Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results

Abstract

Background Blockade of the lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) is a potentially attractive mechanism for lowering inflammatory and lipid risk in patients with atherosclerosis. This study aims to assess the safety, tolerability, and target engagement of MEDI6570, a high‐affinity monoclonal blocking antibody to LOX‐1. Methods and Results This phase 1, first‐in‐human, placebo‐controlled study (NCT03654313) randomized 88 patients with type 2 diabetes to receive 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. Primary end point was safety; secondary and exploratory end points included pharmacokinetics, immunogenicity, free soluble LOX‐1 levels, and change in coronary plaque volume. Mean age was 57.6/58.1 years in the single ascending doses/multiple ascending doses groups, 31.3%/62.5% were female, and mean type 2 diabetes duration was 9.7/8.7 years. Incidence of adverse events was similar among cohorts. MEDI6570 exhibited nonlinear pharmacokinetics, with terminal half‐life increasing from 4.6 days (30 mg) to 11.2 days (500 mg), consistent with target‐mediated drug disposition. Dose‐dependent reductions in mean soluble LOX‐1 levels from baseline were observed (>66% at 4 weeks and 71.61–82.96% at 10 weeks in the single ascending doses and multiple ascending doses groups, respectively). After 3 doses, MEDI6570 was associated with nonsignificant regression of noncalcified plaque volume versus placebo (−13.45 mm 3 versus −8.25 mm 3 ). Conclusions MEDI6570 was well tolerated and demonstrated dose‐dependent soluble LOX‐1 suppression and a pharmacokinetic profile consistent with once‐monthly dosing. Registration URL: https://clinicaltrials.gov/ ; Unique identifier: NCT03654313.

Association of oxidized ApoB and oxidized ApoA-I with high-risk coronary plaque features in cardiovascular disease

“…Moreover, sLOX-1 levels were shown to be predictive of fatal events beyond traditional risk factors and associated with coronary plaque progression in patients with atherosclerotic CVD ( 11 ). Recent clinical investigation of the LOX-1 pharmacological blockade in type 2 diabetes patients showed promising results that were characterized by regression of noncalcified plaque volume ( 26 ).…”

LOX-1 in Cardiovascular Disease: A Comprehensive Molecular and Clinical Review

“…Dose-dependent reductions in soluble LOX-1 levels were observed, with a favorable safety profile and nonlinear pharmacokinetics. MEDI6570 showed promising results in suppressing soluble LOX-1 levels and demonstrated a pharmacokinetic profile consistent with once-monthly dosing, suggesting its potential as a therapeutic option [57].…”

LOX-1 and MMP-9 Inhibition Attenuates the Detrimental Effects of Delayed rt-PA Therapy and Improves Outcomes After Acute Ischemic Stroke

“…23 Although the LOX-1 receptor is capable of binding oxLDL, there are a multitude of other substrates that share few structural similarities to oxLDL such as C reactive protein, fibronectin, and aged/apoptotic cells all of which are capable of binding to this scavenger receptor. 24 As such LOX-1 has been investigated in the context of vascular pathology such as atherosclerosis, [25][26][27][28] diabetes type II, 29 and in stroke 30,31 ; therefore, targeting LOX-1 may be beneficial in mitigating the pathogenesis of AIS, even in the absence of elevated oxLDL levels. Moreover, at the level of the cerebrovascular endothelium, LOX-1 signaling in part increases MMP-9 activity and decreases tight junction protein expression.…”