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.
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.
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.
Nearly half of all patients with heart failure have a reduced ejection fraction (EF), and despite current therapies, these patients have a diminished quality of life and poor long-term prognosis with an absolute mortality rate of approximately 50% within 5 years of diagnosis. In heart failure with reduced EF (HFrEF), there is activation of neurohumoral responses that attempt to compensate for impaired cardiac performance, but these compensatory mechanisms also increase myocardial energy expenditure. Normal cardiac function is reliant on having an adequate supply of energy in the form of adenosine triphosphate (ATP). The amount of ATP in the myocyte is relatively small compared with demand, which can be 10 000× greater; therefore, myocardial cells must continually resynthesize ATP to maintain normal pump function and cellular viability. However, in the failing heart, energy generation is impaired leading to a progressive loss of ATP, which results in diminished contractile reserve and myocardial pump dysfunction.
Elamipretide (MTP-131, Bendavia) is a novel tetrapeptide that targets mitochondrial dysfunction in energy-depleted myocytes and has the potential to augment cardiac function in patients with HFrEF. In vitro and in vivo studies have demonstrated that elamipretide can ameliorate or prevent many measures of mitochondrial dysfunction, including a reduction in ATP levels. In preclinical studies, elamipretide significantly improved left ventricular (LV) systolic function, prevented pathological LV remodeling after myocardial infarction, increased myocardial ATP synthesis, and restored mitochondria-related gene expression. Based on these results, we hypothesize that elamipretide may present a novel approach to treating HFrEF by reversing the myocardial energy deficit and improving cardiac function. To study this, we conducted the first trial of elamipretide in patients with HFrEF to examine the safety, efficacy, and tolerability of this treatment when added to guideline-directed heart failure therapy.
This study was a prospective, randomized, double-blind, placebo-controlled, single ascending-dose trial that included patients with HFrEF and stable New York Heart Association classes II to III heart failure. Patients were randomized (2:1) to a single 4-hour intravenous infusion of elamipretide or an equivalent volume placebo infusion. Enrollment occurred in 3 successive cohorts of increasing elamipretide dose (0.005, 0.05, and 0.25 mg·kg−1·h−1).
Patients with New York Heart Association class II or III heart failure who had an LV EF ≤35% on a baseline screening 2-dimensional echocardiogram were recruited for the study. Eligible patients were required to be between 45 and 80 years of age, have either nonischemic or ischemic cardiomyopathy of at least 6 months duration, and have been treated with guideline-based pharmacological heart failure therapy at stable doses for a minimum of 1 month before enrollment. Heart failure therapy included treatment with β-blocker and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, with or without a mineralocorticoid antagonist. Patients were not eligible if they had a heart failure hospitalization, acute myocardial infarction, or cerebrovascular event in the prior 3 months. Patients with atrial fibrillation or cardiac resynchronization therapy were also excluded. Additional inclusion and exclusion criteria are provided in Table I in the Data Supplement.
The study was conducted at a single site: Bulgarian Cardiac Institute, Medical University of Pleven, Bulgaria. All patients provided written informed consent to participate. Screening evaluations were performed within 28 days of enrollment. Enrolled patients were randomized and admitted to the clinical study unit for a baseline evaluation on day 1. On day 2, predose assessments were conducted within 2 hours before study drug infusion. Each patient then received a single 4-hour intravenous infusion of elamipretide or placebo. Both the study drug and placebo, manufactured by Patheon, were provided to the site as a lyophilized powder in identical sterile glass vials and reconstituted with 250 mL of normal saline before administration. Study participants and site investigators were blinded to treatment allocation. Patients were discharged from the clinical study unit after a minimum of 24 hours after the end of study drug administration. Final study evaluations were performed on day 7.
The primary end point of this study was to evaluate the safety and tolerability of a single 4-hour intravenous infusion of elamipretide in 3 ascending-dose cohorts of patients with HFrEF, as assessed by the occurrence of serious and nonserious adverse events (AEs). Secondary end points included (1) the pharmacokinetic analysis of elamipretide, (2) the effect of elamipretide on cardiac structure and function, and (3) the influence of elamipretide on cardiac and renal biomarkers.
All participants and investigators were blinded to study treatment. Safety was assessed by physical examination, blood and urine laboratory testing, electrocardiography, serial 2-dimensional echocardiography, and clinical monitoring for AEs. AEs were adjudicated by a blinded clinical events committee. All AEs were characterized as mild, moderate, or severe according to predefined protocol definitions. The trial was monitored by an independent Data Safety Monitoring Board. Safety data were reviewed by the Data Safety Monitoring Board at the completion of each cohort before initiating enrollment in the subsequent ascending-dose cohort. The Duke University Institutional Review Board approved the study protocol, and Ethics Committee approval was obtained at the study site.
Cardiac biomarkers, including NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity C-reactive protein, were collected on days 2 (predose and 6 hours postinfusion start) and 7. Kidney function was monitored by serial serum creatinine and estimated glomerular filtration rate calculated by the Modification of Diet in Renal Disease Study equation. The exploratory renal biomarkers of urinary 8-isoprostane and 8-hydroxy-2-deoxyguanosine were obtained on day 2 (predose and 6 hours postinfusion start) and analyzed with an enzyme-linked immunosorbent assay.
The pharmacokinetic analysis determined plasma elamipretide concentrations in blood samples collected at predose (immediately before starting the infusion) and 1, 2, 4, 5, 6, 7, 8, 12, 18, and 24 hours postinfusion start. All pharmacokinetic analyses were independently performed by IDDI Company (Ottignies-Louvain-la-Neuve, Belgium).
Echocardiographic assessments were performed at predose (before elamipretide infusion), mid-infusion, end-infusion, and 6, 8, 12, and 24 hours postinfusion. All 2-dimensional transthoracic, noncontrast echocardiograms were analyzed by an independent core laboratory at Duke Clinical Research Institute (Durham, NC) according to current American Society of Echocardiography guidelines. Interpreting cardiologists were blinded to treatment allocation. Cardiac structure and function was evaluated by serial assessment of LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), EF, left atrial volume, right ventricular (RV) fractional area change, RV systolic pressure (RVSP), valve regurgitation, and LV global longitudinal strain. Left heart volumes and EF were quantified by the biplane Simpson method using Digisonics Digiview software (version 3.8.4; Houston, TX). Spectral Doppler tracings of tricuspid regurgitation were used to determine peak tricuspid regurgitation velocity, and RVSP was estimated using the modified Bernoulli equation. Valve regurgitation severity was based on an integration of quantitative methods and expert visual interpretation, and then graded on a scale ranging from none to severe. LV longitudinal strain was obtained in the apical 4- and 2-chamber views and averaged to determine a global longitudinal value using TOMTEC software (version 4.6.2; Unterschleissheim, Germany).
All sonographers and interpreting cardiologists adhered to established best practice standards for echocardiography core laboratories, which included reproducibility testing for LVEDV, LVESV, and EF. Inter-reader reproducibility for these echocardiographic parameters demonstrated high reproducibility across all readers (intraclass correlation coefficient: 0.95 for LVEDV, 0.98 for LVESV, and 0.99 for LV EF).
Differences in baseline characteristics among the 3 elamipretide cohorts and pooled placebo patients were assessed using χ 2 tests for categorical variables and Kruskal–Wallis tests for continuous variables. Discrete data are presented as a proportion of observations, and continuous data are expressed as mean±SD or median with interquartile range, as appropriate. The sample size for the primary end point of safety and tolerability of elamipretide was chosen based on data from phase I clinical safety trials of elamipretide. Based on this prior safety data, as well as logistical and feasibility considerations, it was estimated that 36 patients randomized (2:1) into 3 successive ascending-dose cohorts of elamipretide would be needed to evaluate safety in this initial HFrEF population. For secondary end points, paired t tests were used at each time point to evaluate change from baseline within each treatment cohort and 2 group t tests were used to compare whether the change from baseline in each elamipretide cohort was significantly different from the pooled placebo cohort within a 1-way ANOVA framework. Given the exploratory nature of secondary end points, there was no prespecified adjustment for multiple comparisons. Multivariate regression analysis compared the change from baseline between elamipretide cohorts and placebo with adjustment for age, sex, diabetes mellitus, and coronary artery disease. Overall differences in pharmacokinetic parameters of systemic exposure were evaluated by ANOVA across all dosing cohorts. To estimate the power model and assess dose proportionality, a simple linear regression model was fit to the res
