Abstract
L-4F, an apolipoprotein A-I (apoA-I) mimetic peptide (also known as APL180), was administered daily by either intravenous (IV) infusion for 7 days or by subcutaneous (SC) injection for 28 days in patients with coronary heart disease in two distinct clinical studies. L-4F was well tolerated at all doses tested. Despite achieving plasma levels (mean maximal plasma concentration of 2,907 ng/ml and 395 ng/ml, following IV infusion and SC injection, respectively), that were effective in previously published animal models, treatment with L-4F, as assessed by biomarkers of HDL function such as HDL-inflammatory index (HII), and paraoxonase activity, did not improve. Paradoxically, there was a 49% increase in high-sensitivity C-reactive protein (hs-CRP) levels after seven IV infusions of 30 mg L-4F (P < 0.05; compared with placebo) and a trend for hs-CRP increase in subjects receiving 30 mg SC injection for 28 days. In a subsequent, ex vivo study, addition of L-4F at concentrations of 150, 375, or 1,000 ng/ml to plasma from subjects prior to L-4F treatment resulted in significant dose-dependent HII improvement. In conclusion, in vivo L-4F treatment, delivered by either SC injection or IV infusion, did not improve HDL functional biomarkers despite achieving plasma levels that improved identical biomarkers ex vivo and in animal models.
Highlights
L-4F, an apolipoprotein A-I mimetic peptide, was administered daily by either intravenous (IV) infusion for 7 days or by subcutaneous (SC) injection for 28 days in patients with coronary heart disease in two distinct clinical studies
We report here that despite achieving plasma levels of L-4F comparable to or well above those achieved in mouse models (8, 9) and in the early human studies with D-4F (5), no significant change in HDL-inflammatory index (HII) or PON were observed
Most of the adverse event (AE) reported in the study were mild and were similar in frequency between
Summary
L-4F, an apolipoprotein A-I (apoA-I) mimetic peptide ( known as APL180), was administered daily by either intravenous (IV) infusion for 7 days or by subcutaneous (SC) injection for 28 days in patients with coronary heart disease in two distinct clinical studies. Despite achieving plasma levels (mean maximal plasma concentration of 2,907 ng/ml and 395 ng/ ml, following IV infusion and SC injection, respectively), that were effective in previously published animal models, treatment with L-4F, as assessed by biomarkers of HDL function such as HDL-inflammatory index (HII), and paraoxonase activity, did not improve. In vivo L-4F treatment, delivered by either SC injection or IV infusion, did not improve HDL functional biomarkers despite achieving plasma levels that improved identical biomarkers ex vivo and in animal models.— Watson, C. After oral administration in mice, these mimetic peptides have been reported to improve the ability of HDL to inhibit LDL-induced monocyte chemoattractant protein-1 (MCP-1) production by human aortic endothelial cells as measured by monocyte migration in vitro and quantified as the HDL-inflammatory index (HII) (6–12)
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