Section 01
What it's used for
Two human heart trials fell short
In the EMBRACE-STEMI trial, IV elamipretide did not significantly shrink heart damage after a heart attack vs placebo. In PROGRESS-HF, it did not improve heart-pumping measures in heart failure patients. Both were negative human trials.
▸Clinical wording
In the Phase 2a EMBRACE-STEMI trial, intravenous elamipretide did not significantly reduce infarct size (CK-MB AUC) compared with placebo in patients undergoing primary PCI. The Phase 2 PROGRESS-HF trial in heart failure with reduced ejection fraction likewise found no significant change in left ventricular end-systolic volume or ejection fraction. Both were human clinical trials with negative primary endpoints; a claim of consistent improvement in mitochondrial biomarkers is not supported by these publications.
Walking-distance trials came up short
In people with primary mitochondrial myopathy, the MMPOWER-2 trial found a 19.8-meter walking-distance gain that missed significance (P=0.083). The larger MMPOWER-3 trial found no improvement at all (-3.2 m, P=0.69) versus placebo.
▸Clinical wording
In human clinical trials for primary mitochondrial myopathy, the MMPOWER-2 crossover trial found a 19.8-meter difference in 6-minute walk distance that did not reach statistical significance (P=0.083), and the pivotal Phase 3 MMPOWER-3 trial found no improvement in 6-minute walk distance (-3.2 m, P=0.69) versus placebo. These trials do not support a claim of improved 6-minute walk test performance with elamipretide in this population.
A rare genetic heart-cell defect
Barth syndrome is a rare inherited disease in which mitochondria cannot properly use cardiolipin, a fat molecule they need to work. SS-31 is designed to target this same cardiolipin problem, which sits at the center of the disease.
▸Clinical wording
Targets the cardiolipin deficiency central to this genetic mitochondrial disease.
Aimed at a driver of aging decline
Many age-related diseases are linked to failing mitochondria, the cell's energy producers. SS-31 is being studied as a way to target this underlying mitochondrial problem directly, rather than treating each disease's symptoms one by one.
▸Clinical wording
Mitochondrial dysfunction underlies many aging pathologies — SS-31 addresses this root cause.
Section 02
Mechanism of Action
Sticking to a fat unique to mitochondria
- The peptide's alternating chemistry makes it latch selectively onto cardiolipin, a fat confined to inner mitochondrial membranes.
- In rat kidney mitochondria and model membranes the binding strength measured near 1.87 micromolar.
- It bound two other membrane fats more weakly than it bound cardiolipin.
- Biophysical work indicates roughly 1.4 to 1.5 cardiolipin molecules engage each peptide at saturation.
▸Clinical wording
Cardiolipin binding and inner-membrane accumulation
The alternating aromatic-cationic motif of SS-31 (D-Arg-Dmt-Lys-Phe-NH2) drives selective, saturable association with cardiolipin, the dianionic phospholipid confined to the inner mitochondrial membrane. Using a polarity-sensitive fluorescent analogue in rat kidney mitochondria and model liposomes, Birk and colleagues measured a dissociation constant near 1.87 uM for cardiolipin, with weaker binding to phosphatidylserine and phosphatidylglycerol. Biophysical work in defined vesicles indicates the basic residues anchor at the lipid phosphates while the aromatic side chains bury into the acyl-chain region, with roughly 1.4-1.5 cardiolipin molecules engaged per peptide at saturation.
Stopping an electron carrier turning destructive
- When cardiolipin binds the electron carrier cytochrome c, that carrier can start oxidising the fat itself.
- In model membranes and rat kidney preparations, SS-31 preserved the carrier's normal internal structure.
- That suppressed the damaging activity in a standard laboratory assay.
- In freshly isolated rat mitochondria the same treatment tightened the link between oxygen use and energy production.
▸Clinical wording
Protection of the cytochrome c-cardiolipin complex
Cardiolipin binding to cytochrome c can disrupt the Met80-Fe heme coordination, converting the electron carrier into a peroxidase that oxidises cardiolipin acyl chains. In liposomes, bicelles and rat kidney mitoplasts, SS-31 penetrated the cytochrome c/cardiolipin complex and preserved Met80-Fe ligation as read by circular dichroism, suppressing peroxidase activity in the Amplex Red assay. In freshly isolated rat kidney mitochondria the same treatment raised state 3 respiration and the P/O ratio, consistent with tighter coupling of oxygen consumption to ATP synthesis rather than with radical scavenging.
Changing the electrical charge of membranes
- Rather than neutralising radicals one by one, the peptide sits at the membrane surface and shifts its charge.
- In artificial vesicles it reduced surface charge to a plateau near minus 30 millivolts without reversing it.
- Three separate structural techniques showed lipids packing more tightly without the membrane breaking down.
- In yeast mitochondria lacking cardiolipin, binding tracked total negative charge rather than the specific fat.
▸Clinical wording
Modulation of membrane surface electrostatics
Rather than acting stoichiometrically as an antioxidant, SS-31 partitions into the bilayer interface with an affinity set by surface charge density. In large unilamellar vesicles it produced a saturable reduction in zeta potential that plateaued near -30 mV without reversing polarity, described by the authors as a controlled down-tuning of the interfacial field. Solid-state NMR, synchrotron SAXS and molecular dynamics showed increased lipid self-association and tighter lateral packing without destabilising the lamellar phase. In yeast mitochondria lacking cardiolipin synthase, binding tracked total anionic charge rather than headgroup identity.
Which proteins the peptide sits beside
- Chemical tagging in hearts from very old mice mapped which proteins the peptide sits near.
- Partners fell into two groups: energy-production machinery and enzymes of one step in metabolism.
- All of them were already known to bind cardiolipin themselves.
- Computer docking placed the peptide next to, not on top of, the fat-binding sites.
▸Clinical wording
Interaction with OXPHOS and 2-oxoglutarate enzymes
Chemical cross-linking with mass spectrometry in mitochondria from 36-37-month-old mouse hearts mapped the peptide's protein neighbourhood. Cross-linked partners fell into two groups: oxidative phosphorylation components, including complex III subunits QCR2 and QCR6, the complex IV subunit NDUFA4, ATP synthase alpha and beta, the ADP/ATP translocase and mitochondrial creatine kinase; and enzymes of 2-oxoglutarate metabolism such as isocitrate dehydrogenase and the 2-oxoglutarate dehydrogenase E1 and E2 subunits. All were known cardiolipin binders, and docking placed the peptide in solvent-accessible regions adjacent to, not overlapping, the cardiolipin sites.
Plugging an energy leak in aged muscle
- Mitochondria from aged mice and rats leaked protons, and blocking one transporter abolished the excess leak.
- That pointed to a shape change in the transporter rather than to more copies of it.
- Tagged peptide pulled that transporter down, stabilised the energy-making assembly and restored membrane voltage.
- In 39 adults aged 60-85 a single infusion raised muscle energy capacity, but the effect vanished by day 7.
▸Clinical wording
ANT1 proton leak and ATP synthasome stabilisation
In permeabilised cardiomyocytes from aged mice and rats, mitochondria showed reduced resistance to an imposed proton gradient; ANT1 inhibitors abolished the excess leak, implicating a conformational change in ANT1 rather than greater abundance. Biotinylated SS-31 pulled down ANT1 and was competed by free peptide, and treatment stabilised the ATP synthasome, restored membrane potential, normalised mitoflash frequency and delayed permeability transition pore opening. In a randomised trial in 39 adults aged 60-85, a single infusion raised in vivo skeletal muscle ATPmax relative to placebo, an effect absent by day 7.
Section 03
Biological Pathways
- Cardiolipin BindingThe alternating aromatic-cationic motif of SS-31 binds cardiolipin, an inner-mitochondrial-membrane phospholipid, with a dissociation constant near 1.87 uM in rat kidney mitochondria and liposomes.
- Cytochrome c-Cardiolipin ProtectionSS-31 penetrates the cytochrome c-cardiolipin complex and preserves Met80-Fe heme coordination, suppressing the peroxidase activity that would otherwise oxidise cardiolipin acyl chains and impair respiration.
- Membrane Surface ElectrostaticsRather than scavenging radicals stoichiometrically, SS-31 partitions into the bilayer interface, producing a saturable drop in surface zeta potential that tightens lipid packing without destabilising the membrane.
- ANT1 and ATP Synthasome StabilisationSS-31 binds ANT1, correcting the conformational change linked to excess proton leak in aged mitochondria, stabilising the ATP synthasome and restoring membrane potential in cardiomyocytes from aged animals.
- Skeletal Muscle ATP ProductionIn a randomised trial of 39 adults aged 60-85, a single SS-31 infusion raised in vivo skeletal-muscle ATPmax relative to placebo, though the effect was no longer detectable by day 7.
Section 04
Dosage Information
D-Arg-Dmt-Lys-Phe-NH2 (Dmt = 2,6-dimethyltyrosine)| Route / system | Context | Range studied | Limitation |
|---|---|---|---|
| Subcutaneous — approved use | FDA label, Barth syndrome (Forzinity, 2025) | 40 mg once daily from 30 kg — about 440–570 µg/kg for a 70–90 kg adult; 20 mg if kidney filtration is under 30 mL/min | Approved for muscle strength in an ultra-rare genetic disease, on knee-strength data from an unblinded extension; the randomised part missed both endpoints. |
| Subcutaneous — mitochondrial myopathy | Phase 3, mitochondrial muscle disease | 40 mg once daily for 24 weeks in 218 randomised patients — the same dose later approved for Barth syndrome | Both main endpoints failed: −3.2 m on the six-minute walk and −0.07 on fatigue. A fully powered negative trial at exactly the dose now sold and injected. |
| Subcutaneous — eye disease trials | Phase 2 and two phase 3 trials, dry macular degeneration | 40 mg once daily for 48 weeks in phase 2; the two phase 3 trials use the same 40 mg daily, with 360 patients enrolling | Phase 2 missed both endpoints — atrophy growth and vision in dim light — and phase 3 switched to a photoreceptor scan. No phase 3 result as of 2026. |
| Intravenous — infusion study | Phase 1/2 dose escalation, 36 patients | 0.01, 0.1 and 0.25 mg/kg per hour over 2 hours — up to 0.5 mg/kg a session, about 35–45 mg for a 70–90 kg adult, over 5 days | Five days of infusion gained 64.5 m on the walk test against 20.4 m on placebo — the signal the 24-week phase 3 then failed to repeat. Not a home injection. |
| Subcutaneous — self-administration | Self-administration outside any trial | 5–10 mg a day is most repeated — about 55–140 µg/kg for a 70–90 kg adult; others say 500 µg a day or up to 20 mg on 5-on/2-off cycles | A fortyfold spread with no study behind any point, all below the 40 mg the trials used. The energy, ageing and performance claims were never tested in anyone. |
Results
Syringe Fill Level (100u syringe)
Set positive values for: Recommended dose per kg.
Research Use Only. This information is for educational and research purposes only. Not intended for medical advice or self-medication.
Section 05
Protocols
No protocols featuring this peptide yet. Browse All Protocols
Section 06
Stability & Storage
Lyophilised powder
It is supplied as a lyophilised powder, kept at −20°C. The D-Arg modification gives the peptide resistance to breakdown by proteases, and its good solubility in water makes it straightforward to reconstitute.
After reconstitution
Once dissolved, the solution — whether reconstituted from powder or supplied ready-made — is kept at 2-8°C and remains stable at physiological pH. Exact in-use shelf life depends on the specific formulation and batch.
Section 07
Side Effects & Precautions
Generally well-tolerated in clinical trials. Injection site reactions. Transient headache. No serious adverse effects in Phase 1-3 studies. Long-term safety data limited.
Section 08
Regulatory Status
The approval is narrow, conditional, and came only after the agency had rejected the same application once.
FDA / United States
Approved, but only for Barth syndrome
FORZINITY (elamipretide) received FDA accelerated approval in September 2025 for improving muscle strength in patients weighing at least 30 kg with Barth syndrome, based on a surrogate endpoint; continued approval depends on a confirmatory trial.
Path to approval
One rejection came first
An FDA advisory committee backed approval 10 to 6 in October 2024, but the agency issued a Complete Response Letter in May 2025 over a third-party manufacturing inspection, not the efficacy data; Stealth resubmitted and won approval months later.
EMA / European Union
No approved therapy for Barth syndrome yet
Stealth BioTherapeutics states that no EMA-approved treatment for Barth syndrome exists as of 2026; a confirmatory trial for the US accelerated approval is still being designed.
Other indications
Two Phase 3 trials missed their endpoints
The MMPOWER-3 trial in primary mitochondrial myopathy and the ReCLAIM-2 trial in dry age-related macular degeneration each failed their primary endpoints; elamipretide is not approved for either.
WADA
Not on the Prohibited List
Elamipretide is not named among the peptide hormones or growth factors banned under category S2, so no anti-doping restriction currently applies to the approved drug.
One approved indication does not make elamipretide a general-purpose therapy — it is authorised for a specific rare disease at a specific dose, under conditions that can still change. Regulatory status differs between jurisdictions and changes over time — check the current documents of your own regulator before relying on any of this.
Section 09
Research Studies
- [1]The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipinBirk AV, Liu S, Soong Y, Mills W, Singh P, Warren JD, Seshan SV, Pardee JD, Szeto HH · Journal of the American Society of Nephrology · 2013
- [2]Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesisBirk AV, Chao WM, Bracken C, Warren JD, Szeto HH · British Journal of Pharmacology · 2014
- [3]The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of actionMitchell W, Ng EA, Tamucci JD, Boyd KJ, Sathappa M, Coscia A, Pan M, Han X, Eddy NA, May ER, Szeto HH, Alder NN · Journal of Biological Chemistry · 2020
- [4]Mitochondrial protein interaction landscape of SS-31Chavez JD, Tang X, Campbell MD, Reyes G, Kramer PA, Stuppard R, Keller A, Zhang H, Rabinovitch PS, Marcinek DJ, Bruce JE · Proceedings of the National Academy of Sciences of the USA · 2020
- [5]Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyteZhang H, Alder NN, Wang W, Szeto H, Marcinek DJ, Rabinovitch PS · eLife · 2020
- [6]In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trialRoshanravan B, Liu SZ, Ali AS, Shankland EG, Goss C, Amory JK, Robertson HT, Marcinek DJ, Conley KE · PLoS One · 2021
- [7]Contemporary insights into elamipretide's mitochondrial mechanism of action and therapeutic effectsSabbah HN, Alder NN, Sparagna GC, Bruce JE, Stauffer BL, Chao LH, Pitceathly RDS, Maack C, Marcinek DJ · Biomedicine & Pharmacotherapy · 2025
Section 10
Frequently Asked Questions
The clinical record is mostly negative. Trials in heart failure (EMBRACE-STEMI, PROGRESS-HF) missed their primary endpoints, and the pivotal Phase 3 trial for mitochondrial myopathy (MMPOWER-3) found no improvement in walk distance versus placebo. Its one approved use, Barth syndrome, rests on strength data from an unblinded extension study, after the randomised portion of that same trial also missed both of its primary endpoints.
Yes, but only for one narrow use: as Forzinity, approved in 2025 for muscle strength in Barth syndrome, an ultra-rare genetic mitochondrial disease, dosed at 40 mg once daily by subcutaneous injection. It has no approval for any other condition, and it is not on the WADA prohibited list.
The approved Barth syndrome dose is 40 mg once daily (20 mg if kidney function is significantly reduced), and every major trial — heart failure, myopathy, dry macular degeneration — used that same 40 mg daily dose. Self-administered doses circulating outside any trial, typically 5–10 mg a day, sometimes cycled up to 20 mg, are well below that and have never been studied.
Trials report injection-site reactions and transient headache as the main effects, with no serious adverse events across Phase 1 through 3 studies. Long-term safety data are explicitly limited, since the completed trials ran for at most several months.
There is no trial evidence for this. The rationale is mechanistic — SS-31 binds cardiolipin in the mitochondrial inner membrane and improves electron transport in isolated tissue and short single-dose studies — but every human trial testing a broader clinical benefit, from heart attack recovery to muscle and eye disease, has failed its primary endpoint so far.
The lyophilised powder is kept at −20°C. Once reconstituted, the solution is stable at physiological pH and is kept at 2–8°C, though the exact in-use shelf life depends on the specific formulation and batch.