Elamipretide

Elamipretide, also called SS-31, is a synthetic peptide developed to influence the membrane environment in which mitochondria produce cellular energy. Its experiments connect the lipid cardiolipin with electron transfer, muscle performance and a rare inherited disease called Barth syndrome. Human results vary with the population and the outcome: the large MMPOWER-3 mitochondrial-myopathy trial failed its walking and fatigue endpoints, while Forzinity received FDA accelerated approval in September 2025 to improve muscle strength in adults and children with Barth syndrome weighing at least 30 kg. Understanding that decision requires following the small Barth trial through its controlled phase and its longer, uncontrolled extension. MMPOWER-3 report, FDA approval announcement.

Overview

Elamipretide consists of four amino-acid residues, with modifications that influence its charge, membrane interactions and stability. SS-31, MTP-131 and Bendavia are names encountered during its development. Forzinity is the approved subcutaneous pharmaceutical product, whose active ingredient is supplied as elamipretide hydrochloride. The molecular fields below identify that salt explicitly; a formula for the hydrochloride includes chemical components absent from the peptide alone. Forzinity prescribing information, section 11.

Molecular profile

Peptide identity: Synthetic tetrapeptide; SS-31 is a development name for elamipretide Source
Sequence: D-Arg–2,6-dimethyl-L-Tyr–L-Lys–L-Phe–NH2 Source
Length and terminal group: Four amino-acid residues; C-terminal amide Source
Approved-product salt: Elamipretide hydrochloride (1:3), the trihydrochloride salt Source
Salt molecular formula: C32H49N9O5·3HCl (elamipretide hydrochloride) Source
Salt molecular weight: 749.2 g/mol (elamipretide hydrochloride) Source

Forms and derivatives

SS-31, MTP-131 and Bendavia

Development names encountered for the elamipretide core compound. Trial reports still identify the formulation and route they examined.

Forzinity / elamipretide hydrochloride

The approved subcutaneous pharmaceutical formulation supplies elamipretide as its hydrochloride salt and contains benzyl alcohol. The label specifies the product's identity and warnings.

[ald]SS-31 fluorescent analogue

A chemically modified fluorescent probe used in the cardiolipin study to investigate membrane interactions. The investigators also used SS-31 in biochemical and mitochondrial respiration experiments.

The sequence contains D-arginine, a dimethylated tyrosine, lysine and an amidated phenylalanine at the terminal end. Arginine and lysine contribute positive charge, while tyrosine and phenylalanine contain aromatic rings. This arrangement helps explain why investigators examine both electrical attraction to membrane surfaces and contact with the membrane's less water-friendly interior. Material identity remains important in these experiments: a fluorescent SS-31 analogue used to locate membrane interactions is a modified laboratory probe. Mitchell and colleagues (2020), Birk and colleagues (2014).

Uses and research areas

Mitochondrial-myopathy trials enrolled people with genetic disorders that predominantly affect skeletal muscle. These disorders can interfere with the conversion of food-derived energy into ATP, the molecule cells use to power work. Investigators therefore measured walking capacity and reported fatigue alongside tolerability. Those functional measures ask whether a biological intervention changes what a person can do or how they feel. Karaa and colleagues (2023).

Barth syndrome supplies a more specific connection to membrane biology. Pathogenic variants in the gene encoding tafazzin disrupt cardiolipin remodeling, the process that gives this lipid its usual composition. Affected people can have skeletal-muscle weakness, heart disease, abnormal growth and low neutrophil counts. The elamipretide trial tested ambulatory male participants with molecularly confirmed disease, so its strength and walking measurements concern that defined clinical setting. Thompson and colleagues (2021).

A separate study in older adults selected participants with impaired muscle mitochondrial capacity and assessed the immediate response to intravenous elamipretide. It provides a useful bridge between the membrane experiments and aging research because it measured energy production inside living human muscle. Its design addressed a short-term physiological response, leaving sustained daily function and lifespan outside the measured outcomes. Roshanravan and colleagues (2021).

Mechanism of action

Mitochondria have an inner membrane folded into structures called cristae. This membrane supports the proteins that pass electrons along the respiratory chain. Their activity builds an electrochemical gradient that powers ATP synthesis. Cardiolipin contributes to the organization of this machinery and helps maintain contact with cytochrome c, a small electron-carrying protein. When that interaction changes under damaging conditions, cytochrome c can acquire peroxidase activity and promote oxidation of cardiolipin. That change links membrane damage with impaired energy production.

Birk and colleagues examined this interaction using artificial lipid membranes, cytochrome-c preparations and isolated rat-kidney mitochondria. SS-31 interacted with cardiolipin-containing membranes, helped preserve cytochrome c's electron-transfer behavior and increased respiration coupled to ATP production in the isolated preparations. Some localization measurements used a fluorescent analogue; experiments assessing respiration used SS-31. Together, these assays explain a molecular route through which peptide–membrane interactions can affect energy production. Birk and colleagues (2014).

Later membrane-biophysics experiments refined the explanation. Mitchell and colleagues found that SS-31 binding depended on the membrane's surface charge; cardiolipin was important in the mitochondrial environment, although other negatively charged lipids could support binding in model membranes. The peptide changed surface electrostatics and lipid packing and reduced the energetic burden of calcium stress in isolated mitochondria. These findings suggest that its activity involves the surrounding membrane environment as well as a particular lipid–protein interaction. They also explain why a schematic of a single receptor would give an incomplete account of the proposed action. Mitchell and colleagues (2020).

Pharmacokinetics

The approved-product label describes systemic exposure after subcutaneous administration. Elamipretide is progressively broken down from its terminal end into the inactive M1 tripeptide and M2 dipeptide metabolites. The parent peptide and these metabolites leave the body in urine. Impaired kidney function increases exposure, making renal function relevant to the interpretation of both pharmacokinetics and safety. Forzinity prescribing information, section 12.3.

Plasma exposure and mitochondrial activity are different measurements. A change in blood concentration does not by itself show how long a membrane interaction or a functional response persists. The current label supplies useful absorption and elimination context but does not give a terminal half-life with the population, analyte and statistical description needed for a defensible exposure illustration here. Consequently, this profile includes no concentration–time graph. The older-adult infusion study is discussed through its measured muscle outcomes in the next section.

Research findings

MMPOWER-2: an uncertain walking signal

MMPOWER-2 was a randomized, double-blind crossover trial in 30 adults with genetically confirmed primary mitochondrial myopathy. Each participant underwent two four-week treatment periods separated by a four-week washout. The estimated difference in six-minute walking distance favored elamipretide by 19.8 m, with a 95% confidence interval from −2.8 to 42.5 m and P = 0.0833. The interval included no benefit, so the trial did not meet its primary walking endpoint. Several patient-reported fatigue measures favored treatment, providing a reason to test the hypothesis in a larger study. Karaa and colleagues (2020).

MMPOWER-3: the larger trial failed both primary endpoints

The subsequent phase 3 trial randomized 218 participants, 109 per group, to elamipretide or placebo for 24 weeks. The treatment difference in walking-distance change was −3.2 m (95% confidence interval −18.7 to 12.3; P = 0.69). Total fatigue also failed to improve significantly. Exploratory genetic subgroup analyses suggested a possible walking response among participants with nuclear-DNA defects. Because those analyses arose within an overall negative trial, they support a prospective, genotype-focused question whose answer remains to be established. Karaa and colleagues (2023).

TAZPOWER: controlled results and an extended observation

TAZPOWER enrolled 12 males aged 12–35 with genetically confirmed Barth syndrome. Its blinded crossover phase compared two 12-week periods separated by a four-week washout. Neither the walking nor fatigue primary endpoint was met; the muscle-strength comparison also failed to show a significant treatment difference. Ten participants entered an open-label extension, and eight had follow-up through week 36. Walking distance and fatigue improved compared with baseline during that extension. Thompson and colleagues (2021).

The 2024 report continued observation of the same cohort through week 168. Eight participants underwent assessments at that visit, with a mean six-minute walk improvement of 96.1 m from extension baseline (P = 0.003). The analyses included a participant who had stopped study treatment at week 72. Pandemic restrictions also interrupted several intermediate assessments. The long follow-up supplies information about changes over time and adverse events, while its lack of a concurrent randomized comparison leaves the contribution of treatment, expectations, growth and selective continuation unresolved. Thompson and colleagues (2024).

The strength endpoint supporting accelerated approval

FDA’s trial snapshot identifies knee-extensor strength as the measurement supporting approval. Investigators used a handheld dynamometer to measure the force participants could produce while straightening the knee. The controlled trial did not establish an advantage, but strength increased during the later period when everyone knew they were receiving elamipretide. At week 168, the label reports a median increase of 63 newtons among eight participants, measured from their baseline before the randomized trial. The walking result above instead used mean distance and the baseline at extension entry. FDA requires a confirmatory trial to establish whether the strength change translates into patient benefit. FDA trial snapshot.

As of 13 October 2026, FDA's ongoing accelerated-approval list retains Forzinity and postmarketing requirement 4802-1. It calls for a randomized, double-blind, placebo-controlled trial in people aged five years and older with Barth syndrome. The list gives 31 March 2030 as the original projected completion date. That regulatory requirement describes the next confirmatory step; it supplies no completed efficacy result. FDA ongoing accelerated approvals.

Older-adult muscle: energy capacity and endurance diverged

Roshanravan and colleagues randomized 39 healthy older adults aged 60–85 who had been selected for impaired mitochondrial function. After intravenous exposure, spectroscopy of a hand muscle showed an immediate increase in maximal ATP-production capacity. Statistical interpretation depended on the expression of change: percentage change gave P = 0.045, while absolute change gave P = 0.055. Resting mitochondrial coupling and the prespecified fatigue-resistance comparison did not improve significantly; the ATP-capacity difference was absent at day seven. The experiment therefore links elamipretide to an acute muscle-energy measurement while showing why that measurement cannot stand in for an established endurance benefit. Roshanravan and colleagues (2021).

Safety and tolerability

Injection-site reactions are a recurrent clinical finding. In the Barth trial used for the FDA snapshot, all 12 participants had a local administration reaction on elamipretide, compared with eight on placebo. In MMPOWER-3, adverse events occurred in 107 of 109 elamipretide recipients and 83 of 109 placebo recipients; events led to treatment discontinuation in eight and two participants, respectively. Most events in that trial were mild or moderate. FDA trial snapshot, MMPOWER-3 safety table.

Forzinity labeling describes serious hypersensitivity reactions and warns against use in neonates because of the formulation's benzyl alcohol. Human pregnancy and lactation data are absent. The approved indication remains improvement of muscle strength in Barth syndrome in patients weighing at least 30 kg, under accelerated approval. Safety findings for the pharmaceutical product concern its formulation and monitored populations. Forzinity prescribing information, sections 1, 4–6 and 8.

What the research means

Elamipretide has a developed molecular rationale: its charge and aromatic groups support membrane interactions, and biochemical experiments connect those interactions with electron transport and ATP production. Clinical studies then ask a further question about the scale of that effect. A muscle can show altered energy capacity without a measurable improvement in endurance, and people with different genetic mitochondrial disorders can have different underlying constraints on function.

The strongest broad mitochondrial-myopathy comparison found no overall walking or fatigue benefit. The Barth program produced encouraging longitudinal observations that supported a narrowly defined accelerated approval, with confirmatory evidence still required. Both findings belong in an account of the compound because they identify where a proposed membrane mechanism has, and has yet to, support a clinically meaningful response. Longer controlled follow-up in Barth syndrome should clarify the strength finding's consequences for daily function. The studies reviewed here do not establish general fatigue treatment, performance enhancement or lifespan extension.

FAQs

Is SS-31 the same compound as elamipretide?

SS-31 is a development name for elamipretide. Forzinity identifies a specific pharmaceutical formulation containing the hydrochloride salt. A fluorescent SS-31 analogue used in a laboratory experiment has an additional chemical modification, so its tracking measurements retain that probe identity. Birk and colleagues (2014).

How can Forzinity be approved when MMPOWER-3 was negative?

The studies addressed different diseases and outcomes. MMPOWER-3 tested walking and fatigue in a broader primary mitochondrial-myopathy population. The Barth syndrome approval rests on a knee-strength measurement from a small open-label extension, with clinical benefit still requiring confirmation under accelerated approval. FDA approval announcement.

What does the 168-week TAZPOWER report add?

It records longer functional and safety follow-up of the original Barth cohort. Eight participants underwent week-168 assessments, including one who had stopped study treatment at week 72. Changes relative to baseline can inform durability questions, while a concurrent controlled comparison is needed to attribute those changes confidently to treatment. Thompson and colleagues (2024).

Did the older-adult trial establish an anti-aging treatment?

The experiment examined acute mitochondrial capacity and hand-muscle performance in selected older adults. The percentage ATP-capacity response favored elamipretide immediately after exposure; the prespecified fatigue-resistance comparison did not improve significantly. Longer function, disability and survival outcomes would be needed to assess effects on aging. Roshanravan and colleagues (2021).

What evidence is still required after accelerated approval?

FDA's current ongoing list calls for a randomized, double-blind, placebo-controlled Barth syndrome trial to verify the clinical benefit predicted by knee-extensor strength. Its listed original projected completion date is March 2030. The requirement remains an ongoing follow-up step as of this profile's October 2026 review. FDA postmarketing requirement 4802-1.

Humanin and MOTS-c offer useful comparisons because their research also involves mitochondria, through different peptide identities and biological pathways. Endogenous peptide measurements, animal interventions and an approved pharmaceutical product answer different questions. The linked profiles help keep each material, population and outcome visible when comparing the literature.

References

The references include the five original studies retained from the previous profile, the original Forzinity label, later membrane-biophysics and older-adult muscle research, and current FDA sources for the approval's conditions and follow-up requirement. The two TAZPOWER publications follow the same cohort.

Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. British Journal of Pharmacology. 2014;171(8):2017–2028. DOI: 10.1111/bph.12468.
Links cardiolipin interactions with cytochrome-c electron transfer and ATP production in biochemical and isolated-mitochondria preparations; identifies the separate fluorescent probe.
Karaa A, Haas R, Goldstein A, Vockley J, Cohen BH. A randomized crossover trial of elamipretide in adults with primary mitochondrial myopathy. Journal of Cachexia, Sarcopenia and Muscle. 2020;11(4):909–918. DOI: 10.1002/jcsm.12559.
Reports the 30-person MMPOWER-2 crossover: the primary walking endpoint remained statistically uncertain despite favorable patient-reported secondary measures.
Karaa A, Bertini E, Carelli V, Cohen BH, Enns GM, Falk MJ, Goldstein A, Gorman GS, Haas R, Hirano M, Klopstock T, Koenig MK, Kornblum C, Lamperti C, Lehman A, Longo N, Molnar MJ, Parikh S, Phan H, Pitceathly RDS, Saneto R, Scaglia F, Servidei S, Tarnopolsky M, Toscano A, Van Hove JLK, Vissing J, Vockley J, Finman JS, Brown DA, Shiffer JA, Mancuso M; MMPOWER-3 Trial Investigators. Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial. Neurology. 2023;101(3):e238–e252. DOI: 10.1212/WNL.0000000000207402.
The 218-person placebo-controlled trial failed walking and fatigue primary endpoints at 24 weeks and reported frequent local reactions and more treatment discontinuations.
Thompson WR, Hornby B, Manuel R, Bradley E, Laux J, Carr J, Vernon HJ. A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism. Genetics in Medicine. 2021;23(3):471–478. DOI: 10.1038/s41436-020-01006-8.
The original TAZPOWER report separates null controlled walking, fatigue and strength comparisons from favorable baseline changes during its early extension.
Thompson WR, Manuel R, Abbruscato A, Carr J, Campbell J, Hornby B, Vaz FM, Vernon HJ. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. Genetics in Medicine. 2024;26(7):101138. DOI: 10.1016/j.gim.2024.101138.
Continues the same small Barth cohort; week-168 walking analyses included an off-treatment participant and had no concurrent randomized control.
Mitchell W, Ng EA, Tamucci JD, Boyd KJ, Sathappa M, Coscia A, Pan M, Han X, Eddy NA, May ER, Szeto HH, Alder NN. The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of action. Journal of Biological Chemistry. 2020;295(21):7452–7469. DOI: 10.1074/jbc.RA119.012094.
Uses model membranes, mitochondrial measurements and simulations to relate peptide binding to surface charge, lipid packing and calcium stress.
Roshanravan B, Liu SZ, Ali AS, Shankland EG, Goss C, Amory JK, Robertson HT, Marcinek DJ, Conley KE. In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trial. PLOS ONE. 2021;16(7):e0253849. DOI: 10.1371/journal.pone.0253849.
In selected older adults, elamipretide increased an immediate measure of ATP-production capacity in a hand muscle. The planned fatigue-resistance and resting-coupling comparisons did not establish improvement.
U.S. Food and Drug Administration. Forzinity (elamipretide) injection: prescribing information, NDA 215244. Revised September 2025. Reference ID 5662523. Current status checked 13 October 2026.
Defines the hydrochloride product, Barth indication, accelerated-approval condition, pharmacokinetic context and formulation-specific warnings.
U.S. Food and Drug Administration. FDA Grants Accelerated Approval to First Treatment for Barth Syndrome. 19 September 2025. Accessed 13 October 2026.
Explains the muscle-strength basis of the narrow approval and the required randomized confirmation of patient benefit.
U.S. Food and Drug Administration. Drug Trials Snapshots: Forzinity (elamipretide). Original approval 19 September 2025. Accessed 13 October 2026.
Shows the small trial population, controlled endpoint failures, descriptive strength changes and local adverse-reaction counts.
U.S. Food and Drug Administration. Ongoing: Non-malignant Hematological, Neurological, and Other Disorder Indications Accelerated Approvals. Forzinity entry, PMR 4802-1. Accessed 13 October 2026.
Retains Forzinity as an ongoing accelerated approval and describes the randomized confirmation requirement and original projected completion date.

Glossary

ATP: Adenosine triphosphate, the molecule cells use to transfer energy to processes such as muscle contraction.
Cardiolipin: A membrane lipid important to the organization and function of the inner mitochondrial membrane.
Cristae: Folds of the inner mitochondrial membrane that support the machinery involved in cellular energy production.
Cytochrome c: A small protein that transfers electrons between respiratory-chain components and can take on other roles when its molecular environment changes.
Peroxidase activity: Chemical activity that uses peroxides to promote oxidation; in the discussed experiments, it can damage cardiolipin.
Tafazzin: A protein involved in cardiolipin remodeling. Pathogenic variants in its gene cause Barth syndrome.
Crossover trial: A trial in which participants receive the compared interventions in successive periods, allowing within-person comparisons.
Open-label extension: Follow-up in which participants and investigators know which treatment is being given; the TAZPOWER extension had no concurrent untreated randomized group.
Dynamometer: An instrument for measuring force, used here to assess knee-extensor muscle strength.
Intermediate clinical endpoint: A clinical measurement used to predict a patient benefit that still needs confirmation, such as the strength measurement supporting this accelerated approval.
Mitochondrial coupling: The relationship between mitochondrial oxygen use and ATP production, reflecting how energy conversion is linked to respiration.