SS-31 (Elamipretide): Complete Guide to the Mitochondrial Cardiolipin Peptide

Unlike peptide hormones that act on cell-surface receptors, elamipretide's target is a lipid, not a protein. Cardiolipin is a phospholipid found almost exclusively in the inner mitochondrial membrane, where it shapes the folded cristae membranes and helps organise the respiratory-chain complexes into efficient supercomplexes. Elamipretide binds cardiolipin selectively through electrostatic and hydrophobic interactions.^[1]

That binding has a specific downstream effect: it prevents cardiolipin from converting cytochrome c into a peroxidase enzyme, while preserving cytochrome c's normal role of carrying electrons through the respiratory chain. In cell and animal studies this is reported to protect cristae structure, reduce production of reactive oxygen species, and support oxidative phosphorylation, the process mitochondria use to generate ATP.^[1][2]

A 2025 mechanistic review adds more recent detail: newer studies describe elamipretide modulating the mitochondrial membrane's electrostatic potential and the assembly of cardiolipin-dependent proteins central to mitochondrial physiology, extending the original cytochrome c model published in 2014.^[3]

Yes, for one specific indication. On September 19, 2025, the FDA granted accelerated approval to Forzinity (elamipretide) injection as the first treatment for Barth syndrome, a rare, X-linked, life-threatening mitochondrial disease that typically begins with heart failure in infancy. The approval covers adult and pediatric patients weighing at least 30 kg, to improve muscle strength.^[4][5]

It is an accelerated approval, granted under section 506(c) of the Federal Food, Drug, and Cosmetic Act and 21 CFR 314.510 — a pathway that lets FDA approve a drug for a serious condition on an intermediate endpoint reasonably likely to predict clinical benefit, ahead of proof that patients feel or function better long-term. The intermediate endpoint here is knee extensor muscle strength, measured by handheld dynamometry. Continued approval is contingent on a confirmatory trial verifying that the strength gain translates into clinical benefit.^[6][5]

The approval followed an earlier setback: FDA sent Stealth BioTherapeutics a complete-response action letter on May 15, 2025. The company's August 15, 2025 resubmission was accepted as a complete response, and FDA approved the application about five weeks later, alongside a rare pediatric disease priority review voucher.^[6]

The approval's evidentiary base is more layered than 'a trial succeeded.' The core study, TAZPOWER, randomised 12 genetically confirmed Barth syndrome patients (aged 12 and older, weighing more than 30 kg) to elamipretide 40 mg subcutaneously once daily or placebo in a crossover design, each period lasting 12 weeks. On the trial's primary endpoints — distance walked on the six-minute walk test and the Total Fatigue Score on the Barth Syndrome Symptom Assessment — elamipretide was not superior to placebo.^[5]

Knee extensor muscle strength was only a secondary endpoint in that blinded comparison, and it did not separate from placebo there either. Ten of the twelve patients then entered a single-arm, open-label extension, continuing the same 40 mg daily dose; eight reached the week-168 visit. It was during this uncontrolled extension period that strength measurements rose: median muscle strength increased by 34 newtons at week 12 of the extension and by 63 newtons at week 168, against a pre-dose baseline median of 124 newtons — the open-label data behind the accelerated approval.^[5]

A separate analysis strengthens that open-label signal with an external comparison. Researchers built a propensity-matched natural-history control group of 19 untreated Barth syndrome patients and compared them with the 8 patients who stayed on elamipretide through the extension. Relative to the untreated group, elamipretide was associated with a 79.7-metre greater six-minute-walk distance at week 64 and 91.0 metres at week 76 (both p<.001), alongside a 40.8-to-56.7-newton greater gain in muscle strength over the same period. A 2024 publication of the full 168-week extension also reported a cumulative 96.1-metre improvement in walk distance from the extension's own baseline (p=.003), and reduced fatigue scores at every extension time point.^[8][7]

Put plainly: the randomised, blinded portion of the pivotal trial did not beat placebo on any endpoint. The approval rests on what happened afterward, without a placebo group, reinforced by a retrospective comparison against patients who were never treated — real evidence, but a lower tier than a positive randomised trial, which is why FDA required a confirmatory trial as a condition of continued approval. That confirmatory trial, a Phase 3b/4 randomised, double-blind, placebo-controlled study named 4TAZPower (72 weeks), began recruiting in July 2026.^[5][15]

Before Barth syndrome, Stealth BioTherapeutics' broader mitochondrial-disease programme tested elamipretide in primary mitochondrial myopathy (PMM), a wider group of genetic disorders that impair oxidative phosphorylation. An early Phase 1/2 dose-escalation trial gave elamipretide intravenously for five days to 36 adults with genetically confirmed PMM. The highest-dose group walked a mean 64.5 metres farther on the six-minute walk test than at baseline, against 20.4 metres for placebo, and an adjusted analysis found a statistically significant 51.2-versus-3.0-metre difference.^[9]

The Phase 3 follow-up did not confirm that early signal. MMPOWER-3, a larger randomised, placebo-controlled trial in the same PMM population (registered as NCT03323749, 218 participants), did not meet its primary endpoints in the double-blind portion, and its planned open-label extension was subsequently terminated. A further Phase 3 trial in primary mitochondrial disease caused specifically by nuclear DNA mutations (NuPower, 102 participants) completed in December 2024; as of September 2026 it has not led to any additional FDA approval for elamipretide beyond the single Barth syndrome indication — a pattern consistent with the Barth syndrome data above, where short, blinded comparisons did not separate from placebo while longer or open-label measurements more often showed a positive trend.^[10][11][12]

A separate elamipretide programme targets dry age-related macular degeneration (AMD), specifically geographic atrophy, using subcutaneous injection rather than an eye-drop or intravitreal route. A Phase 2 trial in patients with non-central geographic atrophy (ReCLAIM-2, 176 participants) completed in 2022.^[13]

That programme has since advanced to Phase 3: ReNEW began in May 2024, is testing subcutaneous elamipretide against placebo in 313 participants with dry AMD, and is measuring the rate of change in the macular area of photoreceptor loss. It remained active and unreported as of September 2026, with an estimated primary completion date of August 2027. Dry AMD is not an FDA-approved indication for elamipretide.^[14]

All three compounds turn up in the same mitochondrial-research searches, but they work through unrelated mechanisms. SS-31 (elamipretide) is a synthetic four-amino-acid peptide that binds cardiolipin directly on the inner mitochondrial membrane — a structural, lipid-binding mechanism. MOTS-c is a naturally occurring 16-amino-acid peptide encoded inside mitochondrial DNA itself, which activates AMPK and, under stress, moves into the cell nucleus to regulate gene expression — a signalling mechanism, not a membrane-binding one.

NAD+ is not a peptide at all: it is a small dinucleotide coenzyme that cells consume and regenerate, acting as the obligate substrate for sirtuin and PARP enzymes. Of the three, only SS-31/elamipretide currently holds an FDA approval of any kind — and that approval covers one narrow, rare-disease population, not general mitochondrial support.

Outside the United States, elamipretide's regulatory position is earlier-stage. The European Medicines Agency has granted elamipretide orphan drug designation — for myopathic mitochondrial DNA depletion syndrome, designated on 16 May 2022 — which qualifies the sponsor for scientific and regulatory support during development. Orphan designation is not a marketing authorisation: EMA states explicitly that a designated orphan medicine must still complete the full evaluation process before it can be authorised and made available to patients.^[16]

As of September 2026, the EMA's public medicines listings show no marketing authorisation for elamipretide, so it cannot legally be sold as a medicine anywhere in the EU. The single approval described in this guide is a US-only, accelerated approval for one indication.^[16]

Peptyds does not sell SS-31 or elamipretide, in any form. That is a deliberate distinction, not an oversight: elamipretide is now a prescription-only, FDA-approved medicine (Forzinity) manufactured and distributed by Stealth BioTherapeutics for a specific rare-disease population, under a structured accelerated-approval framework with confirmatory-trial obligations. That regulatory category is different in kind from the lyophilised research compounds in Peptyds' own catalogue.^[6]

The research interest is genuine and well documented: a defined cardiolipin-binding mechanism, a real if narrow FDA approval, and an evidence record that is honestly mixed outside Barth syndrome. Readers who came to this page from mitochondrial-research searches around MOTS-c or NAD+ will find both of those compounds in Peptyds' own research-peptide catalogue, each with its own batch documentation.