Compound reference
SS-31
Also known as Elamipretide, Bendavia, MTP-131, Forzinity
SS-31 (elamipretide) is a mitochondria-targeting tetrapeptide that in 2025 earned its first FDA approval — Forzinity, for the rare Barth syndrome. But its broader clinical record is mixed, with missed primary endpoints in mitochondrial myopathy, heart failure, and STEMI. The 'SS-31' sold for anti-aging is the unapproved research compound.
- CAS
- 736992-21-5
- Formula
- C₃₂H₄₉N₉O₅
- Molar mass
- ≈639.8 g/mol
- Sequence
- D-Arg-Dmt-Lys-Phe-NH₂ (Dmt = 2′,6′-dimethyltyrosine); a Szeto-Schiller tetrapeptide
FDA accelerated approval has been granted for elamipretide in Barth syndrome; broader mitochondrial indications remain indication-specific and source-dependent.
Mode of action
SS-31 is a synthetic tetrapeptide (D-Arg-Dmt-Lys-Phe-NH₂) from the Szeto-Schiller peptide class, developed clinically as elamipretide and previously known as MTP-131 and Bendavia. Its alternating cationic/aromatic structure lets it cross cell membranes and concentrate — without a transporter — in the inner mitochondrial membrane, where it binds the phospholipid cardiolipin. Cardiolipin is essential for organizing the electron-transport chain and stabilizing the cytochrome c/cardiolipin interaction; by binding it, SS-31 helps preserve cristae structure, supports electron transport and ATP synthesis, and reduces the peroxidase activity and reactive-oxygen-species leak associated with damaged mitochondria. In short, it is a mitochondrial "structural" protectant rather than an antioxidant in the conventional sense, and that mechanism is unusually well characterized across biophysical, isolated-mitochondria, and animal studies.
Main intended effect
To restore the function of dysfunctional mitochondria — improving bioenergetics and preserving mitochondrial structure in tissues with high energy demand (muscle, heart, kidney, retina).
Areas of interest
The clinical focus has been primary mitochondrial diseases (Barth syndrome, primary mitochondrial myopathy), heart failure and cardiac ischemia-reperfusion, dry age-related macular degeneration (geographic atrophy), and kidney injury. In the consumer market, SS-31 is sold as an "anti-aging" and energy/recovery peptide, on the back of preclinical work showing it rapidly restores energetics in aged muscle.
Evidence for intended effects
This is where SS-31 needs an honest, two-sided reading. On one side, the mechanism is strong and the drug crossed the approval line: in September 2025 the FDA granted accelerated approval to Forzinity (elamipretide) as the first treatment for Barth syndrome, a rare X-linked mitochondrial cardiomyopathy — based on an intermediate endpoint (knee-extensor muscle strength). That approval rested heavily on the long-term open-label extension of the TAZPOWER trial, because the original double-blind crossover portion in 12 patients did not meet its co-primary endpoints; sustained strength gains emerged over the multi-year extension.
On the other side, elamipretide has a striking record of missed endpoints in larger, broader trials. The Phase 3 MMPOWER-3 trial in genetically heterogeneous primary mitochondrial myopathy did not meet its primary endpoints (a genotype post-hoc later suggested a possible mtDNA-subgroup signal). In cardiology, the PROGRESS-HF Phase 2 trial did not improve left-ventricular volumes in heart failure, and the EMBRACE-STEMI trial (as MTP-131/Bendavia) did not reduce infarct size after heart attack. In dry AMD, the ReCLAIM-2 Phase 2 trial missed its geographic-atrophy growth endpoint while showing some secondary signals, and a Phase 3 program is ongoing. So the proven benefit is narrow and rare-disease-specific; the broad "mitochondrial rejuvenation" promise has repeatedly failed to confirm in controlled trials.
| Strand | What exists | Tier |
|---|---|---|
| Barth syndrome | TAZPOWER + open-label extension; FDA accelerated approval (2025) | Approved (intermediate endpoint) |
| Primary mitochondrial myopathy | MMPOWER-3 Phase 3 — missed primary endpoints | Negative (subgroup signal) |
| Heart failure / STEMI | PROGRESS-HF, EMBRACE-STEMI — negative | Negative |
| Dry AMD | ReCLAIM-2 missed primary; Phase 3 ongoing | Mixed / ongoing |
| Mechanism / preclinical | Cardiolipin binding, cristae, aged-muscle energetics | Strong |
Studied amounts (literature dosing context)
Clinical trials used 40 mg/day subcutaneously in the muscle/mitochondrial-disease programs, and intravenous infusions (e.g. 0.05 mg/kg/h) in the acute-cardiac studies; the approved Forzinity product has its own label-defined regimen for Barth syndrome. These are trial and prescribing figures for specific indications; this page does not provide dosing guidance for off-label or research use.
Safety and regulatory status
As Forzinity, elamipretide is now an FDA-approved prescription drug — but only for Barth syndrome, under accelerated approval (which carries a requirement to confirm benefit). It is not approved for mitochondrial myopathy, heart failure, AMD, anti-aging, or general "energy," and several of those programs produced negative trials. Material sold as research-grade "SS-31" for those uses is the unapproved compound, of unverified identity and purity. It is the best-developed member of a small group of mitochondrial peptides that includes the mitochondrial-derived peptides MOTS-c and humanin, though it works by a different (cardiolipin-binding) mechanism.
Sources
Serendipity and the Discovery of Novel Compounds That Restore Mitochondrial Plasticity
Discovery account and mechanistic review by Szeto and Birk published in Clinical Pharmacology and Therapeutics describing the serendipitous identification of the Szeto-Schiller (SS) peptide class, including SS-31 (H-D-Arg-Dmt-Lys-Phe-NH2), as the first compounds selectively targeting the mitochondrial inner membrane via cardiolipin interaction. Cardiolipin's conical structure organises respiratory supercomplexes and acts as a proton trap to facilitate ATP synthesis; SS peptides bind cardiolipin to restore mitochondrial cristae architecture and electron transport chain efficiency specifically in diseased or ageing cells. The authors argue that restoring mitochondrial plasticity — the capacity to upregulate ATP production under metabolic stress — represents a broadly applicable therapeutic strategy across age-related and ischaemic diseases. SS-31 was advancing through multiple clinical trials at time of publication.
Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis
In vitro mechanistic study (Birk and colleagues; British Journal of Pharmacology 2014, PMID 24134698) using liposomes, bicelles, isolated rat mitochondria, and mitoplasts to characterise SS-31's interaction with cardiolipin and cytochrome c. SS-31 showed selective, approximately 1:1 binding to cardiolipin, with aromatic residues penetrating deep into cardiolipin-containing bilayers but not phosphatidylcholine-only membranes. SS-31 modulated the cytochrome c–cardiolipin complex, preventing the pathological conformational change that converts cytochrome c into a peroxidase; state 3 respiration and the P/O ratio increased dose-dependently in the 50–100 µM range, and peroxidase activity was suppressed while electron transfer was preserved. The proposed mechanism is electrostatic and hydrophobic stabilisation of cardiolipin-bound cytochrome c in its native folded state. All findings are from isolated mitochondrial preparations; clinical relevance to mitochondrial disease has not been directly demonstrated.
The Mitochondrial-Targeted Compound SS-31 Re-Energizes Ischemic Mitochondria by Interacting with Cardiolipin
Mechanistic study (Birk and colleagues; JASN 2013, PMID 23813215) combining in vitro biochemical assays with a rat renal ischemia-reperfusion model to characterise SS-31's interaction with cardiolipin. SS-31 bound cardiolipin with KD 1.87 ± 0.64 µM and inhibited cardiolipin-induced cytochrome c peroxidase activity with EC50 0.8 ± 0.06 µM; the mechanism is prevention of heme-iron exposure in cytochrome c by blocking lipid-induced conformational change. Electron microscopy showed SS-31 preserved mitochondrial cristae architecture during 30-minute ischemia (p < 0.001), and the peptide accelerated ATP restoration on reperfusion, reduced TUNEL-positive tubular apoptosis (p < 0.001), and restored actin cytoskeleton polarity markers (E-cadherin, β1-integrin). The authors note SS-31 was in clinical trials for ischemia-reperfusion injury at the time of publication; however, rat kidney models may not fully predict human efficacy or optimal dosing.
Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice
Experimental study (Siegel and colleagues; Aging Cell 2013, PMID 23692570) in young (5-month) and aged (27-month) C57BL/6 mice testing a single intraperitoneal SS-31 injection at 3 mg/kg. Within one hour, the P/O ratio (oxidative phosphorylation coupling), depressed in aged muscle, was fully restored to young levels, resting and maximal ATP production capacity increased significantly, and mitochondrial H2O2 emission and glutathione content were restored to near-young levels. Force fatigue resistance improved markedly within one hour, and an 8-day treatment protocol increased whole-animal endurance capacity, though maximum specific force was unchanged. The proposed mechanism is reduction of mitochondrial oxidative stress and improved energy coupling. These results provide a preclinical basis for interest in SS-31 for age-related skeletal-muscle decline; the authors note translation to human use requires further investigation.
Elamipretide: A Review of Its Structure, Mechanism of Action, and Therapeutic Potential
Comprehensive narrative review by Tung and colleagues examining elamipretide (SS-31/MTP-131), a synthetic tetrapeptide (D-Arg-Dmt-Lys-Phe-NH₂) that selectively accumulates in the inner mitochondrial membrane and stabilizes cardiolipin, thereby preserving cristae architecture, enhancing electron transport chain function, reducing reactive oxygen species, and inhibiting mitochondrial permeability transition pore opening. The review surveys the clinical-trial landscape, covering EMBRACE-STEMI (reduced post-PCI heart failure), TAZPOWER (improvements in skeletal muscle and cardiac parameters in Barth syndrome), ReCLAIM (slowed photoreceptor degeneration), and MMPOWER-3 (benefits in mitochondrial myopathy subgroups), alongside PROGRESS-HF where the primary endpoint was not met. The authors conclude elamipretide represents a meaningful advance in mitochondria-targeted therapy but acknowledge that clinical outcomes have been variable and require optimization, longer treatment durations, and evaluation in larger, more diverse populations.
FDA Grants Accelerated Approval to First Treatment for Barth Syndrome
FDA press announcement dated September 19, 2025 describing the accelerated approval of Forzinity (elamipretide) injection, the first treatment approved for Barth syndrome, a rare and life-threatening X-linked mitochondrial cardiomyopathy. Elamipretide (also known as SS-31 and MTP-131) is a mitochondria-targeting peptide approved to improve muscle strength in adult and pediatric patients weighing at least 30 kg. Approval was based on improvement in knee extensor muscle strength as an intermediate clinical endpoint reasonably likely to predict clinical benefit; confirmatory trials may be required to maintain the accelerated approval. Elamipretide is administered by subcutaneous injection and is the first approved drug product for any mitochondrial cardiomyopathy indication in the United States.
FORZINITY (elamipretide hydrochloride) injection — Prescribing Information
FDA-approved prescribing information for Forzinity (elamipretide hydrochloride injection), granted accelerated approval in 2025 based on an intermediate endpoint (knee extensor strength). The drug is indicated to improve muscle strength in adult and pediatric patients with genetically confirmed Barth syndrome who weigh at least 30 kg; neonates are excluded due to benzyl alcohol content. Recommended dosing is 40 mg subcutaneously once daily, reduced to 20 mg daily for adults with severe renal impairment (eGFR below 30 mL/min not on dialysis). The label carries warnings for benzyl alcohol toxicity in neonates and for serious hypersensitivity reactions including rash and respiratory symptoms. Pharmacokinetics show approximately 92% subcutaneous bioavailability and peak concentration at 0.5–1 hour post-injection; the drug is supplied as 280 mg/3.5 mL (80 mg/mL) single-patient-use vials.
https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=146bf34c-76f2-48db-ac07-fb29cce2cd75
A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome (TAZPOWER)
TAZPOWER Phase 2/3, randomized, double-blind, placebo-controlled crossover trial followed by an open-label extension (Thompson and colleagues; Genetics in Medicine 2021) in 12 patients with genetically confirmed Barth syndrome (TAZ-gene defect). Part 1 randomized participants to 40 mg/day subcutaneous elamipretide or placebo for 12 weeks, separated by a 4-week washout, then crossed over; co-primary endpoints of 6-minute walk distance and Barth Syndrome Symptom Assessment fatigue score were not met. In the 36-week open-label extension (Part 2, n = 10 continuing), 6-minute walk distance improved by 95.9 m (P = 0.024) and fatigue score improved by 2.1 points (P = 0.031) from Part 2 baseline; knee extensor strength, patient global impression, and some cardiac parameters also improved. Safety details were not fully reported in this publication but tolerability was characterized as acceptable. The divergence between negative crossover and positive open-label results is a recognized limitation of the trial design.
Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER
168-week open-label extension of the TAZPOWER trial (Thompson and colleagues; Genetics in Medicine 2024) in 10 Barth syndrome patients receiving 40 mg/day subcutaneous elamipretide, of whom 8 completed the week-168 visit. The primary endpoints were safety and tolerability; injection-site reactions were the predominant adverse events and no serious safety concerns emerged over more than three years of treatment. On the 6-minute walk test, significant improvements from OLE baseline were maintained at all OLE timepoints, with a cumulative gain of 96.1 m at week 168 (P = 0.003). Mean Barth Syndrome Symptom Assessment Total Fatigue scores remained below baseline throughout; three-dimensional left ventricular volumes showed significant improvement trends; and monolysocardiolipin/cardiolipin ratios improved and correlated with clinical outcomes. These data contributed to the regulatory evidence base supporting accelerated approval of elamipretide for Barth syndrome.
Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial
Phase 3, randomized, double-blind, placebo-controlled parallel-group trial (Karaa and colleagues; Neurology 2023) of 40 mg/day subcutaneous elamipretide over 24 weeks in a genetically heterogeneous population with primary mitochondrial myopathy. Co-primary endpoints were change in 6-minute walk distance and total fatigue score; neither reached statistical significance versus placebo across the overall trial population, constituting Class I evidence of no benefit on those endpoints. A post hoc genotype-stratified analysis reported in a separate publication identified a potential signal in nuclear DNA replisome-variant patients. Injection-site reactions were the predominant adverse events. The trial established a definitive negative primary result in the overall PMM population while informing genotype-specific hypotheses for future study.
Effects of Elamipretide on Left Ventricular Function in Patients With Heart Failure With Reduced Ejection Fraction: The PROGRESS-HF Phase 2 Trial
PROGRESS-HF Phase 2, randomized, double-blind, placebo-controlled trial (Butler and colleagues; Journal of Cardiac Failure 2020) enrolling 71 patients with stable heart failure and reduced ejection fraction (LVEF ≤40%, mean 31% ± 7%) in a 1:1:1 ratio to placebo, elamipretide 4 mg/day, or elamipretide 40 mg/day subcutaneously for 28 days. The primary endpoint was change in left ventricular end-systolic volume (LVESV): the 4 mg arm showed −4.4 mL versus −3.8 mL for placebo (difference −0.3 mL; 95% CI −4.6 to 4.0; P = 0.90), and the 40 mg arm showed −1.2 mL versus placebo (difference 2.3 mL; 95% CI −1.9 to 6.5; P = 0.28) — neither dose met the primary endpoint. LVEF was also unchanged. Adverse event rates were similar across all three groups, confirming tolerability at both doses. The trial provided definitive negative phase 2 evidence for short-term subcutaneous elamipretide in HFrEF, effectively closing that development path.
EMBRACE STEMI study: a Phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention
Phase 2a, multicentre, randomized, double-blind trial (Gibson and colleagues, Eur Heart J 2016) of intravenous MTP-131 (Bendavia/elamipretide) at 0.05 mg/kg/h for 1 hour versus placebo in patients with first-time anterior STEMI undergoing primary PCI for proximal or mid left anterior descending artery occlusion. The primary endpoint — CK-MB area under the curve over 72 hours as a measure of infarct size — did not differ significantly between arms (placebo 5785 ± 426 ng·h/mL vs. MTP-131 5570 ± 486 ng·h/mL; p = NS). MTP-131 was not associated with improvement in any pre-specified MRI, angiographic, electrocardiographic, or clinical secondary outcomes. The drug was safe and well tolerated. The study failed its primary endpoint, providing no evidence that elamipretide reduces reperfusion injury in the setting of successful primary PCI for STEMI.
ReCLAIM-2: A Randomized Phase II Clinical Trial Evaluating Elamipretide in Age-Related Macular Degeneration, Geographic Atrophy Growth, Visual Function, and Ellipsoid Zone Preservation
ReCLAIM-2 Phase 2, prospective, randomized, double-masked, placebo-controlled multicenter trial (Ehlers and colleagues; Ophthalmology Science 2025; NCT03891875) enrolling 176 patients (117 elamipretide, 59 placebo) aged ≥55 years with dry AMD and noncentral geographic atrophy, treated with 40 mg/day subcutaneous elamipretide or placebo for 48 weeks. Co-primary endpoints — change in low-luminance best-corrected visual acuity and square-root-converted geographic atrophy area — did not reach statistical significance. However, prespecified secondary endpoints showed a 43% reduction in macular total ellipsoid zone attenuation/loss progression (nominal P = 0.0034) and a 47% reduction in partial EZ attenuation (nominal P = 0.0040); significantly more elamipretide patients gained ≥10 BCVA letters (14.6% vs. 2.1%; P = 0.0404). Adverse events occurred in 86% of the treatment group versus 71% of placebo, predominantly injection-site reactions. EZ preservation was subsequently selected as the primary endpoint for Phase 3 development.