Elamipretide
SS-31 (Elamipretide) — approved for Barth, failed for heart failure: the honest evidence

Class: peptide
INN: Elamipretide
Synonyms: SS-31
Elamipretide (INN, the approved-drug name)
Bendavia (the name used in the cardiac-ischemia trials)
MTP-131
trade name Forzinity (FDA-approved formulation)
sequence D-Arg-2,6-dimethyltyrosine-Lys-Phe-NH₂. INCI: none
Trade names: Forzinity
Bendavia
Function tags: mitochondrial
(approved:) Barth-syndrome muscle strength
(research/failed:) heart failure
cellular energy / "anti-aging."
Overall evidence grade: A
WADA prohibited: no
Last updated: 2026-07-13

In brief: SS-31 (elamipretide) is a mitochondria-targeting tetrapeptide that binds cardiolipin and stabilises the inner-membrane machinery that produces cellular energy. In September 2025 it became the first FDA-approved therapy for a mitochondrial disease — Barth syndrome — where a Phase 3 trial's open-label extension and a natural-history comparison showed improved muscle strength, walk distance and cardiac stroke volume over ~48 weeks. Crucially, its trials in the conditions people popularly associate it with have a much weaker record: the pivotal Barth randomized crossover phase and the primary mitochondrial myopathy Phase 3 both missed their primary endpoints, the heart-failure (HFpEF) program improved mitochondrial bioenergetics without functional benefit, and dry AMD results were mixed/negative. The "cellular energy / anti-aging" story rests almost entirely on aged-mouse studies, not human data.

## Identity a synthetic **tetrapeptide** (4 amino acids, < 40 aa → peptide) that carries a positive charge and readily crosses cell membranes to **concentrate ~1,000–5,000× inside mitochondria**, where it binds the unique inner-membrane phospholipid **cardiolipin**. One of the most-studied mitochondria-targeting compounds in existence. ## Mechanism (as proposed) SS-31 is a cell-penetrating tetrapeptide that accumulates in mitochondria and **binds cardiolipin** on the inner mitochondrial membrane. By stabilising cardiolipin, it **props up the respiratory-chain supercomplexes** (the assembled Complexes I–IV), improving **electron-transport efficiency** and **ATP production** while lowering **reactive-oxygen-species** leak. In Barth syndrome — an X-linked disease where *tafazzin* mutations cripple cardiolipin remodeling — this directly addresses the molecular root. The exact downstream mechanism beyond cardiolipin binding "remains unclear" (its own mechanistic literature says so), which is part of why it works in the disease built on cardiolipin but **repeatedly failed** in messier, multifactorial diseases like heart failure.

Evidence grades by outcome:
outcome: Barth syndrome — muscle strength (the approved use)
grade: A
base: Phase 3 (TAZPOWER) crossover + open-label extension + natural-history comparison (Hornby 2022); ~48-wk gains in 6-min walk, symptom scale, cardiac stroke volume → FDA accelerated approval Sep 2025
caveat: Approved, but for an ultra-rare disease (~1 in 300,000–500,000 births); accelerated approval → confirmatory trial still owed; the randomized phase actually missed its primary endpoint — approval leaned on the extension + intermediate endpoint
outcome: Primary mitochondrial myopathy
grade: F
base: MMPOWER-3 Phase 3 — did NOT meet primary endpoints (6-min walk, symptom score) in the overall population
caveat: The pivotal trial for the "mito myopathy" use failed; a short earlier study (5-day) had shown a walk-distance signal that didn't hold up
outcome: Heart failure (HFpEF / cardiac)
grade: F
base: Multiple Phase 2 trials (Bendavia/elamipretide; Daubert 2017) — improved myocardial bioenergetics but no functional/clinical benefit
caveat: "Fixed the chemistry, didn't move the patient" — a recurring theme; long-term HFpEF trials did not translate mechanism into outcomes
outcome: Dry age-related macular degeneration (AMD)
grade: D
base: Phase 2 (ReCLAIM) — mixed/negative on primary endpoints
caveat: Some exploratory signals; did not establish efficacy
outcome: Acute kidney injury / ischemia-reperfusion
grade: D
base: Preclinical + early clinical
caveat: Strong animal data (kidney protection sustained months after dosing); human efficacy not established
outcome: "Cellular energy / anti-aging / exercise capacity in healthy people" (the popular use)
grade: F
base: Aged-mouse studies (Siegel 2013; Campbell 2019 — restored redox balance, improved exercise tolerance in old mice)
caveat: The headline longevity claim is animal-only; not demonstrated in healthy humans. This is what most gray-market buyers want it for — and it's the weakest-evidenced use
outcome: Cognitive / neuroprotection
grade: F
base: Preclinical models only
caveat: Improves mitochondrial/synaptic health in rodent models; not confirmed in humans
outcome: Safety
base: FDA trial program + Phase 2 across indications
caveat: Generally well tolerated; most common AE is injection-site reaction; rare serious hypersensitivity reactions possible (per FDA label); water-soluble, renally excreted

Legal status:
region: INT
status: investigational outside the US Barth indication
note: investigational outside the US Barth indication.

Cosmetic claims:

Note: The mitochondrial anchor — and the register's cleanest "approved vs failed" split on one page. Three honest points define this entry: (1) as of September 2025 it is FDA-approved (Forzinity) for one ultra-rare disease — the first-ever approved therapy for a mitochondrial disease; (2) for the popular uses people actually want it for — heart failure, "cellular energy," anti-aging — the human trials failed or don't exist; (3) it is the mechanistic counterpart to MOTS-c (#10), and together they anchor the mitochondrial cluster.
Status note: status evolving — accelerated approval requires a confirmatory trial; re-check the confirmatory-trial outcome and any label expansion

Sources:
FDA. FDA Grants Accelerated Approval to First Treatment for Barth Syndrome (Forzinity/elamipretide). Sept 19, 2025; FDA Integrated Review, NDA 215244.
Reid Thompson W, et al. Phase 2/3 randomized trial + open-label extension of elamipretide in Barth syndrome. Genet Med. 2021; Hornby B, et al. Natural-history comparison. Orphanet J Rare Dis. 2022.
Daubert MA, et al. Novel mitochondria-targeting peptide in heart failure: randomized placebo-controlled trial of elamipretide. Circ Heart Fail. 2017.
Siegel MP, et al. Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal-muscle performance in aged mice. Aging Cell. 2013; Campbell MD, et al. Free Radic Biol Med. 2019.
Elamipretide mechanistic review — first cardiolipin-directed mitochondrial therapeutic approved under accelerated approval. Drug Discov Ther. 2026.