Myeloperoxidase inhibition with mitiperstat in patients with heart failure (HF) with preserved or mildly reduced ejection fraction (HFpEF or HFmrEF, respectively) was safe and well-tolerated, but did not improve symptoms or exercise function, based on findings from the ENDEAVOR trial presented at AHA 2024.

The double-blind trial conducted from 2021–2024 at 142 sites in 18 countries randomized 711 patients into three groups, one receiving mitiperstat 2.5 mg (n=235), another receiving mitiperstat 5.0 mg (n=240), and another receiving placebo (n=236). All participants had symptomatic HF with LVEF >40%; a Kansas City Cardiomyopathy Questionnaire Total Summary Score (KCCQ-TSS) of ≤90 points, a 6-minute walk distance (6MWD) of 30–400 meters; elevated NTproBNP; and either structural heart disease, increased left ventricular filling pressure, significant diastolic dysfunction, or recent hospitalization for HF.

Overall results found that mitiperstat (2.5 mg + 5.0 mg groups pooled) vs. placebo did not improve KCCQ-TSS or 6MWD from baseline to 16 weeks (the primary endpoint), nor were there significant improvements at 24 and 48 weeks (secondary endpoints). Additionally, no significant improvements were seen in any of other secondary endpoints looking at biomarkers and echo parameters. However, researchers observed mitiperstat to be well-tolerated, with the exception of a self-limited maculopapular rash in roughly 5% of patients. Also of note, mitiperstat resulted in numerically fewer cardiovascular events (HR 0.71 [95% CI 0.42, 1.19]; p=0.20) and fewer HF hospitalizations (HR 0.64 [95% CI 0.35, 1.16]; p=0.14) compared with placebo.

"The potential benefits of decreased hospitalizations and death require further exploration in larger confirmatory randomized clinical trials," said lead author Sanjiv J. Shah, MD, FACC, when presenting the findings.