Background Apremilast (APR), an oral phosphodiesterase 4 inhibitor, works intracellularly to regulate inflammatory mediators. PALACE 1 compared the efficacy and safety of APR with placebo in patients with active psoriatic arthritis despite prior conventional DMARDs and/or biologics. In this phase 3 trial, APR demonstrated significant efficacy, including improvement in signs and symptoms and physical function related to psoriatic arthritis, and demonstrated maintenance of response through Week 52.
Objectives This exploratory analysis evaluated the pharmacodynamic effects of APR on plasma biomarkers associated with inflammation in a subset of patients.
Methods Patients were randomized 1:1:1 to placebo, APR 20 mg BID (APR20), or APR 30 mg BID (APR30) stratified by baseline DMARD use (yes/no). Peripheral blood plasma samples were collected from consenting patients at baseline and at Weeks 4, 16, 24, and 40 for analysis in a multiplexed cytometric bead array assay measuring 47 proteins (Human InflammationMAP, Myriad RBM, Austin, TX, USA). The statistical analysis identified significant differences (P<0.05; rank ANCOVA) in the percent change from baseline among the treatment groups. Logistic regression analyses assessed the association between the percent change of the biomarkers and the achievement of an ACR20 clinical response.
Results The biomarker subset included 150 patients (placebo: n=51; APR20: n=51; and APR30: n=48). Subjects in the biomarker subset had demographics and disease characteristics comparable with those of the full analysis set, with the exception of prior exposure to a biologic DMARD such as a TNF blocker, which was higher in the biomarker subset (48.8%) than in the full analysis set (23.6%). In the APR20 or APR30 treatment arms, there were significantly lower percent changes from baseline, compared with placebo, for the following markers. At Week 4: interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α), macrophage inflammatory protein beta (MIP-1β), and monocyte chemotactic protein 1 (MCP-1). At Week 16: IL-8, TNF-α, IL-6, and ferritin. At Week 24: IL-8, TNF-α, IL-6, MIP-1β, MCP-1, and ferritin. Logistic regression analyses indicated that clinical responses correlated with the percent changes in TNF-α in both the APR20 and APR30 treatment groups. A significant increase in von Willebrand Factor (vWF) was observed at Weeks 16 and 24 (although all vWF values remained within the normal range, <120 μg/mL, and returned to baseline levels by Week 40). After 40 weeks of APR30 treatment, there were significant decreases in IL-17, IL-23, IL-6, and ferritin from baseline levels, and significant increases in IL-10 and IL-1 receptor antagonist from baseline levels.
Conclusions Treatment with APR for 4-24 weeks was associated with significant reductions in circulating levels of IL-8, TNF-α, IL-6, MIP-1β, MCP-1, and ferritin, representing components of pro-inflammatory innate Th1 immunity. After 40 weeks, there was significant inhibition of IL-6, IL-23, and IL-17 on APR30 treatment, suggesting that long-term APR therapy inhibits components of the systemic Th17 immune response in patients with psoriatic arthritis.
Disclosure of Interest P. Schafer Employee of: Celgene Corporation, P. Chen Employee of: Celgene Corporation, L. Fang Employee of: Celgene Corporation, A. Wang Employee of: Celgene Corporation, R. Chopra Employee of: Celgene Corporation