SS-31

Elamipretide, a cardiolipin-binding mitochondrial tetrapeptide developed as SS-31, granted FDA accelerated approval in September 2025 as Forzinity for Barth syndrome after failed trials in mitochondrial myopathy and heart failure, and sold widely as a research peptide.

Also referenced as: elamipretide, Forzinity, MTP-131, Bendavia, SS31, elamipretide hydrochloride

Also appears in: Cardiovascular · Tissue repair

What is SS-31?

SS-31 is the research designation of elamipretide, an aromatic-cationic tetrapeptide with the sequence D-Arg-Dmt-Lys-Phe-NH2, where Dmt is 2’,6’-dimethyltyrosine. It belongs to the Szeto-Schiller family of peptides designed by Hazel Szeto and Peter Schiller in the early 2000s to concentrate in mitochondria regardless of membrane potential, and it was later developed by Stealth BioTherapeutics under the codes MTP-131 and Bendavia before receiving the nonproprietary name elamipretide. Its distinguishing property is high-affinity binding to cardiolipin, the signature phospholipid of the inner mitochondrial membrane (Birk et al., Journal of the American Society of Nephrology, 2013;24(8):1250–1261).

Two things keep the molecule in view. On September 19, 2025 the FDA granted accelerated approval to elamipretide hydrochloride injection, branded Forzinity, to improve muscle strength in patients with Barth syndrome weighing at least 30 kg, making it the first approved therapy for that disease. At the same time, a decade of mouse studies linking the peptide to improved mitochondrial function in aged heart, muscle and kidney has made SS-31 one of the most widely listed “mitochondrial” or “longevity” peptides in research-vendor catalogs, where it is almost always sold under the SS-31 name rather than as elamipretide.

How it works

• Cardiolipin binding on the inner mitochondrial membrane. The peptide’s two basic residues bind electrostatically to the anionic head groups of cardiolipin while its aromatic residues insert into the membrane. A polarity-sensitive fluorescent analog showed high-affinity cardiolipin binding, and in rats the peptide protected cristae membranes during renal ischemia and accelerated ATP recovery on reperfusion (Birk et al., Journal of the American Society of Nephrology, 2013;24(8):1250–1261). The FDA label describes the drug simply as a mitochondrial cardiolipin binder that localizes to the inner mitochondrial membrane.
• Protection of the cytochrome c–cardiolipin interaction. When cytochrome c binds cardiolipin tightly it can switch from an electron carrier to a peroxidase that oxidizes cardiolipin and initiates apoptosis. SS-31 inhibits that peroxidase activity and preserves electron transfer through cytochrome c, which is the proposed basis for its effects on oxidative phosphorylation and reactive oxygen species (Birk et al., British Journal of Pharmacology, 2014;171(8):2017–2028). A structure-activity study of the tetrapeptide series found that all analogs with the alternating cationic-aromatic pattern bound cardiolipin-containing membranes and reached mitochondria, but that side-chain composition and sequence register changed membrane surface charge, binding behavior and potency in cell-stress assays, pointing to modulation of membrane electrostatics as a core part of the mechanism (Mitchell et al., eLife, 2022;11:e75531).
• Broad interactions with inner-membrane proteins. Cross-linking mass spectrometry in intact mitochondria mapped SS-31 contacts with a set of known cardiolipin-binding proteins, grouped into oxidative phosphorylation components and enzymes of 2-oxoglutarate metabolism, with cross-linked residues often adjacent to the proteins’ cardiolipin-binding regions; the picture is of a peptide that stabilizes a membrane microenvironment rather than acting on one receptor (Chavez et al., Proceedings of the National Academy of Sciences, 2020;117(26):15363–15373).
• Restoration of function in aged tissue (preclinical). In old mice the peptide rapidly improved skeletal muscle energetics and endurance (Siegel et al., Aging Cell, 2013;12(5):763–771), reversed age-related cardiac dysfunction (Chiao et al., eLife, 2020;9:e55513) and improved ADP sensitivity in aged mitochondria (Pharaoh et al., GeroScience, 2023;45(6):3529–3548). These are the studies that underpin the molecule’s reputation in aging research; none has a human counterpart beyond a small pilot study.

Research status

Barth syndrome: TAZPOWER (NCT03098797). Barth syndrome is an X-linked disorder caused by TAFAZZIN variants that disrupt cardiolipin remodeling, producing cardiomyopathy, skeletal myopathy and neutropenia; it was the rational match for a cardiolipin-binding drug. TAZPOWER randomized 12 males aged 12 and older to 12 weeks of daily subcutaneous elamipretide 40 mg or placebo in a crossover design with a 4-week washout. Neither primary endpoint, the 6-minute walk test or the Barth Syndrome Symptom Assessment total fatigue score, was met in the blinded phase. In the open-label extension, 8 participants reaching 36 weeks improved by 95.9 m on the 6-minute walk (p=0.024) and 2.1 points on the symptom scale (p=0.031), with gains in knee extensor strength and some echocardiographic measures (Reid Thompson et al., Genetics in Medicine, 2021;23(3):471–478). The extension ran to 168 weeks: 10 participants entered it and 8 reached the week 168 visit, the cumulative 6-minute walk improvement reached 96.1 m (p=0.003), three-dimensional left ventricular stroke, end-diastolic and end-systolic volumes trended toward improvement and the monolysocardiolipin-to-cardiolipin ratio moved toward normal (Thompson et al., Genetics in Medicine, 2024;26(7):101138). A propensity-matched comparison of the 8 extension participants against 19 untreated natural-history controls was published separately (Hornby et al., Orphanet Journal of Rare Diseases, 2022;17(1):336).

Regulatory path to approval. Stealth submitted the New Drug Application on January 29, 2024, and the Cardiovascular and Renal Drugs Advisory Committee voted 10 to 6 on October 10, 2024 that the evidence supported effectiveness. The FDA issued a complete response letter dated May 15, 2025 that cited observations from an inspection of a third-party manufacturing facility, raised no concerns about clinical safety, and offered a potential accelerated approval pathway with knee extensor muscle strength as an intermediate clinical endpoint. Stealth resubmitted on August 15, 2025, and on September 19, 2025 the FDA granted accelerated approval under NDA 215244 for Forzinity (elamipretide hydrochloride) injection to improve muscle strength in adult and pediatric patients with Barth syndrome weighing at least 30 kg, on the basis of an improvement in knee extensor strength that was observed only in the open-label extension and was deemed reasonably likely to predict clinical benefit; the approval letter requires a randomized, placebo-controlled trial to verify clinical benefit, and continued approval may be contingent on that result (Shirley, Drugs, 2026;86(3):377–383). On June 16, 2026 Stealth BioTherapeutics announced that it would operate as Mighty Therapeutics; the label still names Stealth BioTherapeutics Inc. as labeler.

Confirmatory trial: 4TAZPower (NCT07531251). The required confirmatory study is a randomized, double-blind, parallel-group, placebo-controlled phase 3b/4 trial of 72 weeks of daily subcutaneous elamipretide in an estimated 48 males aged 5 to 55 with genetically confirmed Barth syndrome. It began on July 2, 2026, the first participant was dosed by July 8, 2026, sites have opened in the United Kingdom, Ireland, Canada and Australia, and primary completion is estimated for September 30, 2029. The label currently covers only patients weighing at least 30 kg, and younger children are treated through an expanded access program.

Primary mitochondrial myopathy: MMPOWER-3 (NCT03323749). The largest trial of the drug was a phase 3, double-blind, placebo-controlled study that randomized 218 adults with genetically confirmed primary mitochondrial myopathy to 24 weeks of daily subcutaneous elamipretide 40 mg or placebo. It failed both primary endpoints: the difference in 6-minute walk distance was −3.2 m (95% CI −18.7 to 12.3; p=0.69) and the difference in Primary Mitochondrial Myopathy Symptom Assessment total fatigue score was −0.07 (p=0.37). The drug was well tolerated, and the paper reports Class I evidence that elamipretide does not improve these endpoints at 24 weeks (Karaa et al., Neurology, 2023;101(3):e238–e252). A post hoc analysis reported that participants with nuclear DNA defects, 26 percent of the trial and mostly carrying POLG and TWNK variants, walked 25.2 m farther on elamipretide versus 2.0 m on placebo (p=0.06), while the mitochondrial DNA cohort showed no difference (Karaa et al., Orphanet Journal of Rare Diseases, 2024;19(1):431). Earlier trials in this population were a phase 1/2 dose-escalation study (Karaa et al., Neurology, 2018;90(14):e1212–e1221) and a 4-week crossover study (Karaa et al., Journal of Cachexia, Sarcopenia and Muscle, 2020;11(4):909–918).

Nuclear DNA mitochondrial disease: NuPOWER (NCT05162768). Following the subgroup signal, a phase 3, double-blind, placebo-controlled trial randomized 102 adults with primary mitochondrial disease caused by nuclear DNA variants to 48 weeks of daily subcutaneous elamipretide 60 mg or placebo, with 6-minute walk distance as the primary endpoint. The trial completed on December 4, 2024. No peer-reviewed publication or posted results exist; the company presented the data as a poster at the Euromit meeting on June 4, 2026 under a title describing overall outcomes and “emerging evidence” of a genotype-dependent response in a POLG1 subgroup, and has since said it is seeking FDA alignment on a new pivotal trial restricted to POLG-related disease. No filing in the broader nuclear DNA population has been announced.

Heart failure and ischemia-reperfusion. Elamipretide’s first clinical programs were cardiovascular, and all of them returned negative primary endpoints. EMBRACE STEMI, a multicenter phase 2a trial of a 1-hour intravenous MTP-131 infusion in patients undergoing primary percutaneous coronary intervention for a first anterior ST-elevation myocardial infarction, did not reduce infarct size measured by creatine kinase-MB area under the curve, nor improve prespecified imaging, angiographic or clinical outcomes (Gibson et al., European Heart Journal, 2016;37(16):1296–1303). A single 4-hour infusion in 36 patients with heart failure with reduced ejection fraction produced a transient reduction in left ventricular volumes at the highest dose (Daubert et al., Circulation: Heart Failure, 2017;10(12):e004389), but PROGRESS-HF, which randomized 71 patients with reduced ejection fraction to 28 days of daily subcutaneous placebo, 4 mg or 40 mg elamipretide, found no difference in left ventricular end-systolic volume on cardiac magnetic resonance for either dose versus placebo (Butler et al., Journal of Cardiac Failure, 2020;26(5):429–437). No heart-failure trial has been started since.

Dry age-related macular degeneration. Two phase 1 studies tested subcutaneous elamipretide in intermediate AMD with high-risk drusen and in noncentral geographic atrophy (Allingham et al., Ophthalmology Science, 2022;2(1):100095; Mettu et al., Ophthalmology Science, 2022;2(1):100086). ReCLAIM-2 (NCT03891875), a phase 2, double-masked trial, randomized 176 patients aged 55 and older with dry AMD and noncentral geographic atrophy 2:1 to 48 weeks of daily subcutaneous elamipretide 40 mg or placebo. It missed both primary endpoints, change in low-luminance best-corrected visual acuity and change in square-root geographic atrophy area, but reported a 43 percent reduction in progression of ellipsoid zone attenuation (nominal p=0.0034) and a 10-letter or greater low-luminance acuity gain in 14.6 percent versus 2.1 percent of patients (nominal p=0.0404); adverse events occurred in 86 percent versus 71 percent, mostly injection site reactions (Ehlers et al., Ophthalmology Science, 2025;5(1):100628). The phase 3 ReNEW trial (NCT06373731), which began on May 30, 2024 and enrolled 313 patients, uses the rate of change in the macular area of photoreceptor loss at week 48 as its primary endpoint over 96 weeks of treatment; it is fully enrolled, with primary completion estimated for August 2027. A second phase 3 named ReGAIN was announced alongside ReNEW on June 5, 2024 but has no ClinicalTrials.gov record and has not appeared in later company updates.

Other human studies. MOTION (NCT02245620), a phase 2 study of a single intravenous infusion in 41 adults aged 60 to 85 with skeletal muscle mitochondrial dysfunction, completed in 2016, and early-phase topical ophthalmic studies in Fuchs corneal dystrophy (NCT02653391) and Leber hereditary optic neuropathy (NCT02693119) were completed without leading to further development. An investigator-initiated phase 1/2 study in 20 patients with Friedreich ataxia at Children’s Hospital of Philadelphia (NCT05168774) completed on June 25, 2024; its results were posted to ClinicalTrials.gov on December 12, 2025 and no peer-reviewed report has appeared. SHAPE (NCT07275424), an investigator-initiated, open-label, single-arm phase 2a pilot at the University of Washington, began on November 26, 2025 to assess 4 weeks of daily subcutaneous elamipretide in 30 adults aged 65 to 80, with safety and tolerability as its primary outcome; it is unpublished. It is the only registered human study of the peptide in aging, and it has no control arm; the company has said it is preparing a placebo-controlled trial in older adults in connection with the XPRIZE Healthspan competition, with no registration yet.

Common dosage forms

• Forzinity (elamipretide hydrochloride) injection, the FDA-approved product, is supplied as a 280 mg per 3.5 mL (80 mg per mL) multiple-dose vial for subcutaneous injection.
• Investigational subcutaneous solution in the same 80 mg per mL vial format, and in earlier years an intravenous infusion formulation, supplied only to clinical-trial sites.
• Topical ophthalmic solution, an investigational eye-drop formulation used in two small completed trials and no longer in development for elamipretide; the company’s follow-on peptide bevemipretide is being tested as drops instead.
• Lyophilized powder in research vials labeled for laboratory use, typically in 10 mg to 50 mg quantities, is the presentation sold under the SS-31 name by research-chemical vendors and is not an approved drug product.

Key considerations

• Regulatory status. The FDA Approved status reflects the September 19, 2025 accelerated approval of Forzinity (elamipretide hydrochloride) injection under NDA 215244 for Barth syndrome. The indication rests on an intermediate endpoint rather than demonstrated functional benefit, continued approval depends on the 4TAZPower confirmatory trial, and no regulator has approved elamipretide for any other condition or in any other jurisdiction.
• The approved indication is the exception in the trial record. Every adequately powered placebo-controlled trial of the drug outside Barth syndrome has missed its primary endpoint, and the Barth syndrome data themselves come from 12 participants whose blinded crossover was negative, with the supporting evidence drawn from an uncontrolled open-label extension and a natural-history comparison. Claims that elamipretide has “proven” effects on energy, endurance or cardiac function in humans are not supported by that record.
• Aging evidence is preclinical. The mouse literature on aged heart, skeletal muscle, kidney and aorta is extensive, but whether the peptide changes any measure of healthspan in people has not been tested in a controlled trial.
• Safety signals. Across trials the dominant adverse events are injection site reactions, which in the placebo-controlled part of TAZPOWER affected nearly every participant on elamipretide. The label’s warnings are hypersensitivity, including serious reactions that have occurred from minutes to months after starting treatment, and benzyl alcohol toxicity in neonates. Long-term safety data beyond the 10-person TAZPOWER extension are limited.
• Naming and identity. SS-31, elamipretide, MTP-131, Bendavia and Forzinity all refer to the same tetrapeptide; the approved product is the hydrochloride salt, while material sold for laboratory use often does not state its salt form. The compound is unrelated to the other mitochondria-associated peptides it is grouped with in research catalogs, such as MOTS-c and humanin, which are mitochondrial-encoded or mitochondria-derived signaling peptides rather than synthetic cardiolipin binders. Bevemipretide is a distinct next-generation analog from the same company, not an alias.