CSL112 (apolipoprotein A-I [human]) reduces the elevation in neutrophil-lymphocyte ratio (NLR) induced by acute myocardial infarction

Abstract

Abstract Background CSL112 (apolipoprotein A-I [human]) is a novel therapy designed to reduce the risk of recurrent cardiovascular events following acute myocardial infarction (AMI). Preclinical data suggest that apolipoprotein A-I has anti-inflammatory properties which might contribute to atherosclerotic plaque stabilization (1). The neutrophil-lymphocyte ratio (NLR) is a clinically accessible measure of inflammatory status and predicts incident cardiovascular events in large outcome trials (2). It is unknown whether CSL112 can reduce inflammation as measured by the NLR. Purpose To evaluate whether infusion of CSL112 inhibits post-AMI inflammation as measured by NLR. Methods In a Phase 2 multicenter, double-blind study, 83 AMI patients with stage 3 chronic kidney disease were randomized 2:1 to receive 4 infusions of either 6 g CSL112 (n=55) or saline placebo (n=28) each separated by one week. The first infusion delivered on protocol Day 1 occurred 12h to 7d after presentation (mean 83 h). Blood samples were drawn prior to each infusion on Days 1, 8, 15 and 22 as well as at both Day 29 and 60 post the first infusion. Leukocyte data were available for up to 75 participants across the 6 sampling timepoints and neutrophil and lymphocyte counts were measured at the central laboratory. NLR was calculated and found to be non-normal in distribution and so analyses were performed on Loge transformed data. A mixed model repeated measures (MMRM) analysis was used to compare change from baseline (Day 1) in LogeNLR, neutrophil count and lymphocyte count between treatment groups (CSL112 6g versus Placebo) at the other 5 timepoints. An analysis of covariance (ANCOVA) was used to assess the effect of time from index MI to first infusion on change from baseline (Day 1) in LogeNLR at Day 8. Results The LogeNLR increased after AMI (between Day 1 and Day 8) with placebo treatment, whereas CSL112 infusion given after the Day 1 blood sample resulted in a decline (p=0.012; Fig 1, left panel, mean±SD). This effect of CSL112 was driven by reduction in neutrophil count (p=0.002; Fig 1, right panel) with lymphocyte levels remaining stable (p=0.537). Importantly, the magnitude of the effect of CSL112 to reduce NLR was greater if the timing of administration was closer to the index MI (treatment X time interaction and treatment effect both p=0.008). Conclusion CSL112 inhibits post-AMI elevation in NLR and this effect is maximized when infusion occurs early after presentation. It remains to be determined whether these anti-inflammatory effects of CSL112, in conjunction with previously demonstrated enhancement in cholesterol efflux capacity, will improve cardiovascular outcomes (3).Fig 1: Change in LogeNLR from baseline