Mitochondria-targeting synthetic tetrapeptide (Szeto–Schiller / MTP class) — mitochondrial / longevity research; FDA-approved 2025 for Barth syndrome (FORZINITY)

Elamipretide

Also Known As: SS-31, MTP-131, Bendavia, Forzinity, RX-31

Elamipretide (INN; synonyms SS-31, MTP-131, Bendavia, brand name Forzinity) is a synthetic, cell-permeable, mitochondria-targeting tetrapeptide with the sequence H-D-Arg-Tmt-Lys-Phe-NH₂, in which Tmt denotes the non-proteinogenic residue 2′,6′-dimethyltyrosine. It is the prototype of the Szeto–Schiller (SS) / mitochondria-targeting tetrapeptide (MTP) class developed in the early 2000s by Hazel Szeto and Peter Schiller at Weill Cornell Medicine (Szeto 2014, Br J Pharmacol, PMID 24117165; Birk 2013, J Am Soc Nephrol, PMID 23813215). Studies report that the alternating aromatic-cation motif (D-Arg(+) / Tmt(aromatic) / Lys(+) / Phe(aromatic)) binds reversibly to cardiolipin on the inner mitochondrial membrane (IMM), stabilises cristae architecture, prevents cardiolipin peroxidation by the cytochrome-c–cardiolipin complex, and preserves respiratory supercomplex assembly. A central mechanistic feature is that mitochondrial accumulation is INDEPENDENT of the membrane potential (ΔΨm) — in contrast to the triphenylphosphonium (TPP⁺) conjugates of the MitoQ class, which require an intact ΔΨm. On 19 September 2025 the U.S. Food and Drug Administration granted FORZINITY (elamipretide HCl injection, NDA 215244, sponsor Stealth BioTherapeutics Inc.) accelerated approval "to improve muscle strength in adult and pediatric patients with Barth syndrome weighing at least 30 kg" — the FIRST FDA-approved therapy for Barth syndrome and the FIRST FDA-approved mitochondria-targeted peptide therapeutic. The supporting Advisory Committee (FDA Peripheral and Central Nervous System Drugs Advisory Committee, PCNS) voted 10 to 6 in favour of accelerated approval on 10 October 2024 — a widely discussed vote because the underlying TAZPOWER trial (NCT03098797, n = 12) had missed its randomised crossover primary endpoint and approval rests on the open-label extension. Honest framing: most non-Barth Phase 2/3 trials have MISSED their primary endpoints — MMPOWER-3 (NCT03323749, primary mitochondrial myopathy, n = 218, both co-primary endpoints missed; Karaa 2023, Neurology, PMID 37268435), EMBRACE-STEMI (NCT01572909, STEMI reperfusion, n = 300, primary infarct-size endpoint missed), PROGRESS-HF (NCT02814097, HFrEF, n = 71, LVESV endpoint missed), and ReCLAIM-2 (NCT03891875, dry AMD, n = 176, minimal between-group differences). Only the Barth-syndrome / TAZPOWER pillar carries the approval; all other indications remain investigational and are described for research purposes only. The Phase 3 confirmatory programme in geographic atrophy (ReNEW / SPIAM-301, NCT06373731) is active-not-recruiting at the 2026-05-01 audit; primary completion estimated August 2027. Important disambiguation versus the in-category sibling: MOTS-c (see [/portfolio/mots-c](/portfolio/mots-c)) is a mitochondria-DERIVED peptide (encoded within the MT-RNR1 / 12S rRNA gene on mitochondrial DNA), whereas elamipretide is a mitochondria-TARGETING synthetic peptide that is NOT encoded by any human gene — the two share the category but are chemically and mechanistically distinct. Pre-approval, elamipretide fell under WADA category S0 (non-approved substances) for sport; the classification on the 2026 WADA Prohibited List should be re-checked at point of use after the September 2025 approval.

Identity & Chemistry

Skeletal chemical structure of elamipretide (SS-31), a four-residue mitochondria-targeting tetrapeptide H-D-Arg-Tmt-Lys-Phe-NH₂, showing the alternating aromatic-cation motif (D-Arg, 2′,6′-dimethyltyrosine, Lys, Phe) responsible for cardiolipin binding on the inner mitochondrial membrane and the C-terminal primary amide.
Image credit: Edgar181, via Wikimedia Commons · Public Domain
Amino Acid Sequence
H-D-Arg-Tmt-Lys-Phe-NH₂ (four-residue mitochondria-targeting tetrapeptide; Tmt = 2′,6′-dimethyltyrosine, a non-proteinogenic residue; D-arginine at position 1 confers proteolytic stability; the alternating aromatic-cation motif D-Arg(+)/Tmt(aromatic)/Lys(+)/Phe(aromatic) drives cardiolipin binding on the inner mitochondrial membrane)
Molecular Formula
C₃₂H₄₉N₉O₅
Molecular Weight
639.79 g·mol⁻¹ (free base; PubChem CID 11764719). The HCl salt is the FDA-approved drug substance for FORZINITY (NDA 215244, September 2025); a tetra-trifluoroacetate salt (CAS 1606994-55-1) is the common research-grade form.
CAS Number
736992-21-5 (free base; canonical) + 1606994-55-1 (tetra-TFA salt, research-grade supply form). The HCl salt is the FDA-approved FORZINITY drug substance (NDA 215244, 19 September 2025).
PubChem CID
11764719
DrugBank ID
DB13099
IUPAC Name
(2S)-6-amino-2-[[(2S)-2-[[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-N-[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]hexanamide
Solubility
Water-soluble; supplier sheets report ≥10 mg/mL in water and DMSO at research concentrations. FORZINITY is supplied as a sterile aqueous injection of the HCl salt form.
Storage
Lyophilised peptide: store at −20 °C, desiccated, protected from light (long-term). Reconstituted aqueous solutions: short-term at 2–8 °C, longer-term at −20 °C; avoid freeze–thaw cycles. FORZINITY (HCl salt, FDA-approved form) per manufacturer label.

Mechanism of Action

Studies report that elamipretide binds reversibly to cardiolipin on the inner mitochondrial membrane (IMM), stabilises cristae architecture, prevents cardiolipin peroxidation by the cytochrome-c–cardiolipin complex, and preserves the assembly of respiratory supercomplexes (Complex I + III + IV, the "respirasome"). Unlike TPP⁺ / MitoQ-class compounds, mitochondrial accumulation is ΔΨm-INDEPENDENT.

The Szeto and Schiller laboratories at Weill Cornell designed the SS-peptide series in the early 2000s as cell-permeable, mitochondria-targeting tetrapeptides. The aromatic-cation alternation in the H-D-Arg-Tmt-Lys-Phe-NH₂ sequence yields the dual physicochemical signature that defines the class: a net positive charge of +3 at physiological pH (driving electrostatic attraction to the anionic cardiolipin headgroup) plus aromatic side chains (driving hydrophobic stacking and partial membrane embedding). Birk et al. 2013 (J Am Soc Nephrol, PMID 23813215) demonstrated by isothermal titration calorimetry and lipid-binding assays that SS-31 binds cardiolipin with sub-micromolar affinity, accelerating ATP recovery after ischaemia in renal mitochondria. Szeto 2014 (Br J Pharmacol, PMID 24117165) consolidated the mechanism: by occupying cardiolipin, SS-31 prevents the cytochrome-c–cardiolipin peroxidase complex from peroxidising cardiolipin acyl chains, preserves Complex I-III-IV supercomplex assembly, and protects cristae architecture. Critically, SS-31 differs from triphenylphosphonium-cation-conjugated antioxidants (the MitoQ class): TPP⁺ conjugates require an intact mitochondrial membrane potential ΔΨm to accumulate in the mitochondrial matrix (Nernst-equation-driven, ~1000-fold accumulation per ~120 mV), whereas SS-31 binding to cardiolipin is ΔΨm-independent and therefore retains efficacy in depolarised / dysfunctional mitochondria — the very setting of disease. This ΔΨm-independence is the principal pharmacological argument for SS-31 in conditions where mitochondrial bioenergetics are already compromised, including Barth syndrome (in which pathogenic TAZ variants disrupt cardiolipin remodelling) and ischaemia–reperfusion (in which ΔΨm collapses). Mechanism statements are intentionally hedged — studies report, observed in research settings — and never framed as established human pharmacology for non-Barth indications.

Molecular Targets

  • Cardiolipin (1,3-bis-(sn-3′-phosphatidyl)-sn-glycerol) — the signature anionic phospholipid of the inner mitochondrial membrane; the primary molecular target
  • Respiratory supercomplexes (Complex I + III + IV; the "respirasome") — assembly is preserved; ATP synthase efficiency is downstream-restored
  • Cytochrome c — by occupying cardiolipin, elamipretide prevents the cytochrome-c–cardiolipin "peroxidase" complex from oxidising cardiolipin and from initiating apoptotic cytochrome-c release
  • OPA1-dependent cristae junctions — preservation of IMM curvature and lamellar cristae geometry (Szeto 2014, PMID 24117165)
  • ΔΨm-INDEPENDENT accumulation — structural basis: the alternating aromatic-cation motif (D-Arg / Tmt / Lys / Phe) creates an electrostatic + hydrophobic stacking interface against the cardiolipin headgroup that does not require a membrane potential

Signaling Pathways

  • Cardiolipin binding → stabilisation of IMM cristae architecture → preservation of OPA1 oligomerisation at cristae junctions
  • Cardiolipin binding → prevention of the cytochrome-c–cardiolipin peroxidase complex → protection from apoptotic cytochrome-c release
  • Preservation of I-III-IV supercomplex assembly → reduced electron leak from Complex I and Complex III → secondary ROS modulation
  • ΔΨm-INDEPENDENT mitochondrial accumulation — the principal mechanistic distinction versus triphenylphosphonium (TPP⁺) antioxidants (MitoQ, SkQ1), which require an intact mitochondrial membrane potential ΔΨm to accumulate in the matrix (Nernst-equation-driven, ~1000-fold accumulation per ~120 mV)

Research Applications

Elamipretide has undergone broad clinical development across multiple indications. A systematic ClinicalTrials.gov v2 API query on 1 May 2026 for "elamipretide" / "SS-31" / "MTP-131" / "Bendavia" identified six page-relevant Phase 2/3 trials: TAZPOWER (NCT03098797, Barth syndrome — basis of FDA approval), MMPOWER-3 (NCT03323749, primary mitochondrial myopathy, Phase 3 missed), EMBRACE-STEMI (NCT01572909, STEMI reperfusion, Phase 2a missed), PROGRESS-HF (NCT02814097, HFrEF, Phase 2 missed), ReCLAIM-2 (NCT03891875, dry AMD, Phase 2 missed), and ReNEW / SPIAM-301 (NCT06373731, dry AMD, Phase 3 active-not-recruiting). Honest framing: with the exception of the Barth-syndrome pillar (TAZPOWER), which carries the FDA accelerated approval, most Phase 2/3 trials have missed their primary endpoints; the ReNEW programme remains the active Phase 3 confirmatory pathway.

TAZPOWER — Barth syndrome, Phase 2/3 (PIVOTAL, basis of FDA approval)

Phase III

Studies report in a randomised, double-blind, placebo-controlled crossover trial (12 weeks per arm with 4-week washout) followed by an open-label extension that, in 12 genetically confirmed Barth syndrome patients on subcutaneous elamipretide 40 mg/day, the randomised primary endpoints (6-minute walk test and BTHS-SA fatigue score at week 12) were NOT met. In the open-label extension at week 36 a clinically meaningful improvement was observed — 6MWT change +95.9 m (p = 0.024) and BTHS-SA change −2.1 points (p = 0.031) versus baseline; long-term 168-week extension data (Hornby 2024) supported persistence. These open-label-extension data formed the basis of NDA 215244 and the 19 September 2025 FDA accelerated approval. Observed in research settings; the unusual approval pathway based on a trial whose randomised primary endpoint was missed was explicitly discussed in the AdCom 10–6 vote (10 October 2024).

— Reid Thompson et al. 2021, Genet Med 23(3):471–478 (PMID 33077895); Hornby et al. 2024 Genet Med (TAZPOWER 168-week extension)

MMPOWER-3 — primary mitochondrial myopathy, Phase 3 (MISSED)

Phase III

Studies report in a multicentre (27 sites in 7 countries) randomised, double-blind, placebo-controlled, parallel-group 24-week trial that, in 218 adult subjects with primary mitochondrial myopathy on elamipretide 40 mg/day subcutaneous, NEITHER co-primary endpoint (6MWT change and PMM Symptom Assessment fatigue at week 24) reached statistical significance versus placebo. A pre-specified subgroup of subjects with nuclear-DNA pathogenic variants showed numerical 6MWT improvement; the primary endpoints remained missed.

— Karaa et al. 2023, Neurology 101(3):e238–e252 (PMID 37268435; DOI 10.1212/WNL.0000000000207402)

EMBRACE-STEMI — STEMI reperfusion injury, Phase 2a (MISSED)

Phase II

Studies report in 300 first-anterior STEMI subjects undergoing primary PCI that intravenous MTP-131 (Bendavia) administered prior to reperfusion did NOT reduce the primary endpoint of 72-hour CK-MB AUC as a surrogate of infarct size (CK-MB AUC 6,582 ng-hr/mL elamipretide vs 6,738 ng-hr/mL placebo). Mechanistic biomarker analyses (Chakrabarti 2017, Circ Res, PMID 28534645) reported reduced circulating HtrA2 in the elamipretide arm.

— Chakrabarti et al. 2017, Circ Res (PMID 28534645); rationale paper Kloner / Daubert 2013, Am Heart J (PMID 23537966)

PROGRESS-HF — heart failure with reduced ejection fraction, Phase 2 (MISSED)

Phase II

Studies report that in 71 HFrEF subjects (LVEF ≤40%) elamipretide (placebo, 4 mg, or 40 mg subcutaneous daily for 28 days) did NOT improve the primary endpoint of left ventricular end-systolic volume (LVESV) at week 4. The peptide was well tolerated but did not produce LVESV reduction versus placebo.

— Daubert et al. 2017, Circ Heart Fail 10:e004389; Butler et al. 2020 J Card Fail (PMID 32068002)

ReCLAIM-2 — dry AMD with non-central geographic atrophy, Phase 2 (MISSED)

Phase II

Studies report in 176 subjects (117 elamipretide / 59 placebo) at week 48 minimal between-group differences — low-luminance best-corrected visual acuity (LL-BCVA) decline −2.8 letters elamipretide vs −4.6 letters placebo; geographic atrophy growth +0.328 mm² vs +0.281 mm². Higher rate of injection-site pruritus on active drug (46 vs 0). Results posted 17 October 2023.

— ClinicalTrials.gov NCT03891875 (results posted Oct 2023; audit 2026-05-01)

Mechanism foundation — Szeto 2014 + Birk 2013

in vitro

Studies report in vitro and in mitochondrial preparations using isothermal titration calorimetry and lipid-binding assays that SS-31 (elamipretide) binds cardiolipin with sub-micromolar affinity, accelerates ATP recovery after ischaemia in renal mitochondria, and preserves cristae architecture and Complex I-III-IV supercomplex assembly in vivo. The ΔΨm-independence of accumulation is mechanistically demonstrated here — the principal point of distinction from TPP⁺ / MitoQ-class compounds.

— Szeto 2014 Br J Pharmacol 171(8):2029–2050 (PMID 24117165); Birk 2013 J Am Soc Nephrol 24(8):1250–1261 (PMID 23813215)

Clinical Status

Regulatory Status
Elamipretide is APPROVED by the U.S. Food and Drug Administration (FDA) since 19 September 2025 as FORZINITY (elamipretide HCl injection, NDA 215244, sponsor Stealth BioTherapeutics Inc.) under accelerated approval "to improve muscle strength in adult and pediatric patients with Barth syndrome weighing at least 30 kg" — the FIRST FDA-approved therapy for Barth syndrome and the FIRST FDA-approved mitochondria-targeted peptide therapeutic. Designations granted: Orphan Drug, Rare Pediatric Disease, Priority Review. Approval pathway: accelerated approval based on the TAZPOWER trial (NCT03098797) and its open-label extension. Post-marketing requirements include a confirmatory clinical-benefit trial for continued approval and a label-expansion commitment for patients <30 kg. The supporting FDA Advisory Committee (Peripheral and Central Nervous System Drugs Advisory Committee, PCNS) voted 10 to 6 in favour of accelerated approval on 10 October 2024 — a widely discussed vote because the TAZPOWER trial (n = 12) had missed its randomised crossover primary endpoint and approval rests on the open-label extension. The European Medicines Agency (EMA) has NOT approved elamipretide as of the 1 May 2026 audit date; no other regulator (PMDA, Health Canada, MHRA, TGA) has issued public approval. Honest framing: the majority of Phase 2/3 trials outside the Barth indication have MISSED their primary endpoints — MMPOWER-3 (primary mitochondrial myopathy), EMBRACE-STEMI (STEMI reperfusion), PROGRESS-HF (HFrEF), and ReCLAIM-2 (dry AMD); all indications other than Barth syndrome remain investigational. A systematic ClinicalTrials.gov v2 API query on 1 May 2026 for "elamipretide" / "SS-31" / "MTP-131" / "Bendavia" identified six Phase 2/3 trials (TAZPOWER NCT03098797, MMPOWER-3 NCT03323749, EMBRACE-STEMI NCT01572909, PROGRESS-HF NCT02814097, ReCLAIM-2 NCT03891875, ReNEW / SPIAM-301 NCT06373731). For athletes, prior to approval elamipretide fell under WADA category S0 (non-approved substances); the classification on the 2026 WADA Prohibited List should be re-checked at point of use after the FDA approval — the current public list does not yet reclassify the substance.
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Highest Trial Phase
Highest reached phase: FDA-approved (FORZINITY, NDA 215244, accelerated approval, 19 September 2025) for Barth syndrome (≥30 kg). Active Phase 3 in dry AMD (ReNEW / SPIAM-301, NCT06373731, primary completion estimated August 2027).
Sponsor
Stealth BioTherapeutics Inc. (Needham, MA, USA — Boston metropolitan area). Original development at Weill Cornell Medicine in the laboratories of Hazel Szeto and Peter Schiller; advanced as SS-31 / MTP-131 in pre-clinical and Phase 1 work, branded as Bendavia in early Stealth cardiology programmes, and approved as FORZINITY for the Barth-syndrome indication in 2025.
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Key Clinical Trials

  • TAZPOWER — A Phase 2/3 randomised, double-blind, placebo-controlled crossover trial of elamipretide subcutaneous 40 mg/day in patients with Barth syndrome (n=12), followed by open-label extension; sponsor: Stealth BioTherapeutics. Randomised crossover primary endpoints (6MWT, BTHS-SA fatigue) were missed; the open-label extension at 36 weeks (and through 168 weeks per Hornby 2024) showed clinically meaningful improvement and was the basis of the September 2025 FDA accelerated approval (FORZINITY).
    Phase II/III
    NCT03098797
  • MMPOWER-3 — A Phase 3 randomised, double-blind, placebo-controlled, multicentre (27 sites in 7 countries) parallel-group trial of elamipretide 40 mg/day subcutaneous in adults with primary mitochondrial myopathy (n=218); sponsor: Stealth BioTherapeutics. Both co-primary endpoints (6-minute walk test change at 24 weeks and PMM Symptom Assessment fatigue) were MISSED versus placebo (Karaa 2023, Neurology, PMID 37268435).
    Phase III
    NCT03323749
  • EMBRACE-STEMI — A Phase 2a randomised, double-blind, placebo-controlled trial of intravenous MTP-131 (Bendavia) administered prior to reperfusion in first-anterior STEMI subjects undergoing primary PCI (n=300); sponsor: Stealth BioTherapeutics. Primary endpoint (72-hour CK-MB AUC) was MISSED — 6,582 vs 6,738 ng-hr/mL, no significant infarct-size reduction (Chakrabarti 2017, Circ Res, PMID 28534645).
    Phase IIa
    NCT01572909
  • PROGRESS-HF — A Phase 2 randomised, double-blind, placebo-controlled, ascending-dose trial of elamipretide (placebo / 4 mg / 40 mg subcutaneous daily for 28 days) in heart failure with reduced ejection fraction (LVEF ≤40 %, n=71); sponsor: Stealth BioTherapeutics. Primary endpoint (LVESV change at week 4) was MISSED — well-tolerated but did not improve LVESV vs placebo (Daubert 2017, Circ Heart Fail; Butler 2020 J Card Fail, PMID 32068002).
    Phase II
    NCT02814097
  • ReCLAIM-2 — A Phase 2 randomised, double-masked, placebo-controlled trial of elamipretide 40 mg/day subcutaneous in dry age-related macular degeneration with non-central geographic atrophy (n=176; 117 elamipretide / 59 placebo); sponsor: Stealth BioTherapeutics. Primary endpoints at week 48 (LL-BCVA change and GA-area change on OCT) showed minimal between-group differences (LL-BCVA −2.8 vs −4.6 letters; GA growth +0.328 vs +0.281 mm²); not a regulatory-grade win. Results posted October 2023.
    Phase II
    NCT03891875
  • ReNEW / SPIAM-301 — A Phase 3 randomised, double-masked, placebo-controlled confirmatory trial of elamipretide subcutaneous in dry age-related macular degeneration with geographic atrophy; sponsor: Stealth BioTherapeutics; status: active, not recruiting at the 2026-05-01 audit; primary completion estimated August 2027.
    Phase III
    NCT06373731

Safety Profile

Observed in research settings

The safety profile across more than 2,000 patient-years of clinical exposure has been generally favourable. All findings below are reported in research / clinical-trial settings (and the post-approval FORZINITY label as noted).

Adverse Events Reported in Studies

  • Injection-site reactions (pruritus, erythema, induration, pain, hypoesthesia) — the most common adverse event class for subcutaneous administration; in ReCLAIM-2 (NCT03891875), 46 of 117 elamipretide subjects reported injection-site pruritus vs 0 of 59 placebo. Observed in research settings
  • Common systemic adverse events: headache, dizziness, nausea, fatigue, hypoesthesia (Phase 3 trials). Observed in research settings
  • Hypersensitivity / skin reactions — rare but reported; the FORZINITY US prescribing information (NDA 215244, September 2025) lists hypersensitivity reactions among warnings
  • No consistent signal of cardiac arrhythmia, hepatotoxicity, or nephrotoxicity in Phase 2/3 trials (EMBRACE-STEMI, PROGRESS-HF, MMPOWER-3). Observed in research settings

Serious Adverse Events

  • Hypersensitivity reactions — listed as warnings in the FORZINITY US prescribing information (NDA 215244); incidence in the pivotal data is limited
  • Special populations: paediatric data at NDA submission limited to TAZPOWER and its open-label extension (n = 12); the FORZINITY label restricts approved use to patients ≥30 kg, with a post-marketing requirement to generate data in patients <30 kg
  • Long-term safety: the TAZPOWER 168-week open-label extension (Hornby 2024) reported continued favourable tolerability with no new safety signal
  • Editorial safety flag: all adverse-event descriptions are from clinical trial reports and the FDA labelling; none of the above constitutes prescribing or dosing guidance outside the FDA-approved Barth-syndrome indication

References

  1. Szeto HH First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics British Journal of Pharmacology 2014;171(8):2029–2050. 2014 .

    DOI: 10.1111/bph.12461 PMID: 24117165 View Source

  2. Birk AV, Liu S, Soong Y, Mills W, Singh P, Warren JD, Seshan SV, Pardee JD, Szeto HH The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin Journal of the American Society of Nephrology 2013;24(8):1250–1261. 2013 .

    DOI: 10.1681/ASN.2012121216 PMID: 23813215 View Source

  3. Reid Thompson W, DeCroes B, McClellan R, Rubens J, Vaz FM, Kahana K, Schexnayder P, Wanders RJA, Stacpoole PW, Steele P, Roullet JB, Taylor C, 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. 2021 .

    DOI: 10.1038/s41436-020-01006-8 PMID: 33077895 View Source

  4. 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 Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial Neurology 2023;101(3):e238–e252. 2023 .

    DOI: 10.1212/WNL.0000000000207402 PMID: 37268435 View Source

  5. Chakrabarti AK, Feeney K, Abueg C, Brown DA, Czyz E, Tamez H, Pina I, Sabbah HN, Warnica JW, Alexander JH, Solomon SD, Sabatine MS, Gibson CM Rationale and design of the EMBRACE STEMI study: evaluating Bendavia (MTP-131) on reperfusion injury in primary-PCI STEMI patients American Heart Journal 2013;165(4):509–514.e7. 2013 .

    DOI: 10.1016/j.ahj.2012.12.008 PMID: 23537966 View Source

  6. Daubert MA, Yow E, Dunn G, Marchev S, Barnhart H, Douglas PS, O’Connor C, Goldstein S, Udelson JE, Sabbah HN Novel Mitochondria-Targeting Peptide in Heart Failure Treatment: A Randomized, Placebo-Controlled Trial of Elamipretide Circulation: Heart Failure 2017;10(12):e004389. 2017 .

    DOI: 10.1161/CIRCHEARTFAILURE.117.004389 View Source

  7. Butler J, Khan MS, Anker SD, Fonarow GC, Kim RJ, Nodari S, O’Connor CM, Pieske B, Pieske-Kraigher E, Sabbah HN, Senni M, Voors AA, Udelson JE, Carr J, Gheorghiade M, Filippatos G Effects of Elamipretide on Left Ventricular Function in Patients With Heart Failure With Reduced Ejection Fraction: The PROGRESS-HF Phase 2 Trial Journal of Cardiac Failure 2020;26(5):429–437. 2020 .

    DOI: 10.1016/j.cardfail.2020.02.001 PMID: 32068002 View Source

  8. Hornby B, Vernon HJ, Stacpoole PW, et al. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER Genetics in Medicine 2024. 2024 .

    View Source

  9. U.S. Food and Drug Administration FORZINITY (elamipretide HCl) injection — accelerated approval letter and prescribing information, NDA 215244 FDA, 19 September 2025. 2025 .

    View Source

  10. World Anti-Doping Agency (WADA) The 2026 Prohibited List — International Standard WADA, effective 1 January 2026. 2026 .

    View Source

  11. PubChem (U.S. National Library of Medicine, NCBI) PubChem Compound Summary CID 11764719 — Elamipretide (free base; canonical chemistry record). PubChem. 2026 .

    View Source

Frequently Asked Questions

What is elamipretide, and what are SS-31, MTP-131, Bendavia, and Forzinity?
Elamipretide is the international nonproprietary name (INN). SS-31 is the original Cornell research code (Szeto–Schiller peptide #31). MTP-131 was the pre-clinical / Phase 1 development code at Stealth BioTherapeutics. Bendavia was an earlier Stealth trade name used during the EMBRACE-STEMI cardiology programme. Forzinity is the post-approval US brand name (FDA, 19 September 2025). All names refer to THE SAME four-residue tetrapeptide H-D-Arg-Tmt-Lys-Phe-NH₂ (CAS 736992-21-5).
Is elamipretide FDA-approved?
Yes, but only for one specific indication. On 19 September 2025 the FDA granted accelerated approval to FORZINITY (elamipretide HCl injection), NDA 215244, "to improve muscle strength in adult and pediatric patients with Barth syndrome weighing at least 30 kg." This is the first FDA-approved therapy for Barth syndrome and the first FDA-approved mitochondria-targeted peptide. All other clinical uses (mitochondrial myopathy, heart failure, dry AMD, etc.) remain investigational. The EMA has NOT approved elamipretide as of 2026-05-01.
What is the difference between elamipretide and MOTS-c?
They are very different molecules despite both being categorised under "mitochondrial / longevity". MOTS-c (see [/portfolio/mots-c](/portfolio/mots-c)) is a 16-amino-acid mitochondria-DERIVED peptide, encoded within the human MT-RNR1 (12S rRNA) gene on mitochondrial DNA — a natural human peptide. Elamipretide is a 4-residue mitochondria-TARGETING synthetic peptide that is NOT encoded by any human gene; it is a designed drug containing a non-proteinogenic D-amino acid (D-Arg) and a non-proteinogenic residue (Tmt = 2′,6′-dimethyltyrosine). MOTS-c acts via AMPK signalling and gene expression; elamipretide acts by directly binding cardiolipin on the inner mitochondrial membrane to stabilise cristae and respiratory supercomplexes.
How does elamipretide work mechanistically?
Elamipretide binds reversibly to cardiolipin, the signature anionic phospholipid of the inner mitochondrial membrane. Studies report that the peptide’s alternating aromatic-cation motif (D-Arg, Tmt, Lys, Phe) creates an electrostatic + hydrophobic stacking interface against cardiolipin. Cardiolipin-bound elamipretide stabilises cristae geometry, prevents the cytochrome-c–cardiolipin complex from peroxidising cardiolipin acyl chains, and preserves Complex I-III-IV respiratory supercomplex assembly. Critically, mitochondrial accumulation does NOT require the membrane potential ΔΨm, which distinguishes elamipretide from triphenylphosphonium-based mitochondrial drugs (e.g., MitoQ).
Did the Phase 3 trials succeed?
Mostly no, with one critical exception. MMPOWER-3 (primary mitochondrial myopathy, n = 218) missed both co-primary endpoints. EMBRACE-STEMI (STEMI reperfusion, n = 300) missed its CK-MB infarct-size endpoint. PROGRESS-HF (HFrEF, n = 71) missed its LVESV endpoint. ReCLAIM-2 (dry AMD, n = 176) showed minimal between-group differences. The exception was TAZPOWER (Barth syndrome, n = 12): the randomised crossover primary endpoint was also missed, but the open-label extension at 36 weeks (and through 168 weeks) showed clinically meaningful and durable improvement — and that data set was the basis of the FDA accelerated approval. ReNEW / SPIAM-301 (NCT06373731) is the active Phase 3 confirmatory programme in dry AMD; primary completion estimated August 2027.
What are the most common side effects observed in research settings?
Across the Phase 2/3 programme the dominant tolerability finding has been local injection-site reactions (pruritus, erythema, induration, hypoesthesia) for subcutaneous administration. The most commonly reported systemic adverse events are headache, dizziness, nausea, and fatigue. Hypersensitivity reactions are listed as warnings on the FORZINITY US prescribing information. Long-term tolerability through the TAZPOWER 168-week extension was favourable.

Related Peptides

MOTS-c

≥98%

Mitochondrial-derived peptide (MDP) — Mitochondrial / Longevity Research

Mitochondrial-derived peptide (MDP) — natural 16-amino-acid peptide (MRWQEMGYIFYPRKLR) encoded by a small open reading frame within human MT-RNR1 (12S mt-rRNA) on mitochondrial DNA (mtDNA); not nuclear DNA. First MDP with a defined systemic metabolic role (AMPK activation). Not approved by FDA or EMA. On the WADA Prohibited List as of 2024 (Class S4, AMPK activators). Research use only.

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Epitalon

≥98%

Synthetic Pineal Tetrapeptide (AEDG, Bioregulator Class — Mitochondrial / Longevity Research)

Synthetic tetrapeptide Ala-Glu-Asp-Gly (AEDG) modeled on the active fraction of the bovine pineal extract Epithalamin. In vitro telomerase findings were independently replicated in 2025; human data are limited to small single-center open-label observational studies from one research group. Research use only; not approved by FDA or EMA.

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Thymosin Alpha-1

≥98%

Thymic peptide hormone analogue / immune modulator (slug: immune-other; pleiotropic TLR2/TLR9-mediated effect rather than a classical single-receptor agonist)

Synthetic 28-amino-acid N-acetylated thymic peptide (thymalfasin / Zadaxin); pleiotropic TLR2/TLR9-mediated immune modulator — approved as Zadaxin in 35+ countries (Italy, China, Vietnam, Mexico and others) for chronic hepatitis B and as a vaccine adjuvant in immunocompromised populations, but NOT FDA-approved in the United States — only orphan-drug designations exist there.

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