Early Clinical Experience With AZD4831, A Novel Myeloperoxidase Inhibitor, Developed for Patients With Heart Failure With Preserved Ejection Fraction

Abstract

We evaluated safety, tolerability, pharmacokinetics and pharmacodynamics of AZD4831, a novel oral myeloperoxidase (MPO) inhibitor, in a randomized, single blind, placebo-controlled study, following once daily multiple ascending dosing to steady state in healthy subjects. Target engagement was measured as specific MPO activity in plasma following ex vivo zymosan stimulation of whole blood. Except for generalized maculopapular rash in 4 out of 13 subjects receiving the two highest doses, 15 mg and 45 mg AZD4831, no clinically relevant safety and tolerability findings were observed. AZD4831 was rapidly absorbed and plasma concentrations declined slowly with an elimination half-life of approximately 60 hours. A dose/concentration-effect relationship between MPO inhibition vs. AZD4831 exposure was established with >50 % MPO inhibition in plasma at concentrations in the low nanomolar range. Steady state levels were achieved within 10 days. Taken together the pharmacokinetic profile, the sustained dose/concentration dependent MPO inhibition, and available clinical data support further clinical development of AZD4831 in patients with heart failure with preserved ejection fraction (HFpEF).

Inflammation in Human Heart Failure: Major Mediators and Therapeutic Targets

“…Despite several lines of evidence indicating an association between increased MPO concentrations and HF pathogenesis and severity, the clinical benefit of MPO inhibition in HF patients remains unknown (Ng et al, 2006;Tang et al, 2006Tang et al, , 2007Reichlin et al, 2010;Ndrepepa, 2019). A clinical trial is currently evaluating the hemodynamic effects of an oral MPO inhibitor, AZD4831, following baseline, resting and exercise testing in HFpEF patients during right heart catheterization (Gan et al, 2019;Nelander et al, 2021).…”

Discovery of AZD4831, a Mechanism-Based Irreversible Inhibitor of Myeloperoxidase, As a Potential Treatment for Heart Failure with Preserved Ejection Fraction

“…The consequence of this flatter pharmacokinetic profile was that the targeted unbound trough concentration after multiple doses (11 nM) was obtained in the low end of the predicted dose range: 5 mg in healthy volunteers and 2.5 mg in patients with HFpEF. 42 …”

“…We recently reported results from two phase 1 studies of AZD4831 ( 16 ) in healthy volunteers, one using single ascending doses and one using multiple ascending dosing to steady state . Results indicated that exposure in humans was well predicted from the preclinical pharmacokinetic data.…”

“…The likely reason for the underprediction of AUC was that we used a model with a monoexponential decline of the drug concentration, while the observed concentration–time profiles showed a biexponential decline with a longer terminal half-life ( t 1/2 ) than predicted ( t 1/2,obs ∼45 h vs t 1/2,pred ∼ 11 h), mainly due to a larger volume of distribution than predicted. The consequence of this flatter pharmacokinetic profile was that the targeted unbound trough concentration after multiple doses (11 nM) was obtained in the low end of the predicted dose range: 5 mg in healthy volunteers and 2.5 mg in patients with HFpEF …”

“…Preclinical efficacy assessments in animal models showed that AZD4831 dose-dependently inhibits MPO, and safety assessments did not reveal any findings of concern. In phase 1 clinical studies in healthy volunteers, AZD4831 was generally well tolerated, was rapidly absorbed with a long plasma half-life, and dose-dependently inhibited MPO in whole blood. , In a phase 2a clinical study of AZD4831 ( 16 ) in patients with HFpEF, target engagement (inhibition of MPO) was confirmed and in exercise capacity (6 min walking distance) and health-related quality of life (Kansas City Cardiomyopathy Questionnaire–overall summary score) increased numerically (SATELLITE; NCT03756285; manuscript in preparation). A phase 2 b /3 dose-finding and efficacy study in patients with HFpEF started in July 2021 (ENDEAVOR; NCT04986202).…”