AZD5718
Preclinical pharmacology
AZD5718 is a reversible FLAP inhibitor (equilibrium dissociation constant [Kd] 0.0044 μmol/L and estimated binding off-rate (Koff) 1.27 min-1 that inhibits LTB4 production in human whole blood in vitro with a concentration giving 50% of the drug induced inhibitory effect (IC50) of 0.039 μmol/L and a maximum effect >95%. In preclinical studies, AZD5718 inhibited leukotriene production in dog and rabbit blood with a similar potency to human but was inactive in rat and mouse blood. Single and repeat oral administration of AZD5718 to healthy beagle dogs resulted in a concentration dependent inhibition of LTB4 production in blood and robust reduction in leukotriene E4 (LTE4) levels in urine. When administered iv. to rabbits, AZD5718 resulted in a concentration dependent reduction in LTB4 production and inhibition of LTC4 production in blood.
Safety and tolerability
The safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD5718, was evaluated in a randomized, single‐blind, placebo‐controlled, first‐in‐human (FIH) study consisting of single and multiple ascending dosing (SAD and MAD) for 10 days in healthy subjects. No clinically relevant safety and tolerability findings were observed. The AZD5718 was rapidly absorbed and plasma concentrations declined biphasically with a mean terminal half‐life of 10–12 h. Steady‐state levels were achieved after ∼3 days.
AZD5718 was also shown to be well tolerated in patients with a recent MI in the FLAVOUR study with no safety concerns identified.
Clinical pharmacology
Target engagement was measured by ex vivo calcium ionophore stimulated leukotriene B (LTB4) production in whole blood and endogenous leukotriene E (LTE4) in urine. After both SADs and MADs, a dose/concentration‐effect relationship between both LTB4 and LTE4 vs. AZD5718 exposure was observed with concentration of half inhibition (IC50) values in the lower nM range. A reduction in mean uLTE4 levels with AZD5718 was also demonstrated in Patients 7-28 days after MI in the FLAVOUR Ph2a study, with statistically significant reductions at 4- and 12-weeks.
Suitable for and exclusions
Suitable for in vitro experiments (human) and clinical/ESR studies but not pre-clinical in vivo studies.
Mechanism of Action
5-lipoxygenase activating protein (FLAP) inhibitor
Original Therapeutic Area
CVRM
CNS Penetrant
Low/limited distribution to the brain based on QWBA study
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Pettersen D., et al. (2019).
Discovery and Early Clinical Development of an Inhibitor of 5-Lipoxygenase Activating Protein (AZD5718) for Treatment of Coronary Artery Disease. J Med Chem. May 9;62(9):4312-4324. doi: 10.1021/acs.jmedchem.8b02004. Epub 2019 Mar 26. PMID: 30869888.
2. Ericsson H., et al. (2018).
Initial Clinical Experience with AZD5718, a Novel Once Daily Oral 5-Lipoxygenase Activating Protein Inhibitor. Clin Transl Sci. May;11(3):330-338. doi: 10.1111/cts.12546. Epub 2018 Mar 8. PMID: 29517132; PMCID: PMC5944575.
3. Prescott E., et al. (2020).
Design and rationale of FLAVOUR: A phase IIa efficacy study of the 5-lipoxygenase activating protein antagonist AZD5718 in patients with recent myocardial infarction. Contemp Clin Trials Commun. Jul 30;19:100629. doi: 10.1016/j.conctc.2020.100629. PMID: 32875138; PMCID: PMC7451793.