SS-31

Overview

SS-31, also known as elamipretide or MTP-131, is a synthetic tetrapeptide developed by Hazel Szeto at Weill Cornell Medical College. It belongs to the Szeto-Schiller (SS) peptide family: aromatic-cationic peptides that selectively target the inner mitochondrial membrane. SS-31 binds to cardiolipin, a phospholipid found only on that inner membrane. Cardiolipin plays a central structural role in organising the respiratory chain.

The mechanism is notably specific. By binding to cardiolipin, SS-31 prevents cytochrome c from being converted into a peroxidase that causes oxidative damage. Cytochrome c is normally an electron carrier in the respiratory chain. At the same time, SS-31 stabilises the cristae structure of mitochondria and promotes the organisation of respiratory supercomplexes. The result is more efficient oxidative phosphorylation and reduced production of reactive oxygen species.

For a mitochondrial peptide, SS-31 has progressed unusually far along the clinical path. In September 2025 the FDA granted accelerated approval to elamipretide (brand name Forzinity™) to improve muscle strength in Barth syndrome patients weighing 30 kg or more. Approval was granted on 19 September 2025. This makes elamipretide the first agent to act directly on the mitochondrial pathology of Barth syndrome, and one of the few mitochondria-targeted compounds with regulatory registration.

The clinical story of SS-31 is scientifically instructive. In randomised controlled trials, short-term studies did not meet their primary endpoints, while long-term open-label data showed consistent, significant improvements. That pattern of a negative short-term RCT alongside positive long-term data is relevant to how mitochondrial compounds work, and to how trials for rare mitochondrial disorders are best designed.

Mechanism of action

SS-31 binds selectively to cardiolipin on the inner mitochondrial membrane. In doing so it prevents the peroxidase activation of cytochrome c, stabilises the cristae structure, and promotes efficient oxidative phosphorylation.

Cardiolipin binding and protection of cytochrome c

• Binds to cardiolipin on the inner membrane through electrostatic and hydrophobic interactions
• Prevents cardiolipin from binding cytochrome c, thereby blocking its conversion into a peroxidase
• Protects the electron-transport function of cytochrome c under oxidative stress

Stabilisation of mitochondrial cristae

• Stabilises the folds of the inner membrane (cristae), needed for optimal ATP production
• Promotes the organisation of respiratory supercomplexes
• Reduces mitochondrial permeability transition, an early step toward cell death

Improvement of oxidative phosphorylation

• Increases the efficiency of ATP production per unit of oxygen consumed
• Reduces the production of reactive oxygen species as a by-product of the respiratory chain
• First demonstrated pharmacological intervention to acutely improve mitochondrial ATP-production capacity in living human muscle tissue

Research findings

• Single-dose elamipretide significantly increased mitochondrial ATP production capacity in skeletal muscle of older adults in a randomized controlled study, the first demonstrated pharmacological improvement of mitochondrial function in vivo in humans
• In the TAZPOWER open-label extension (168 weeks), Barth syndrome patients cumulatively improved by 96 meters on the 6-minute walk test, a significant difference compared to untreated natural history controls
• Comparative study with 19 untreated Barth syndrome patients as control showed 79.7 meter difference on the walk test and significant improvement in muscle strength (p=0.0004)
• Phase II study in renal function impairment after stent placement showed reduced hypoxia (-6% versus +47% placebo at 24 hours) and improved renal perfusion
• Phase II study in heart failure with reduced ejection fraction showed significant reduction in left ventricular end-systolic volume at the highest dose

What the short-term trials did not achieve

• MMPOWER-3 (phase III, primary mitochondrial myopathy, n=218): no significant improvement on the 6-minute walk test or fatigue scale after 24 weeks
• TAZPOWER phase 2/3 (Barth syndrome, randomised phase): primary endpoints not met in the 12-week double-blind periods
• One explanation: mitochondrial recovery is slow. Twelve to 24 weeks proved too short for a measurable clinical effect in both indications.

What the long-term data did show

• 168-week TAZPOWER open-label extension: significant improvement on walk test (+96 m), fatigue, muscle strength, and cardiac function
• Compared with untreated controls: a difference of 79.7 to 91 metres on the walk test, and significantly improved muscle strength
• Stable safety profile over 168 weeks; injection-site reactions were the most frequently reported observation

Human mechanistic and organ-specific data

• Demonstrated improvement of mitochondrial ATP capacity in human skeletal muscle after a single dose
• Reduced renal hypoxia after ischaemia-reperfusion in impaired kidney function
• Improved left-ventricular dimensions in heart failure after a single infusion

Research context

The clinical path of SS-31/elamipretide touches a fundamental question in mitochondrial pharmacology: how long does it take before mitochondrial protection translates into a measurable clinical improvement? The negative short-term trials are not evidence that the mechanism does not work. They show that 12 to 24 weeks was too short for the chosen clinical endpoints.

The US FDA granted accelerated approval to FORZINITY™ (elamipretide HCl, Stealth BioTherapeutics) for Barth syndrome on 19 September 2025.

The FDA granted accelerated approval on 19 September 2025 (for improving muscle strength in Barth syndrome patients ≥30 kg) on the basis of the long-term open-label data, combined with a comparison against the natural course of the disease. That is an unconventional but scientifically defensible route for rare diseases, where randomised long-term trials are practically unfeasible because of the small patient population.

For the broader research directions (age-related mitochondrial decline, heart failure, kidney-function preservation) the evidence is still incomplete. The open question is in which populations, at which dose, and after which treatment duration a measurable benefit occurs. Patient selection based on markers of mitochondrial dysfunction is likely a key here, and forms a natural next step for research groups in mitochondrial medicine.

Open questions

A recurring lesson from the SS-31 programme: short-term endpoints may underestimate what long-term mitochondrial protection delivers. Longer treatment duration and marker-guided patient selection appear to be the key to mapping the full clinical picture.

• MMPOWER-3 did not meet the primary endpoints for primary mitochondrial myopathy; the optimal treatment duration and patient selection are unknown
• Markers for patient selection (who does respond?) are not standardised
• The optimal treatment duration for a measurable clinical effect differs by indication and is not established
• The long-term safety profile in larger populations and broader indications is still being built
• An effect in age-related mitochondrial decline (not a rare disease) has not been demonstrated in a controlled setting
• The confirmatory trial the FDA required as a condition has no known results yet

Research outlook

The confirmatory trial for Barth syndrome that the FDA attached as a condition to the accelerated approval; a positive outcome would mean full registration.

Marker-guided patient selection for mitochondrial myopathy, which may place the negative MMPOWER-3 outcome in a different light. Identifying responding subpopulations is the priority here.

Extension to age-related mitochondrial decline; the ATP-production data in healthy older adults form the strongest starting point for broader application.

Combination studies with MOTS-c and other mitochondrial peptides, which could reveal synergistic mechanisms.

Kidney protection in ischaemia-reperfusion (transplantation, surgery), a research direction with strong pilot data.

Scientific interest

Cardiolipin protection and stabilisation of mitochondrial cristae

Mitochondrial ATP production in ageing and in rare mitochondrial diseases

Protection against ischaemia-reperfusion damage of heart and kidney

Trial design for mitochondrial compounds

Specifications

References

1. Potent mitochondria-targeted peptides reduce myocardial infarction in rats. · Cho J, Won K, Wu D, et al. · Coronary Artery Disease · 2007
2. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. · Szeto HH. · British Journal of Pharmacology · 2014
3. Phase 2a Clinical Trial of Mitochondrial Protection (Elamipretide) During Stent Revascularization in Patients With Atherosclerotic Renal Artery Stenosis. · Saad A, Herrmann SMS, Eirin A, et al. · Circulation: Cardiovascular Interventions · 2017
4. Novel Mitochondria-Targeting Peptide in Heart Failure Treatment: A Randomized, Placebo-Controlled Trial of Elamipretide. · Daubert MA, Yow E, Dunn G, et al. · Circulation: Heart Failure · 2017
5. Stealth Peptides Target Cellular Powerhouses to Fight Rare and Common Age-Related Diseases. · Szeto HH. · Protein & Peptide Letters · 2018
6. In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trial. · Roshanravan B, Liu SZ, Ali AS, et al. · PLoS One · 2021
7. A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome. · Reid Thompson W, Hornby B, Manuel R, et al. · Genetics in Medicine · 2021
8. Phase 1 Clinical Trial of Elamipretide in Dry Age-Related Macular Degeneration and Noncentral Geographic Atrophy: ReCLAIM NCGA Study. · Mettu PS, Allingham MJ, Cousins SW. · Ophthalmology Science · 2022
9. Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial. · Karaa A, Bertini E, Carelli V, et al. · Neurology · 2023
10. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. · Thompson WR, Manuel R, Abbruscato A, et al. · Genetics in Medicine · 2024
11. MMPOWER-3 genotype post-hoc analysis: nuclear DNA replisome variants and elamipretide response in primary mitochondrial myopathy · Karaa A, Bertini E, Carelli V, et al. · Orphanet Journal of Rare Diseases · 2024
12. TAZPOWER psychometric outcomes: a phase 2 randomised, placebo-controlled trial of elamipretide in Barth syndrome · Gwaltney C, Shields A, Love E, et al. · Orphanet Journal of Rare Diseases · 2025
13. Elamipretide: First Approval. · Shirley M. · Drugs · 2025
14. Elamipretide: The first cardiolipin-directed mitochondrial therapeutic for Barth syndrome approved under accelerated approval. · Zhao C, Zhuang X, Gao J. · Drug Discoveries & Therapeutics · 2025

Availability

In stock · Batch PEP-SS31-2026-01 · HPLC 99.12 % · released 21 Jun 2026

• SS-31 10 mg · product page with price and batch CoA