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).

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease, characterized by eczematous skin lesions and pruritus. There is an unmet need for effective first-line systemic therapies with good safety profiles, particularly oral medications. Orismilast is a novel first-in-class oral phosphodiesterase-4 (PDE4) B/D inhibitor under investigation for the treatment of moderate-to-severe AD.

Objectives: To evaluate the optimal dose, efficacy and safety of orismilast twice-daily (BID) in patients with moderate-to-severe AD.

Methods: This 16-week, multicenter, randomized, placebo-controlled, phase 2b dose-ranging study (NCT05469464) included patients from 48 centers in Europe and the United States. Adults with moderate-to-severe AD were given (1:1:1:1) BID orismilast 20, 30, or 40 mg, or placebo. The primary endpoint was percentage change in Eczema Area and Severity Index (EASI); secondary: achievement of a score of Clear (0) or Almost Clear (1) with ≥2-point improvement by Investigator Global Assessment (IGA 0/1); achievement of peak pruritus numerical rating scale (PPNRS) reduction of ≥4 points; and achievement of a reduction in EASI of 75%, 90%, and 100% (EASI75, EASI90, EASI100, respectively) from baseline; all week 16.

Results: Overall, 233 patients were randomly assigned to orismilast 20 mg (n=58), 30 mg (n=61), 40 mg (n=59), or placebo (n=55). At week 16, Reductions in EASI (%-point) from baseline to week 16 were seen across orismilast groups and placebo (p>0.05 for orismilast versus placebo). Significantly more patients achieved IGA 0/1 with a ≥2-point improvement with orismilast 20 mg and 40 mg versus placebo (p<0.05). Significantly greater proportions of patients achieving a ≥4-point reduction in PPNRS were demonstrated with orismilast at week 2. The safety profile was consistent with that of the PDE4 class, with no major safety concerns reported.

Conclusions: These data support the clinical relevance of selective PDE4B/D inhibition with orismilast, potentially offering a convenient, novel, oral therapy for the treatment of AD.