb, Samsung Bioepis, Pharmacosmos, Ferring, Galapagos, Eli Lilly, Dr Falk Pharma, Celltrion and Orion Pharma.
