Novel Mitochondria-Targeting Peptide in Heart Failure Treatment: A Randomized, Placebo-Controlled Trial of Elamipretide
Daubert MA, Yow E, Dunn G, Marchev S, Barnhart H, Douglas PS, O'Connor C, Goldstein S, +2 more
Circulation Heart Failure (2017) · n=44
A single high-dose elamipretide infusion produced acute reductions in left ventricular end-diastolic (−18 mL) and end-systolic (−14 mL) volume versus placebo in 44 stable heart-failure patients — the early signal that motivated the PROGRESS-HF Phase 2 trial, which then failed to confirm chronic-dosing benefit at 4 weeks.
This 2017 Circulation Heart Failure paper is the first randomized placebo-controlled trial of elamipretide in heart failure and the foundational SS-31 cardiology paper. The investigators enrolled 44 patients with stable heart failure (32 in three sequential elamipretide dose-cohorts of 8 patients each; 12 placebo controls) and administered a single 4-hour intravenous infusion at one of three doses or matched placebo. The primary endpoint was acute change in left ventricular volumes measured by cardiac MRI. High-dose elamipretide produced statistically significant reductions in left ventricular end-diastolic volume (−18 mL) and end-systolic volume (−14 mL) versus placebo within hours of infusion, with a dose-response curve evident across the three active cohorts. Vital signs remained stable, no serious adverse events were observed, and a temporal association between plasma drug concentration and cardiac-volume changes was established. The signal motivated the larger PROGRESS-HF Phase 2 trial (Butler et al., J Card Fail 2020), which randomized 71 HFrEF patients to 4 weeks of daily subcutaneous elamipretide at two doses or placebo. PROGRESS-HF did not confirm the acute findings — left-ventricular end-systolic volume at 4 weeks was not significantly different across treatment arms, ending the lead heart-failure indication for elamipretide.
This is a 44-patient acute-administration trial — the chronic-dosing question that determines clinical relevance was not addressed and was subsequently addressed negatively by PROGRESS-HF. The acute reductions in LV volumes are interesting biologically but do not predict that chronic SS-31 dosing improves heart-failure outcomes; the PROGRESS-HF trial demonstrates that they do not, at the studied dose and duration in stable HFrEF. The Chatfield 2019 JACC Basic Translational Science paper showing improved mitochondrial respiration in elamipretide-treated failing-heart tissue ex vivo (n=12–23 hearts) adds mechanistic support to the acute-effect framing but does not bridge to chronic-dosing efficacy. The Sabbah laboratory at Henry Ford Hospital — Hani Sabbah is a senior author — has been the central preclinical heart-failure investigator for elamipretide; the canine pacing-induced heart-failure model where chronic SS-31 dosing did produce LV-function improvement (Sabbah 2016) is the rodent / canine evidence base that this human trial was designed to translate. Industry sponsorship by Stealth BioTherapeutics is disclosed.
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