in mice that received cyclosporine treatment. Qualitative immunohistochemistry showed decreases in TNF-α, intercellular adhesion molecule-1 and human leukocyte antigen-DR labeling in the epidermal tissue.17 In a separate study, similarly to dexamethasone, apremilast reduced ear swelling in two mouse models of dermatitis using fluorescein isothiocyanate and dinitrochlorobenzene compared with vehicle-treated mice. Apremilast also significantly decreased monocyte chemoattractant protein-1 protein levels in mouse ears (Celgene, data on file).
Apremilast’s Mechanism of Action and Clinical Efficacy
The relationship between how apremilast works on key immune cell populations and how it alters expression of cytokines/inflammatory mediators to produce beneficial clinical effects has been explored using subanalyses of clinical trial data in patients with moderate to severe psoriasis or recalcitrant psoriasis. In the first apremilast psoriasis study, an early open-label pilot study, patients with severe psoriasis were treated with apremilast 20 mg once daily for 29 days.22 Analysis of skin biopsies at the end of treatment (vs baseline) demonstrated that 8 of 15 (53%) patients with evaluable samples experienced a ≥20% reduction in epidermal thickness (ie, “response”); among all the patients, the mean decrease in epidermal thickness was 20.5%. Improvements were seen across most immunohistochemical parameters evaluated, including decreases in the numbers of T cells and CD11c myeloid dendritic cells in the dermis and epidermis; improvements were generally greater in patients who showed reductions in epidermal thickness.22 Also, in this first apremilast psoriasis study, a reduction of TNF-α production was observed using a whole blood ex vivo assay, despite the very low dose administered (20 mg once daily, which is one-third the approved clinical dose of 30 mg twice daily).15,22 Based on these favorable changes in biomarkers measured in the psoriatic skin (epidermal thickness) and blood (TNF-α production ex vivo), apremilast was advanced into further clinical development for psoriasis.In a phase II open-label, single-arm trial in patients with recalcitrant psoriasis, 12 weeks of treatment with apremilast 20 mg twice daily reduced infiltration of myeloid dendritic cells, T cells, and NK cells into the dermis and epidermis.23 In real-time reverse transcriptase polymerase chain reaction analyses of skin biopsy specimens, significant reductions in gene expression were observed for IL-12/IL-23p40, IL-23p19, IL-17A, IL-22, IL-8, and defensin beta 4 (DEFB4), all of which are considered part of the Th17 pathway (Figure 1).23 Among these genes, the reduction in IL-17A and DEFB4 significantly correlated with the reduction in the Psoriasis Area and Severity Index (PASI) score at week 12.23 For example, there was a median −46.7% change from baseline IL-17A gene expression and a median −46.5% change from baseline PASI score at week 12 (n=10, P=0.030).23 Thus, the magnitude of the decreased IL-17A gene expression in the lesional skin was quite similar to the magnitude of the decrease in PASI score at the low apremilast dose of 20 mg twice daily. In general, the inhibition of pro-inflammatory genes was greater in patients with a clear beneficial clinical response (eg, ≥75% reduction from baseline PASI [PASI-75]).23 Notably, there was an increase in IL-10 gene expression in the skin of responders, but a decrease in the non-responders, indicating that apremilast mediates an increase in this anti-inflammatory gene in some but not all patients.Comprehensive analyses of the relationship between normalized cytokine profiles and clinical improvement during apremilast treatment in patients with moderate to severe plaque psoriasis have been performed in randomized, placebo-controlled trials. An analysis was conducted using data
