1. Academic Validation
  2. Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results

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

  • J Am Heart Assoc. 2023 Feb 7;12(3):e027540. doi: 10.1161/JAHA.122.027540.
Andrea L Vavere 1 Marvin Sinsakul 1 Emily L Ongstad 2 Ye Yang 3 Vijayalakshmi Varma 1 Christopher Jones 4 Joanne Goodman 4 Vincent F S Dubois 4 Angelica L Quartino 4 Sotirios K Karathanasis 2 Liron Abuhatzira 1 Anna Collén 5 Charalambos Antoniades 6 Michael J Koren 7 Ruchi Gupta 2 Richard T George 1
Affiliations

Affiliations

  • 1 Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USA.
  • 2 Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USA.
  • 3 Early CVRM Biometrics, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USA.
  • 4 Clinical Pharmacology & Quantitative Pharmacology Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca Gothenburg Sweden.
  • 5 Projects, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gothenburg Sweden.
  • 6 Division of Cardiovascular Medicine, Radcliffe Department of Medicine University of Oxford United Kingdom.
  • 7 Jacksonville Center for Clinical Research (JCCR) Jacksonville FL USA.
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 mm3 versus -8.25 mm3). 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.

Keywords

LOX‐1; atherosclerosis; cardiovascular disease; coronary CTA; diabetes.

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