MEDI6570
Preclinical pharmacology
MEDI6570 can block multiple ligands to the LOX-1 scavenger receptor, including, but not limited to oxidized LDL and other modified lipids. Blockade of the receptor reduced cytokine release via the NFkappaB pathway, inhibited monocyte adhesion, prohibited monocyte differentiation to foam cells and smooth muscle cell apoptosis, and improved endothelial function.
LOX-1 KO mice showed reductions in atherosclerosis and protection from heart failure. Human ex-vivo cell cultures demonstrated MEDI6570 prevents foam cell formation and macrophage apoptosis, reduced inflammation and endothelial dysfunction.
Safety and tolerability
No drug related toxicity signal was observed in the 6-month Cynomolgus monkey chronic tox study, including in bone marrow where LOX-1 is expressed. LOXIN mutation, protective against LOX-1-induced damage, is asymptomatic in man. Single- and multiple-doses were well-tolerated in a Ph1 clinical study.
Clinical pharmacology
HTV - LOX-1 is upregulated in human atherosclerotic plaque; soluble LOX-1 levels predict major CV events (MACE). LOX-1 inactivating mutation LOXIN confers resistance to atherogenesis and CVD (Clin Exp Cardiol 2013;4:232). Inflammatory hypothesis confirmed in CANTOS that canakinumab reduced MACE and heart failure in patients with prior MI (NEJM 2017;377:1119); greatest risk reduction seen in those with CRP reduction. MEDI6570 blocks a wide range of inflammatory mediators.
Suitable for and exclusions
MEDI6570 is suitable for post-MI patients with high residual risk attributed to inflammation via direct inhibition of multi-ligand scavenger receptor involved in oxidized LDL pathogenesis and inflammation. Currently we would not recommend dosing in WOCBP.
Mechanism of Action
Anti-lectin-like oxidized LDL receptor 1 Monoclonal Antibody that inhibits the LOX-1 receptor (anti-LOX-1 mAb)
Original Therapeutic Area
Cardiovascular, Renal and Metabolism
CNS Penetrant
No
Route of administration
Subcutaneous
Modality
Antibody
