Novel Mitochondria-Targeting Peptide in Heart Failure Treatment A Randomized, Placebo-Controlled Trial of Elamipretide

BACKGROUND: Mitochondrial dysfunction and energy depletion in the failing heart are innovative therapeutic targets in heart failure management. Elamipretide is a novel tetrapeptide that increases mitochondrial energy; however, its safety, tolerability, and therapeutic effect on cardiac structure and function have not been studied in heart failure with reduced ejection fraction. METHODS AND RESULTS: In this double-blind, placebo-controlled, ascending-dose trial, patients with heart failure with reduced ejection fraction (ejection fraction, <= 35%) were randomized to either a single 4-hour infusion of elamipretide (cohort 1 [n = 8], 0.005; cohort 2 [n = 8], 0.05; and cohort 3 [n = 8], 0.25 mg.kg(-1).h(-1)) or placebo control (n= 12). Safety and efficacy were assessed by clinical, laboratory, and echocardiographic assessments performed at pre-, mid-and end-infusion and 6-, 8-, 12-and 24-hours postinfusion start. Peak plasma concentrations of elamipretide occurred at end-infusion and were undetectable by 24 hours postinfusion. There were no serious adverse events. Blood pressure and heart rate remained stable in all cohorts. Compared with placebo, a significant decrease in left ventricular end-diastolic volume (-18 mL; P = 0.009) and end-systolic volume (-14 mL; P = 0.005) occurred at end infusion in the highest dose cohort. CONCLUSIONS: This is the first study to evaluate elamipretide in heart failure with reduced ejection fraction and demonstrates that a single infusion of elamipretide is safe and well tolerated. High-dose elamipretide resulted in favorable changes in left ventricular volumes that correlated with peak plasma concentrations, supporting a temporal association and dose-effect relationship. Further study of elamipretide is needed to determine long-term safety and efficacy.