Report on the Investigational Myeloperoxidase Inhibitor: Mitiperstat (AZD4831)

Section 1: Executive Summary

Mitiperstat, also known as AZD4831, is a first-in-class, orally available, irreversible inhibitor of the enzyme myeloperoxidase (MPO) developed by AstraZeneca.[1] The therapeutic rationale for its development was predicated on a compelling biological hypothesis: that by inhibiting MPO, a key enzyme released by neutrophils during inflammation, it could mitigate the downstream effects of oxidative stress and microvascular dysfunction believed to drive the pathophysiology of complex inflammatory conditions.[3] The primary focus of its clinical program was heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF), with parallel investigations in chronic obstructive pulmonary disease (COPD) and non-alcoholic steatohepatitis (NASH).[3]

The clinical journey of Mitiperstat followed a path from initial promise to definitive failure. The Phase 2a SATELLITE trial successfully demonstrated proof of mechanism, confirming that Mitiperstat achieved robust target engagement by significantly reducing MPO activity in patients with HFpEF.[7] This success, coupled with a generally acceptable safety profile, supported its advancement into a large-scale, pivotal trial. However, the subsequent seamless Phase 2b/3 ENDEAVOR trial, involving over 700 patients, failed to meet both of its co-primary endpoints. Mitiperstat did not produce any statistically significant improvement in patient-reported symptoms, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), or in functional capacity, as measured by the 6-minute walk distance (6MWD), when compared to placebo.[9]