573 ME3183, a novel phosphodiesterase-4 (PDE4) inhibitor, showed potent suppressive effects on pathogenic cytokine expression in cultures of peripheral blood mononuclear cells (PBMC) from psoriasis patients and on psoriatic features in mouse models

Abstract

Introduction & Objectives: PDE4 plays an important role in the immune system. ME3183, an oral PDE4 inhibitor, has shown anti-inflammatory effects in non-clinical studies. Here, we evaluated the therapeutic potency of ME3183 for psoriasis both in vitro and in vivo and compared it with apremilast, a marketed oral PDE4 inhibitor. Methods: In the in vitro assay, cultures of PBMC from 10 psoriasis (Ps) patients were stimulated with lipopolysaccharide (LPS) in the presence of ME3183 or apremilast, and the level of tumor necrosis factor-alpha (TNF-α) was measured. In the psoriasis model, imiquimod was applied on shaved dorsal skin for 6 consecutive days. In the arthritis model, collagen antibody was injected on Day 0 and LPS on Day 3. In both models, ME3183 or apremilast was administered twice daily, and clinical score and histological findings were evaluated. Gene expression by real-time polymerase chain reaction and cell population were analyzed in the psoriasis model and paw thickness in the arthritis model. Results: In cultures of PBMC from Ps patients, ME3183 showed a 114-fold inhibitory activity against TNF-α production than apremilast. We next evaluated the effects of ME3183 on psoriasis and arthritis in vivo. In the psoriasis model, ME3183 significantly ameliorated the psoriatic score, epidermal thickness, gene expressions of interleukin (IL)-17A and IL-23p19 and skin infiltration of IL-17A+ cells. In the arthritis model, ME3183 significantly suppressed the arthritis score and paw thickness. In both models, ME3183 was effective at low doses compared to apremilast. Conclusions: Our results indicated that ME3183 had potent anti-psoriatic effects via suppression of pathogenic cytokine expression. ME3183 may have higher therapeutic effects on Ps and psoriatic arthritis compared to the current oral PDE4 inhibitor. The clinical efficacy of ME3183 will be evaluated in the P2a study with Ps patients.