Lectin-like oxidized LDL receptor-1 inhibition safe in patients with diabetes
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A novel agent demonstrated a dose-dependent relationship with lectin-like oxidized LDL receptor-1 suppression, a mechanism to lower inflammatory and lipid risk, and was well tolerated in a small study of patients with type 2 diabetes.
The study of MEDI6570 (AstraZeneca), a high-affinity human immunoglobulin G1 antibody to lectin-like oxidized LDL receptor-1 (LOX-1), was published in the Journal of the American Heart Association.
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“The present study is the first to demonstrate the effect of a high-affinity LOX-1 blocking antibody reducing free soluble LOX-1 levels. MEDI6570 demonstrated high selectivity and low immunogenicity, and no safety concerns related to immunogenicity were identified,” Andrea L. Vavere, MPH, of early clinical development, research and early development, cardiovascular and renal and metabolism at AstraZeneca, and colleagues wrote. “The present study also explored the effect of MEDI6570 on coronary atherosclerosis and inflammation. After 3 monthly doses of MEDI6570, regression of noncalcified plaque volume, low attenuation plaque volume and total plaque volume was observed, but the changes were not statistically significant.”
MEDI6570 and LOX-1 suppression
Vavere and colleagues wrote that LOX-1 is found on many of the cells associated with atherosclerotic CVD, including endothelial and smooth muscle cells, macrophages, neutrophils and platelets. LOX-1 binds multiple atherogenic ligands, including oxidized LDL, dysfunctional HDL, C-reactive protein, advanced glycosylation end products, activated platelets and apoptotic cells, the researchers wrote.
MEDI6570 is a high-affinity human immunoglobulin G1 antibody to LOX-1, designed to block the binding lipid and inflammatory ligands to LOX-1, according to the study.
This present phase 1, first-in-human, placebo-controlled study enrolled 88 patients with type 2 diabetes. Participants were randomly assigned to single ascending doses (10, 30, 90, 250 or 500 mg) or multiple ascending doses (90, 150 or 250 mg once monthly for 3 months) of MEDI6570 or placebo (single-ascending dose groups, mean age, 58 years; 31.3% women; multiple-ascending doses groups, mean age, 58 years; 62.5% women).
Safety and efficacy of MEDI6570
The primary endpoint was safety. Secondary and exploratory endpoints included pharmacokinetics, immunogenicity, free soluble LOX-1 levels and change in coronary plaque as determined on coronary CT angiography.
There were no deaths, life-threatening adverse events or adverse events that led to study withdrawal, and the incidence of adverse events was similar in the single ascending dose, multiple ascending doses and placebo groups.
The researchers reported that MEDI6570 displayed nonlinear pharmacokinetics that were consistent with target-mediated drug disposition after subcutaneous administration.
From baseline, the researchers observed a dose-dependent reduction in mean soluble LOX-1 of more than 66% at 4 weeks in the single-ascending doses group and 71.61% to 82.96% at 10 weeks in the multiple-ascending doses groups.
Among the 20 participants with coronary plaque at baseline, three doses of MEDI6570 was associated with nonsignificant regression of noncalcified coronary plaque volume compared with placebo (MEDI6570 groups, 13.45 mm3; 90% CI, 26.11 to 0.79; placebo group, 8.25 mm3; 90% CI, 30.42 to 13.92; P = .732).
Levels of CRP were not affected by MEDI6570 administration, according to the study.
“As the role of inflammation in atherosclerosis has been revealed, anti-inflammatory therapies have become a major focus of research, with mixed results to date in reducing the risk of major adverse CV events,” the researchers wrote. “Anti-LOX-1 therapy may offer an additional line of defense against atherosclerosis, alongside lipid-lowering therapies and emerging anti-inflammatory therapies.
“Further studies in patients with coronary heart disease are required to establish whether these initial results translate into reductions in atherosclerosis and underlying inflammation, and benefits for longer-term survival,” the researchers wrote.
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