FDA APPROVEDMitochondria-targeted aromatic-cationic tetrapeptide

SS-31

Also known as Elamipretide, MTP-131, Bendavia, Forzinity

A mitochondria-targeted tetrapeptide with an FDA accelerated approval in Barth syndrome and large negative trials in mitochondrial myopathy.

  • Mitochondrial bioenergetics
  • Muscle strength and fatigue
  • Heart failure
  • Age-related muscle decline

What it is

SS-31 is a four-amino-acid aromatic-cationic peptide developed by Hazel Szeto and Peter Schiller as part of a series of cell-permeable peptides that concentrate in the inner mitochondrial membrane. It entered clinical development as elamipretide, also labeled MTP-131 and Bendavia, and is the rare research peptide to have been carried through phase 3 trials and a regulatory review. It is the same molecule in the preclinical aging literature and in the rare-disease clinical program, which is why the animal and human records sit side by side here.

Mechanism of action

SS-31 binds cardiolipin, a phospholipid concentrated in the inner mitochondrial membrane. Szeto (2014) describes the peptide as a cardiolipin-protective compound: cardiolipin organizes cristae architecture and holds the electron transport chain complexes in place, and its oxidation destabilizes that organization. By associating with cardiolipin, SS-31 is proposed to limit cardiolipin peroxidation, preserve cytochrome c as an electron carrier rather than a peroxidase, and restore electron flow and ATP synthesis. In aged mouse muscle, Siegel and colleagues (2013) linked the same intervention to lower mitochondrial hydrogen peroxide emission and a more reduced glutathione redox state. The rationale in Barth syndrome is mechanistically direct, because TAFAZZIN variants disrupt cardiolipin remodeling itself.

What it’s most studied for

Research on SS-31 clusters around tissues that fail when mitochondria fail. The largest trials examined primary mitochondrial myopathy, measuring walking distance and fatigue, and Barth syndrome, a rare X-linked cardiolipin disorder. Cardiology groups have examined it in heart failure with reduced ejection fraction, where a single infusion study measured left ventricular volumes. A separate line of work, closer to the longevity question, asks whether the peptide can raise mitochondrial energy production in older skeletal muscle; that has been examined in both aged mice and healthy older adults. Ophthalmology and nephrology work exists as well, but the published controlled evidence is concentrated in the myopathy, Barth syndrome and heart failure programs.

Notable findings

Each finding carries the species or population it was observed in and the dose that study used. Doses are reported as research context, exactly as published. They are not guidance.

Humans FDA accelerated approval on an intermediate clinical endpoint

Accelerated approval in Barth syndrome

The US Food and Drug Administration (2025) granted elamipretide accelerated approval as the first treatment for Barth syndrome in adult and pediatric patients weighing at least 30 kg. The approval rests on an improvement in knee extensor muscle strength, which the agency describes as reasonably likely to predict clinical benefit without directly measuring it. The agency required a randomized, double-blind, placebo-controlled confirmatory trial and may withdraw the approval if that trial does not verify benefit. Injection-site reactions, mostly mild to moderate, were the most commonly reported adverse reactions.

Dose studied
40 mg subcutaneously once daily, adult and pediatric patients weighing at least 30 kg (FDA label)

[1] US Food and Drug Administration · 2025 · source ↗

Humans Double-blind, placebo-controlled crossover trial (n=12)

Randomized crossover trial in Barth syndrome

Reid Thompson et al. (2021) reported TAZPOWER, a 28-week double-blind, placebo-controlled crossover trial in 12 male patients aged 12 and older with genetically confirmed Barth syndrome. The randomized phase did not meet its primary endpoints, the 6-minute walk test and the Barth Syndrome Symptom Assessment total fatigue score. Functional improvements were reported only afterward, during the uncontrolled open-label extension.

Dose studied
40 mg subcutaneously once daily for 12 weeks per treatment period, with a 4-week washout, in a 28-week crossover trial (12 male patients aged 12 and older)

[2] Reid Thompson W et al. · 2021 · DOI 10.1038/s41436-020-01006-8 ↗

Humans Single-arm open-label extension (n=10 entered, 8 reached week 168)

168-week open-label extension

Thompson et al. (2024) followed the TAZPOWER participants through an open-label extension. Ten patients entered the extension and eight reached week 168, at which point the authors reported a cumulative gain of about 96 m on the 6-minute walk test from extension baseline, with fatigue scores also improved. There was no concurrent control group, so the extension cannot separate treatment from natural variation, learning effects on the walk test or attrition.

Dose studied
40 mg subcutaneously once daily, open-label, through week 168 (10 male patients with Barth syndrome)

[3] Thompson WR et al. · 2024 · PMID 38602181 ↗

Humans Randomized, double-blind, placebo-controlled phase 3 trial (n=218)

Phase 3 trial in mitochondrial myopathy

Karaa et al. (2023) reported MMPOWER-3, which randomized 218 participants with genetically confirmed primary mitochondrial myopathy 1:1 to elamipretide or placebo for 24 weeks. The trial missed both primary endpoints: the difference from placebo on the 6-minute walk test at week 24 was -3.2 m (95% CI -18.7 to 12.3; p=0.69), and total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment did not differ either. The investigators reported that treatment was well tolerated, with most adverse events mild to moderate.

Dose studied
40 mg/day subcutaneously for 24 weeks (218 adults, mean age 45.6 years, 64% women)

[4] Karaa A et al. · 2023 · PMID 37268435 ↗

Humans Randomized, double-blind, placebo-controlled trial (n=39)

Mitochondrial ATP production in older adults

Roshanravan et al. (2021) gave 39 healthy adults aged 60 to 85, selected for poor mitochondrial function, a single infusion or placebo and measured the first dorsal interosseous muscle by magnetic resonance and optical spectroscopy. In vivo mitochondrial energetic capacity rose immediately after the infusion relative to placebo, with borderline significance (p=0.055 for the absolute change, p=0.045 for the percent change). The difference was gone by day 7, resting mitochondrial coupling did not change, and there was no significant effect on muscle fatigue resistance.

Dose studied
One single two-hour infusion, healthy adults aged 60 to 85, with repeat measurement at day 7

[6] Roshanravan B et al. · 2021 · PMID 34264994 ↗

Mice Controlled animal study, young versus aged mice

Aged mouse muscle energetics

Siegel et al. (2013) injected young (5 month) and old (27 month) mice and measured skeletal muscle energetics in vivo one hour later. Age-related declines in resting and maximal mitochondrial ATP production, oxidative phosphorylation coupling and cell energy state were reversed in aged muscle, with no observable effect in young muscle, alongside lower mitochondrial hydrogen peroxide emission. Aged muscle was also more fatigue resistant one hour after a single injection, and eight days of treatment increased whole-animal endurance capacity.

Dose studied
3 mg/kg intraperitoneally as a single injection, measured one hour later; an eight-day treatment arm was used for the endurance experiment (mice)

[7] Siegel MP et al. · 2013 · PMID 23692570 ↗

Study quality

The human record here is far larger than for most research peptides, and much of it is negative. MMPOWER-3 randomized 218 participants and missed both primary endpoints, and the earlier phase 1/2 dose-escalation trial of 36 participants (Karaa et al., 2018) was borderline on walking distance (p=0.053). The Barth syndrome program is very small: a 12-patient crossover trial that missed its primaries, followed by an uncontrolled extension in 8 to 10 patients, which is the basis the FDA accepted for accelerated approval on a surrogate endpoint, with a randomized confirmatory trial still required. The older-adult trial (n=39) found a short-lived energetic change and no functional benefit. Safety reporting is consistent across studies: mild-to-moderate injection-site reactions predominate, and no serious adverse events were reported in the 2017 single-infusion heart failure study. Most trials were sponsor-run.

References

  1. 1
    US Food and Drug Administration (2025). FDA Grants Accelerated Approval to First Treatment for Barth Syndrome. U.S. Food and Drug Administration press announcement.
  2. 2
  3. 3
    Thompson WR, Manuel R, Abbruscato A, et al. (2024). Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. Genetics in Medicine. PMID 38602181
  4. 4
  5. 5
    Karaa A, Haas R, Goldstein A, et al. (2018). Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology. PMID 29500292
  6. 6
  7. 7
  8. 8
  9. 9
    Daubert MA, Yow E, Dunn G, et al. (2017). Novel mitochondria-targeting peptide in heart failure treatment: a randomized, placebo-controlled trial of elamipretide. Circulation: Heart Failure. PMID 29217757

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