Abstract 874: MLN1202, a Novel CCR2 Antagonist, Decreases C-reactive protein in Patients at Risk for Atherosclerotic Cardiovascular Disease in a Double Blind Placebo Controlled study

Abstract

Background: Macrophages play a central role in atherosclerotic plaque formation. The CC chemokine receptor 2 (CCR2), expressed on the surface of circulating monocytes, and its ligand MCP-1 (CCL2), are present in atherosclerotic plaques and may play a critical part in endothelial monocyte recruitment and activation. MLN1202 is a humanized monoclonal antibody with high specificity to CCR2, which interrupts MCP-1 binding to CCR2. MLN1202 is being developed for the treatment of immune mediated diseases. Hypothesis: We tested the hypothesis that MLN1202 significantly influences disease activity in patients at risk for ASCVD as measured by a reduction in circulating levels of high sensitivity C-reactive protein (hsCRP), an established biomarker of inflammation. Trial Design: In this double-blind placebo controlled study patients with at least 2 or more risk factors for ASCVD, no history or symptoms of ASCVD disease, and circulating levels of hsCRP > 3mg/L, were randomized 1:1 to receive a single infusion of 10 mg/kg MLN1202 (n 56) or placebo (n = 56). Subjects with hypercholesterolemia on stable doses of lipid-lowering agents were included. Circulating levels of hsCRP were determined every 2 weeks, and clinical examination performed every 4 weeks for 16 weeks following treatment. Results and Conclusion: Patients were recruited from nine centers in the US. The study population had a mean age of 60.9 years and included subjects with hypertension (59%), hypercholesterolemia (70%), significant smoking history (28%), and type 2 diabetes (16%). At screening the median value CRP was 6.8 mg/L with interquartile range from 4.7–9.3 mg/L. PK/PD results showed that the plasma level of MLN1202 required for > 90% receptor saturation was maintained for 6 to 8 weeks. A between-group difference in reduction of hsCRP was statistically significant from week 4 through week 8 following dosing. The maximum difference in absolute median reduction was observed at week 8 and it was 1.6 mg/L (p = 0.0275; Wilcoxon); the observed median percent reduction of hsCRP was 24.2% for MLN1202 group versus 2.5% increase for placebo group at 8 weeks (p = 0.0089; Wilcoxon). These data indicate that blockade of CCR2 reduces a biomarker related to inflammation in patients at risk for ASCVD.