Background

Heart failure with preserved ejection fraction (HFpEF), which accounts for about half of heart failure patients, is a refractory disease characterized by systemic congestion and dyspnea due to impaired diastolic function, despite maintained myocardial contractility. Hypertension, obesity, diabetes, and other metabolic comorbidities are complexly intertwined in its pathogenesis. Despite sodium-glucose cotransporter 2 (SGLT2) inhibitors becoming the standard of care recently, therapeutic options that fundamentally block myocardial fibrosis and microvascular damage remain limited.

The medical community has identified systemic microvascular endothelial inflammation as a primary driver of disease progression. Myeloperoxidase (MPO), secreted when circulating neutrophils are excessively activated, generates large amounts of reactive oxygen species, drastically reducing nitric oxide bioavailability. This contributes to the acceleration of vascular endothelial dysfunction and myocardial cell stiffness.

Mitiperstat, developed by AstraZeneca, is an oral small-molecule inhibitor that irreversibly covalently binds to the heme site of MPO to fundamentally block enzyme activity. Under the hypothesis that inhibiting the inflammatory cascade from neutrophils to MPO could restore microvascular function and directly improve patients' exercise capacity and quality of life, a global multicenter clinical trial was launched.

Key Findings

The ENDEAVOR Phase 2b study, published in Nature Medicine, was a large-scale project designed to verify this pathophysiological hypothesis using a randomized, double-blind, placebo-controlled method. Researchers recruited patients with HFpEF and heart failure with mildly reduced ejection fraction (HFmrEF) who had a left ventricular ejection fraction of 40% or higher, and assigned them to the mitiperstat or placebo groups.

Analysis of the primary endpoint at 16 weeks of treatment revealed no significant functional improvement as expected by the investigators. Neither the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS), a quality-of-life indicator perceived by patients, nor the 6-minute walk distance (6MWD), representing physical exercise capacity, showed statistical differences compared to the placebo group. In essence, the drug failed to significantly alleviate dyspnea or extend walking capacity.

Secondary endpoints showed a similar pattern. No significant improvements compared with placebo were observed in key cardiovascular biomarkers, including left ventricular diastolic function measured by echocardiography and blood N-terminal pro-B-type natriuretic peptide (NT-proBNP). Regarding safety evaluation, transient maculopapular skin rashes were reported in approximately 5% of patients, but overall tolerability was good.

A notable aspect was the clinical signal captured in the exploratory composite endpoint. Separately from the failure to improve symptoms, the composite event rate—comprising hospitalizations due to worsening heart failure, myocardial infarction, and cardiovascular death—showed a numerical trend that was 29% lower (hazard ratio 0.71) compared to the placebo group. Specifically, looking only at the risk of heart failure hospitalization, the relative risk decreased by approximately 36%. Although the analysis was not designed to establish statistical significance, it is difficult to rule out the possibility that enzyme inhibition had some impact on the long-term pathway of cardiovascular events.

Implications and Outlook

These results clearly demonstrate that the strategy of inhibiting the microvascular inflammatory cascade in heart failure patients does not directly translate to short-term improvements in exercise capacity or symptom alleviation. Even if MPO-derived oxidative stress is extensively involved in the disease formation process, it was insufficient to reverse long-standing myocardial fibrosis and structural changes within a short 16-week dosing period.

The future task lies in precise stratification to identify patient groups capable of demonstrating actual drug response. Companion diagnostic indicators must be established to identify specific phenotypes, such as those with extremely high systemic inflammation levels or prominent microvascular endothelial damage.

The signal of reduced heart failure hospitalization rate identified in the exploratory analysis also requires thorough verification through long-term follow-up studies. Rather than focusing on short-term subjective symptom alleviation, large-scale follow-up trials with a primary goal of reducing cardiovascular events and improving survival rates based on long-term administration of over one year are necessary to determine the true value of the therapeutic agent.