CHICAGO -- Mitiperstat, a novel myeloperoxidase (MPO) inhibitor, has failed to demonstrate significant improvements in quality of life or functional capacity for patients suffering from heart failure with mid-range to preserved ejection fraction (HFmrEF, HFpEF). The results come from the phase II ENDEAVOR trial, presented at the American Heart Association (AHA) Scientific Sessions.
Primary Endpoints Not Met
The trial's primary endpoint, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ-TSS), showed a minimal least squares (LS) mean difference of -1.4 points compared to placebo (P = 0.29). This difference falls short of the clinically significant threshold of 5 points on the 100-point scale. Similarly, the co-primary endpoint, the 6-minute walk distance (6MWD), showed an LS mean difference of only +3.8 meters (P = 0.28).
Potential Signal in Heart Failure Hospitalization
Despite the failure to meet primary endpoints, an exploratory composite outcome of heart failure hospitalization, myocardial infarction, or death showed a numerical reduction with mitiperstat (HR 0.71, 95% CI 0.42-1.19, P = 0.196). This was largely driven by a 36% relative reduction in heart failure hospitalization, a finding that Sanjiv J. Shah, MD, of Northwestern University, suggested merits further investigation in larger confirmatory randomized controlled trials.
Context of Heart Failure Treatment
Amanda Vest, MBBS, MPH, head of heart failure and transplant cardiology at the Cleveland Clinic, noted the precedent for heart failure medications that reduce heart failure hospitalizations without impacting 6MWD or quality of life, citing SGLT2 inhibitors and angiotensin receptor neprilysin inhibitors as examples.
Mitiperstat's Mechanism and Proteomics Analysis
Mitiperstat targets the inflammatory enzyme MPO, primarily produced by neutrophils. Proteomics analysis from the ENDEAVOR trial suggested a potential benefit of mitiperstat on clinical events by reducing monocyte activation through decreased mitochondrial stress, according to Shah.
Trial Details
The phase IIb trial involved 709 adults aged 40-85 with symptomatic heart failure and a left ventricular (LV) ejection fraction greater than 40%. Participants were randomized to receive either 2.5 mg or 5.0 mg of mitiperstat, or a placebo, for 48 weeks. Key inclusion criteria included New York Heart Association class II-IV heart failure, a KCCQ-TSS score of ≤90, a 6MWD of 30-400 meters, elevated NT-proBNP levels, and at least one risk factor such as LV hypertrophy, left atrial enlargement, elevated LV filling pressure, or recent heart failure hospitalization.
Secondary Endpoints and Adverse Events
None of the secondary endpoints, including KCCQ-TSS and 6MWD results at 24 and 48 weeks, and inflammatory markers such as interleukin 6 and high-sensitivity C-reactive protein, NT-proBNP, or echocardiography parameters at 16, 24, and 48 weeks, showed a significant advantage with mitiperstat. Overall and serious adverse event rates were similar across groups, although maculopapular rash was more common with mitiperstat.
Proteomics Substudy Insights
The ENDEAVOR proteomics substudy, involving 397 patients, identified three clusters of proteins that changed with mitiperstat treatment, related to the immune system, metabolism and biological oxidation, and platelets, cell surface receptors, and chemokines. Changes in six "hub proteins" were observed in the mitiperstat groups compared to placebo (P < 0.05), with GRPEL1, a stress resistance protein, associated with lower heart failure hospitalizations in U.K. Biobank data.
