Regression of coronary atherosclerosis with infusions of the high-density lipoprotein mimetic CER-001 in patients with more extensive plaque burden

Abstract

Background: CER-001 is an engineered pre-beta high-density lipoprotein (HDL) mimetic, which rapidly mobilizes cholesterol. Infusion of CER-001 3 mg/kg exhibited a potentially favorable effect on plaque burden in the CHI-SQUARE (Can HDL Infusions Significantly Quicken Atherosclerosis Regression) study.Since baseline atheroma burden has been shown as a determinant for the efficacy of HDL infusions, the degree of baseline atheroma burden might influence the effect of CER-001.Methods: CHI-SQUARE compared the effect of 6 weekly infusions of CER-001 (3, 6 and 12 mg/kg) vs. placebo on coronary atherosclerosis in 369 patients with acute coronary syndrome (ACS) using serial intravascular ultrasound (IVUS). Baseline percent atheroma volume (B-PAV) cutoff associated with atheroma regression following CER-001 infusions was determined by receiver-operating characteristics curve analysis.369 subjects were stratified according to the cutoff. The effect of CER-001 at different doses was compared to placebo in each group.Results: A B-PAV ≥30% was the optimal cutoff associated with PAV regression following CER-001 infusions. CER-001 induced PAV regression in patients with B-PAV ≥30% but not in those with B-PAV <30% (−0.45%±2.65% vs. +0.34%±1.69%, P=0.01). Compared to placebo, the greatest PAV regression was observed with CER-001 3mg/kg in patients with B-PAV ≥30% (−0.96%±0.34% vs. −0.25%±0.31%, P=0.01), whereas there were no differences between placebo (+0.09%±0.36%) versus CER-001 in patients with B-PAV <30% (3 mg/kg; +0.41%±0.32%, P=0.39; 6 mg/kg; +0.27%±0.36%, P=0.76; 12 mg/kg; +0.32%±0.37%, P=0.97).Conclusions: Infusions of CER-001 3 mg/kg induced the greatest atheroma regression in ACS patients with higher B-PAV. These findings identify ACS patients with more extensive disease as most likely to benefit from HDL mimetic therapy.

Relation of High‐Density Lipoprotein Charge Heterogeneity, Cholesterol Efflux Capacity, and the Expression of High‐Density Lipoprotein‐Related Genes in Mononuclear Cells to the HDL‐Cholesterol Level

“…In general, the ABCA1 and ABCG1 expression pattern may indicate a reduced intracellular cholesterol level and/or an inhibition of expression of transporter genes by increased HDL content. Indeed, an inhibition of ABCA1 expression by high doses of native HDL 3 and reconstituted HDL with recombinant apoA‐I was previously demonstrated in vivo and in vitro (Kataoka et al, ; Tardy et al, ). Moreover, the tendency to decrease of the CUBN transcript in hyperalphalipoproteinemics (Fig.…”

Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings

“…Despite this concern of a down-regulation at higher doses, the clinical effectiveness of CER-001 has also been observed in plaque regression in patients with genetic dyslipidaemia or acute coronary syndrome [8–10]. …”

Effect of serial infusions of reconstituted high-density lipoprotein (CER-001) on coronary atherosclerosis: rationale and design of the CARAT study

“…Whether this reflects saturation of cholesterol efflux transporters or the effects of increasing administration of the lipid contents of CER-001 is unknown. F u r t h e r a n a l y s i s d e m o n s t r a t e d m u c h g r e a t e r regression with CER-001 3 mg/kg in those patients whose baseline PAV was greater than 30%, suggesting a more substantial effect on regression in patients with a greater burden of atherosclerotic plaque at baseline (49). In composite, these findings suggest that CER-001 may have an anti-atherosclerotic effect in humans, which appears to be more robust in patients with a greater baseline plaque burden and is observed at lowest tested dose.…”