Novel Mitochondria-Targeting Peptide in Heart Failure Treatment: A Randomized, Placebo-Controlled Trial of Elamipretide. (December 2017)

• Record Type: Journal Article
• Authors: Daubert, Melissa A.; Yow, Eric; Dunn, Gary; Marchev, Sotir; Barnhart, Huiman; Douglas, Pamela S.; O'Connor, Christopher; Goldstein, Sidney; Udelson, James E.; Sabbah, Hani N.
• Is Part Of: Circulation. Volume 10:Number 12(2017)
• Publication Date: 2017-12
• Subjects: blood pressure -- heart failure -- heart rate -- humans -- stroke volume; Heart failure -- Periodicals; 616.129005
• DOI: 10.1161/CIRCHEARTFAILURE.117.004389
• Languages: English
• ISSNs: 1941-3289

Abstract

Abstract : 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. Clinical Trial Registration: URL:https://www.clinicaltrials.gov . Unique identifier: NCT02388464. Abstract : Supplemental Digital Content is available in the text.