PMID-29217757 – Elamipretide Heart Failure RCT
Daubert MA, Yow E, Duber G, Marchev S, Barnhart H, Douglas PS, O'Connor C, Goldstein S, Sabbah HN, Shah SH. Novel mitochondria-targeting peptide in heart failure treatment: a randomized, placebo-controlled trial of elamipretide. Circ Heart Fail. 2017;10(12):e004389.
Quick Reference
| Property | Value |
|---|---|
| PMID | 29217757 |
| DOI | 10.1161/CIRCHEARTFAILURE.117.004389 |
| Year | 2017 |
| Journal | Circulation: Heart Failure |
| Study Type | RCT (Phase 1/2) |
| Evidence Level | II (Oxford CEBM) |
| Sample | Heart failure patients with reduced ejection fraction (HFrEF) |
| Peptide(s) Studied | SS-31 |
Key Findings
- First-in-class human randomized controlled trial of elamipretide (SS-31) in patients with heart failure with reduced ejection fraction (HFrEF)
- Elamipretide demonstrated a novel mechanism of action targeting mitochondrial cardiolipin to restore energy production in failing cardiomyocytes
- The study established safety and tolerability of elamipretide in heart failure patients
- Trends toward improvement in cardiac function parameters were observed, though the trial was not powered for definitive efficacy endpoints
- Biomarker analyses suggested favorable effects on mitochondrial bioenergetics
- This Phase 1/2 trial provided proof-of-concept for mitochondria-targeted therapy in heart failure, a paradigm shift from conventional neurohormonal blockade strategies
Study Design
Randomized, double-blind, placebo-controlled Phase 1/2 clinical trial. Patients with stable HFrEF were randomized to elamipretide or placebo. Multiple doses were evaluated to establish safety, tolerability, and preliminary efficacy signals. Cardiac function was assessed via echocardiography and biomarker panels. The study was designed primarily to evaluate safety and pharmacokinetics, with exploratory efficacy endpoints including left ventricular volumes and ejection fraction.
Limitations
- Phase 1/2 design with limited sample size, not powered for definitive efficacy conclusions
- Short treatment duration may not capture the full therapeutic potential of mitochondrial restoration
- Heart failure population is heterogeneous; response may vary by etiology
- Elamipretide's mechanism (cardiolipin stabilization) requires long-term studies to confirm sustained benefit
- Subsequent larger trials (EMBRACE-STEMI, ReCOVER) had mixed results, tempering initial optimism
Clinical Relevance
This landmark trial established elamipretide (SS-31) as the first mitochondria-targeting peptide tested in a human heart failure RCT. The novel mechanism — stabilizing cardiolipin in the inner mitochondrial membrane to restore electron transport chain efficiency — represents a fundamentally different therapeutic approach from existing heart failure therapies. While subsequent larger trials showed mixed results for heart failure specifically, this study validated the concept of mitochondrial peptide therapy in humans and paved the way for successful application in Barth syndrome (leading to FDA consideration). For the vault, this study supports SS-31's positioning as a mitochondrial-targeted therapeutic with cardiovascular applications.
Related
#research #RCT #evidence-level-II #ss-31 #mitochondrial #cardiovascular