SS-31 (Elamipretide): The First Approved Mitochondrial Peptide

SS-31 is a synthetic tetrapeptide with the sequence D-Arg-2′,6′-dimethylTyr-Lys-Phe-NH2 (CAS 736992-21-5, molecular weight 639.8 Da). It was developed by Dr. Hazel Szeto and Dr. Peter Schiller at Weill Cornell Medical College in the early 2000s as part of a research programme on cell-penetrating peptides that could selectively target mitochondria. The “SS” designation stands for Szeto-Schiller, and “31” identifies its position in the research series.

The compound carries several names across different contexts. In preclinical literature it is typically called SS-31. In clinical development it became elamipretide (INN) and was also designated MTP-131. Stealth BioTherapeutics, the company founded by Szeto to develop the compound commercially, branded it Bendavia during early cardiac-protection trials and Forzinity for the formulation approved for Barth syndrome.

Two design features distinguish SS-31 from conventional peptides. It incorporates D-arginine (the mirror-image form of natural L-arginine) and 2′,6′-dimethyltyrosine, which together give the molecule resistance to enzymatic degradation and the ability to cross plasma and mitochondrial membranes efficiently. This is fundamentally different from the MOTS-c approach to mitochondrial function, which operates through AMPK activation rather than direct membrane interaction.

The bottom line: SS-31 is the first mitochondria-targeted peptide to receive FDA approval, representing a fundamentally different approach to cellular energy than receptor-mediated or gene-expression-based peptides.

SS-31 works by selectively accumulating in the inner mitochondrial membrane (IMM), where it binds to cardiolipin – a phospholipid found almost exclusively in the IMM and critical for mitochondrial energy production. No other cellular membrane contains cardiolipin in significant quantities, which gives SS-31 an exquisitely specific molecular address.

Cardiolipin performs several essential functions: it anchors the respiratory chain complexes (I through V) to the IMM cristae, it maintains the curvature and structural integrity of the cristae themselves, and it keeps cytochrome c – a key electron carrier – properly attached to the membrane. When cardiolipin becomes oxidised or depleted (as happens with ageing, ischaemia and mitochondrial disease), the consequences cascade: cristae fragment, electron transport becomes inefficient, more reactive oxygen species (ROS) leak out, and cytochrome c detaches – which can trigger apoptosis.

A 2020 PNAS study (Birk et al.) using chemical cross-linking and mass spectrometry mapped SS-31’s protein interaction landscape in mitochondria, identifying that its binding partners are all known cardiolipin-associated proteins involved in oxidative phosphorylation and 2-oxoglutarate metabolism. A companion 2020 study in the Journal of Biological Chemistry (Mitchell et al.) characterised SS-31’s membrane biophysics, showing that its amphipathic properties allow it to partition into the membrane interfacial region with affinity directly related to surface charge.

It was originally proposed that SS-31 acted as a mitochondria-targeted antioxidant due to its dimethyltyrosine residue capable of scavenging free radicals. While this activity exists, the current understanding is that cardiolipin stabilisation and prevention of cytochrome c peroxidase activity are the primary therapeutic mechanisms rather than direct ROS scavenging.

The bottom line: SS-31 addresses mitochondrial dysfunction at its structural origin – cardiolipin integrity on the inner membrane – rather than mopping up oxidative damage downstream.

SS-31 has one of the broadest evidence bases of any peptide in the longevity space, spanning preclinical models in multiple organ systems and FDA-regulated human clinical trials. Critically, unlike many peptides covered on this site, SS-31 has been independently replicated across numerous research groups worldwide.

Barth Syndrome: The Approval Pathway

On September 19, 2025, the FDA granted accelerated approval to Forzinity (elamipretide HCl injection) for the treatment of Barth syndrome in patients weighing at least 30 kg, making it the first approved treatment for this ultra-rare mitochondrial cardioskeletal disease affecting approximately 150 individuals in the United States. Barth syndrome is characterised by mitochondrial dysfunction due to defective cardiolipin remodelling, leading to severe heart failure in infancy, fatigue and exercise intolerance.

The approval was supported by data from the TAZPOWER Phase 2/3 trial (NCT03098797). The trial had a complicated regulatory history: in its initial randomised, placebo-controlled phase, elamipretide failed to meet the primary endpoint of change from baseline to week 12 in the six-minute walk test. However, in the open-label extension phase running up to 168 weeks, knee extensor muscle strength improved by approximately 45% from baseline. Stealth BioTherapeutics resubmitted the NDA seeking accelerated approval on the basis of knee extensor strength as an intermediate clinical endpoint, which the FDA accepted after an October 2024 advisory committee meeting concluded elamipretide was effective.

Primary Mitochondrial Myopathy

Stealth BioTherapeutics conducted two earlier trials in primary mitochondrial myopathy (PMM). MMPOWER was a randomised, double-blind, placebo-controlled trial testing three doses of elamipretide administered intravenously over five days to 36 patients aged 16-65. MMPOWER-2 was a Phase 2 randomised trial of daily subcutaneous elamipretide in 30 PMM patients. Both trials demonstrated tolerability and safety but did not achieve their primary efficacy endpoints, contributing to the company’s subsequent strategic pivot toward Barth syndrome.

Heart Failure and Cardiac Ageing

Heart failure with preserved ejection fraction (HFpEF) has been a major research focus. Stealth conducted Phase 2/3 sponsored programmes (including PROGRESS-HF) examining elamipretide in heart failure populations. In preclinical models, eight weeks of SS-31 treatment at 3 mg/kg/day in aged mice substantially reversed cardiac diastolic dysfunction, normalised proton leak, and reduced mitochondrial ROS production in cardiac muscle cells. These results have been replicated across species and refined over time by multiple independent research groups.

Kidney Disease

SS-31 has been studied across multiple categories of kidney disease in animal models. It reduces tubular cell apoptosis, reduces fibrosis, and preserves mitochondrial structure in proximal tubules. In ischaemia-reperfusion injury models, SS-31 protection was sustained for over six months after treatment ended (Szeto et al. 2016). A small human study in patients with severe atherosclerotic renal artery stenosis tested elamipretide infusion during percutaneous transluminal renal angioplasty.

Skeletal Muscle and Ageing

Prolonged SS-31 treatment in aged mice reversed age-related energetic deficits in skeletal muscle, improved both resting and dynamic muscle function, and restored redox homeostasis. A 2021 bioRxiv preprint demonstrated that elamipretide treatment attenuated age-associated post-translational modifications of heart proteins, suggesting the compound modifies the proteome through restoration of mitochondrial energetics rather than direct protein modification.

Area	Key Study/Trial	Key Finding	Evidence Tier
Barth syndrome	TAZPOWER Phase 2/3 (NCT03098797)	Knee extensor strength +45%; FDA accelerated approval Sep 2025	Phase 2/3 (approved)
Mitochondrial myopathy	MMPOWER / MMPOWER-2	Safe and tolerable; primary endpoints not met	Phase 2 (human)
Heart failure (HFpEF)	PROGRESS-HF and preclinical	Reversed cardiac diastolic dysfunction in aged mice	Phase 2 (human) + preclinical
Kidney disease	Multiple preclinical + human pilot	Reduced fibrosis, preserved tubular function; sustained 6+ months post-treatment	Preclinical + Phase 1 (human)
Skeletal muscle ageing	Multiple aged mouse models	Reversed energetic deficits, improved dynamic function, restored redox balance	Preclinical (animal)
Cardiac ageing	Aged mice, 8 weeks treatment	Reversed diastolic dysfunction, normalised proton leak, reduced mitochondrial ROS	Preclinical (animal)

The bottom line: SS-31 has the strongest evidence base of any peptide in the longevity cluster, including FDA approval for Barth syndrome and Phase 2 human data across multiple indications, supported by extensive preclinical work replicated by independent groups worldwide.

Stealth BioTherapeutics is running two Phase 3 clinical trials (ReNEW and ReGAIN) testing elamipretide for dry age-related macular degeneration – the leading cause of vision loss in adults over 65, with no approved systemic treatment for the geographic atrophy stage. The retinal pigment epithelium and photoreceptors are among the most mitochondrially dense tissues in the body, making them natural targets for a cardiolipin-stabilising compound.

Stealth BioTherapeutics has built a multi-stage ophthalmic clinical programme around elamipretide. The ReCLAIM Phase 1 trial (Duke University Medical Center, published in Ophthalmology Science 2022) tested daily subcutaneous elamipretide at 40 mg in patients with dry AMD and noncentral geographic atrophy. The study demonstrated safety and tolerability, with exploratory analyses showing possible positive effects on visual function under low-luminance conditions. ReCLAIM-2, a Phase 2 randomised, placebo-controlled, double-masked multicentre trial (NCT03891875, published in Ophthalmology Science 2024), evaluated elamipretide for 48 weeks in dry AMD patients with GA. The primary efficacy endpoints included mean change in low-luminance best-corrected visual acuity and change in GA area measured by optical coherence tomography.

The programme has now advanced to Phase 3 with two global trials: ReNEW (SPIAM-301, NCT06373731) and ReGAIN, evaluating once-daily self-administered subcutaneous elamipretide at 40 mg in 360 patients randomised 2:1 to treatment or placebo for 96 weeks. The primary endpoint, agreed with the FDA, measures the rate of change in the macular area of photoreceptor loss assessed by spectral domain-OCT and ellipsoid zone mapping. As of September 2025, ReNEW had reached 50% enrolment.

Bevemipretide (SBT-272): The Second Generation

Stealth is also developing bevemipretide (SBT-272), a second-generation clinical-stage candidate designed for ophthalmic and neurological disease indications. Bevemipretide retains the cardiolipin-targeting mechanism but has been optimised for different tissue penetration and pharmacokinetic properties. This suggests Stealth views the mitochondrial membrane as a platform target applicable across multiple organ systems rather than a single-indication compound.

The bottom line: The dry AMD programme represents potentially the largest commercial application of elamipretide, with two Phase 3 trials actively enrolling and a clinical pathway that, if successful, would validate the cardiolipin mechanism in a second major organ system.

SS-31’s regulatory position is unique among longevity peptides because it has an FDA-approved indication. As Forzinity, it is a prescription-only drug for Barth syndrome patients weighing at least 30 kg. This creates a distinct regulatory pathway from the 503A compounding route that applies to most other peptides on this site. The wider legal position in each market is set out in our guides to peptide legality in the US, UK and Australia.

Jurisdiction	Status	Notes
United States (FDA)	Approved (Forzinity)	Accelerated approval Sep 19, 2025 for Barth syndrome (NDA 215244). Prescription-only. Off-label prescribing is legally permitted. Forzinity approval may affect compounding eligibility under FDCA rules for FDA-approved drug components.
United Kingdom (MHRA)	Not licensed	No marketing authorisation. Possible access via Early Access to Medicines Scheme for Barth syndrome patients.
Australia (TGA)	Not approved	No TGA registration. Special Access Scheme may apply for individual patients.
WADA	Not individually listed	Not named on the 2024 Prohibited List. Athletes should verify current status.

The bottom line: SS-31 occupies a unique regulatory position as both an FDA-approved drug (Forzinity for Barth syndrome) and a compound of interest for off-label mitochondrial support, with the two pathways governed by different regulatory frameworks.

SS-31 has the most extensive human safety data of any peptide in the longevity cluster. Across clinical trials including TAZPOWER, MMPOWER, MMPOWER-2 and PROGRESS-HF, elamipretide has been well tolerated as both intravenous infusion (0.01-0.25 mg/kg/h) and daily subcutaneous injection. The most commonly reported adverse event in clinical trials is injection site reaction. As of April 2026, 35 patients worldwide had received elamipretide under expanded or emergency access programmes, including critically ill infants and toddlers.

SS-31 is water-soluble and excreted by the kidneys. Drug interactions with SS-31 have not been well documented in published literature. The compound concentrates most in kidney tissue but is also taken up by heart, liver, skeletal muscle and lungs after subcutaneous administration. For guidance on evaluating peptide source quality, see our guide on how to read a certificate of analysis.

The bottom line: SS-31 has demonstrated a favourable safety profile across multiple human clinical trials, with injection site reactions as the primary reported adverse event.

Within the longevity peptide cluster, SS-31 addresses mitochondrial dysfunction through cardiolipin stabilisation – a different mechanism from every other compound in the group. MOTS-c also targets mitochondrial function but operates through AMPK activation via the folate-methionine cycle, a metabolic signalling pathway rather than a structural membrane interaction. Epitalon and pinealon work through gene-expression modulation. FOXO4-DRI takes a senolytic approach, clearing senescent cells rather than restoring mitochondrial function in existing cells.

SS-20, another member of the Szeto-Schiller peptide family, shares the mitochondria-targeting properties but uses phenylalanine instead of dimethyltyrosine, giving it different ROS-scavenging characteristics. It remains in early preclinical investigation.

What is SS-31?

SS-31 is a synthetic tetrapeptide (D-Arg-dimethylTyr-Lys-Phe-NH2) that selectively targets the inner mitochondrial membrane by binding to cardiolipin. It was developed by Dr. Hazel Szeto and Dr. Peter Schiller at Weill Cornell Medical College and commercialised by Stealth BioTherapeutics. It is also known as elamipretide, MTP-131, Bendavia and Forzinity.

Is SS-31 FDA-approved?

Yes. On September 19, 2025, the FDA granted accelerated approval to Forzinity (elamipretide HCl injection) for the treatment of Barth syndrome in patients weighing at least 30 kg. This is the first approved treatment for Barth syndrome and the first approved mitochondria-targeted therapeutic. It is not approved for longevity, heart failure, kidney disease or any other indication.

How does SS-31 differ from MOTS-c?

Both target mitochondrial function but through completely different mechanisms. SS-31 stabilises cardiolipin on the inner mitochondrial membrane, directly maintaining electron transport chain integrity. MOTS-c is a mitochondrial-derived peptide that activates AMPK through disruption of the folate-methionine cycle. SS-31 is a designed synthetic molecule; MOTS-c is an endogenous signalling peptide.

What happened with the TAZPOWER trial?

The TAZPOWER Phase 2/3 trial initially failed its primary endpoint (change in six-minute walk test at 12 weeks). However, in the open-label extension running up to 168 weeks, knee extensor muscle strength improved by approximately 45%. Stealth resubmitted the NDA seeking accelerated approval based on knee extensor strength as an intermediate endpoint. An October 2024 FDA advisory committee concluded the drug was effective, and the FDA granted accelerated approval in September 2025.

Is SS-31 the same as elamipretide?

Yes. SS-31 is the original research designation (Szeto-Schiller compound 31). Elamipretide is the International Nonproprietary Name (INN) assigned during clinical development. MTP-131 was used in early clinical trial registrations. Bendavia was the brand name during cardiac trials. Forzinity is the approved brand name for the Barth syndrome indication.

Can SS-31 be compounded?

This is a legally complex question. Because elamipretide is now an FDA-approved drug (Forzinity), the FDCA generally restricts compounding of components of approved drugs unless specific conditions are met. This creates a different regulatory pathway from Category 1 peptides on the 503A Bulks List. Consult a healthcare professional and a pharmacy compliance expert for current guidance on compounding eligibility.

What makes SS-31 different from other antioxidants?

Most antioxidants (vitamin C, vitamin E, NAC) scavenge free radicals after they are produced. SS-31 addresses the upstream cause by stabilising cardiolipin on the inner mitochondrial membrane, which prevents the electron transport chain dysfunction that generates excess ROS in the first place. It also prevents cytochrome c from shifting to a damaging peroxidase activity, which other antioxidants do not target.