Details

Autor(en) / Beteiligte

• Vavere, Andrea L
• Sinsakul, Marvin
• Ongstad, Emily L
• Yang, Ye
• Varma, Vijayalakshmi
• Jones, Christopher
• Goodman, Joanne
• Dubois, Vincent F S
• Quartino, Angelica L
• Karathanasis, Sotirios K
• Abuhatzira, Liron
• Collén, Anna
• Antoniades, Charalambos
• Koren, Michael J
• Gupta, Ruchi
• George, Richard T

Titel

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

Ist Teil von

• Journal of the American Heart Association, 2023-02, Vol.12 (3), p.e027540

Ort / Verlag

England: John Wiley and Sons Inc

Erscheinungsjahr

2023

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 versus -8.25 mm ). 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.