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Mitochondrial

SS-31 (Elamipretide)

Elamipretide — Szeto-Schiller tetrapeptide D-Arg-Dmt-Lys-Phe-NH₂·Also known as: Elamipretide, MTP-131, Bendavia, SS-31, SS-02, Szeto-Schiller peptide 31

FDARegulatory status

Not approved. Stealth BioTherapeutics' New Drug Application for Barth syndrome (deficiency energy failure — treatment in pediatric and adult patients) received a Complete Response Letter in May 2024; after submission of additional Phase 2/3 TAZPOWER long-term natural-history comparator data and an FDA Advisory Committee meeting (October 2024, 10–6 vote against accelerated approval), Stealth resubmitted and elamipretide was granted accelerated approval in September 2025 (brand name Forzinity) for adults and pediatric patients ≥1 year with Barth syndrome — the first FDA-approved therapy for that indication. Not approved for any other indication; the MMPOWER-3 primary mitochondrial myopathy program did not meet its primary endpoint and was terminated in 2020, and the ReCLAIM-2 dry-AMD / geographic-atrophy Phase 3 program reported mixed results.

WADARegulatory status

Not listed by name on the 2026 WADA Prohibited List. As an investigational peptide without marketing authorization for most indications, it falls under S0 (non-approved substances) for competitive athletes in non-Barth contexts.

Regulatory note ·Forzinity (elamipretide subcutaneous, 40 mg once daily) is the only approved form and is restricted to Barth syndrome. All other uses — heart failure with preserved or reduced ejection fraction (PROGRESS-HF), primary mitochondrial myopathy (MMPOWER-1/2/3, MMPOWER-3 extension), dry age-related macular degeneration / geographic atrophy (ReCLAIM-1, ReCLAIM-2), Leber hereditary optic neuropathy, Friedreich's ataxia, and age-related mitochondrial dysfunction — remain investigational. The compound is sold in the US only as a research chemical for in-vitro and animal studies outside of approved clinical channels.

§ The quick take

TL;DR · Editor’s summary

SS-31 / elamipretide is the furthest-developed mitochondrial-targeted peptide in clinical medicine, and the late-stage record is more negative than positive. Across three large controlled programs — MMPOWER-3 in primary mitochondrial myopathy (Karaa 2023, Neurology, n=218, negative on both 6MWD and fatigue), PROGRESS-HF in heart failure with reduced ejection fraction (Butler 2020, Eur J Heart Fail, n=261, negative on LV end-systolic volume), and EMBRACE-STEMI in ischemia-reperfusion (Gibson 2016, Eur Heart J, n=297, negative on infarct size) — elamipretide failed its primary endpoints in consecutive pivotal trials despite strong preclinical rationale. ReCLAIM-2 in dry AMD / geographic atrophy (n=176) also missed co-primary endpoints.

The one win is Barth syndrome — a rare cardiolipin-remodeling disorder where the target biology is mechanistically aligned with the drug: the TAZPOWER crossover (Reid Thompson 2021, n=12) missed 12-week co-primary endpoints but showed durable knee-extensor strength and PGI improvement over the 36-week open-label extension, and Stealth Biotherapeutics received FDA accelerated approval in September 2025 (brand name Forzinity, 40 mg SC daily) following a split 10–6 AdCom in October 2024 and a prior Complete Response Letter in May 2024. The Barth approval rests on an ultra-small n and an external natural-history comparator, so it is a defensible B on our rubric, not an A. Mechanistically the cardiolipin-binding and Src-Cav-1-eNOS / ETC supercomplex stabilization story (Szeto 2014, Birk 2014, Mitchell 2020 PNAS) is well-characterized, and human PK / safety across >1,200 participants in the development program is cleaner than most investigational peptides.

The honest read: outside Barth syndrome, the translational record does not support routine use, and claims of cardiac, ocular, or anti-aging benefit are not evidence-backed at Phase 3 level.

§ Grade matrix

The grade
per outcome.

One peptide can earn very different grades for different uses. Here is every outcome we’ve graded for SS-31 (Elamipretide), sorted by strength of evidence.

Grade
Outcome
One-line take
Studies
Updated
B

Barth syndrome (knee-extensor strength, 6MWT, patient global impression)

Promising

TAZPOWER Phase 2/3 crossover (Reid Thompson 2021, Genet Med, n=12) missed its co-primary endpoints at 12 weeks but showed significant improvement on knee-extensor strength and SWAY balance after 36-week open-label extension. The long-term extension plus external natural-history comparator drove FDA accelerated approval in September 2025. Still a small-population signal (n=12 core, ~30 in extension).

6
2026-04-20
D

Primary mitochondrial myopathy (6-minute walk distance, fatigue)

Weak

MMPOWER-3 Phase 3 RCT (Karaa 2023, Neurology, n=218, 24 weeks, 40 mg SC daily) missed both primary endpoints (6MWD and PMM Symptom Assessment Total Fatigue). Phase 2 MMPOWER (Karaa 2018) had shown a 6MWD signal that did not replicate. Program terminated 2020. Grade reflects negative pivotal trial.

5
2026-04-20
C

Dry AMD / geographic atrophy (GA lesion growth, low-luminance visual acuity)

Mixed

ReCLAIM-2 Phase 2b (24 weeks, n=176) missed co-primary endpoints on GA lesion growth and low-luminance best-corrected visual acuity (Allingham 2024, Ophthalmol Retina). ReCLAIM-1 open-label (n=40) had suggested LL-BCVA and reading-speed benefit. Follow-up ReGAIN Phase 3 was initiated but results are not yet available.

4
2026-03-28
D

Heart failure with reduced ejection fraction (LV end-systolic volume, exercise capacity)

Weak

PROGRESS-HF Phase 2 (Butler 2020, Eur J Heart Fail, n=261, 28 days IV infusion) missed primary endpoint of change in LV end-systolic volume. Earlier small IV study (Daubert 2017) was similarly flat. No positive Phase 3 cardiac outcome trial.

6
2026-03-12
D

Ischemia-reperfusion injury in STEMI (infarct size on CMR)

Weak

EMBRACE-STEMI Phase 2 (Gibson 2016, Eur Heart J, n=297) of IV elamipretide as an adjunct to primary PCI missed primary endpoint of infarct size reduction by CMR at day 4. Preclinical I/R data was strong; clinical translation failed.

3
2026-02-18
C

Age-related skeletal muscle dysfunction (muscle function, ATP)

Mixed

Roshanravan (2021, Aging Cell) and Sweetwyne (2017) Phase 1/2 studies in older adults showed improved mitochondrial ATP production on 31P-MRS and fatigue-resistance after single 8-day IV infusions but without consistent functional endpoint gains. Small, short-duration.

4
2026-02-04
D

Acute kidney injury / contrast-induced nephropathy

Weak

Phase 2 trial in patients undergoing percutaneous revascularization for renovascular hypertension (Saad 2017, Clin J Am Soc Nephrol) showed improvement in cortical perfusion but no confirmed clinical renal-outcome benefit. No Phase 3.

3
2026-01-20

§ Why this grade

Sub-scores for this outcome.

Barth syndrome

Every grade rolls up six weighted sub-scores, each rated 1 to 5 with a written justification. Here is how the top-outcome grade was constructed.

Mechanism understood

5 / 5

Cardiolipin binding (Szeto 2014, Birk 2014), ETC supercomplex stabilization (Mitchell 2020 PNAS), and the TAZ/tafazzin disease mechanism are all well-mapped. Drug-target fit is tight — Barth is a cardiolipin remodeling disorder and SS-31 is a cardiolipin-binding peptide.

Human studies (count + quality)

3 / 5

TAZPOWER Phase 2/3 crossover n=12 (Reid Thompson 2021, Genet Med) plus 36-week open-label extension and external natural-history comparator. Supported FDA accelerated approval September 2025 but n is small and the confirmatory trial is still pending.

Effect vs placebo

3 / 5

TAZPOWER missed 12-week co-primary endpoints on knee-extensor strength and 6MWT; the approval pathway leaned on 36-week open-label extension improvement and external comparison. Effect size is real but pivotal-trial-caliber placebo-controlled data is thin.

Long-term safety data

3 / 5

Phase 1–3 development program exposed ~1,200 subjects across indications; subcutaneous injection-site reactions are common but mild. Longest continuous exposure documented in Barth extension is >3 years. Still limited pediatric long-term data.

Side effect profile

4 / 5

Most common adverse events: injection-site reactions, hyperhidrosis, paresthesia, headache — generally mild-to-moderate. No class-specific serious safety signal in >10 years of development. Discontinuation rates in Phase 3 programs were comparable to placebo.

Regulatory status

4 / 5

FDA accelerated approval (Forzinity) September 2025 for Barth syndrome in patients ≥1 year old — the first approved therapy for that indication. Approval is accelerated and contingent on confirmatory data. Not approved for any other use.

§ What the science says

How SS-31 (Elamipretide)
works.

Plain-English explanation of the molecule and its proposed mechanism, written at an 8th-grade reading level so anyone can engage with it. Every claim is linked to a primary source below.

What it is

Elamipretide (SS-31, MTP-131, Bendavia) is a synthetic water-soluble aromatic-cationic tetrapeptide with sequence D-Arg-Dmt-Lys-Phe-NH₂ (Dmt = 2',6'-dimethyltyrosine), molecular weight 639.8 Da, CAS 736992-21-5, molecular formula C₃₂H₄₉N₉O₅. It was discovered by Hazel Szeto and Peter Schiller at Weill Cornell during structure–activity work on opioid analogs, where the alternating aromatic–cationic motif was found to drive selective inner-mitochondrial-membrane uptake independent of membrane potential. Unlike triphenylphosphonium-conjugated mito-targeted antioxidants, SS-31 partitions into the inner membrane by direct high-affinity binding to cardiolipin — the dimeric phospholipid unique to that membrane — making it the first-in-class cardiolipin-targeted therapeutic (Birk 2014, J Am Soc Nephrol; Mitchell 2020, PNAS). Stealth BioTherapeutics licensed the compound and developed it through Phase 3 trials in primary mitochondrial myopathy, heart failure, AMD, and Barth syndrome; only the Barth syndrome indication has reached FDA approval (accelerated, September 2025).

How it works

  1. 01

    Cardiolipin binding and inner-membrane targeting

    Szeto (2014, Br J Pharmacol) and Birk (2014, J Am Soc Nephrol) established that SS-31 concentrates 1,000–5,000× in mitochondria of target tissues and binds cardiolipin with nanomolar affinity. Cardiolipin makes up 10–20 mol% of inner-mitochondrial-membrane lipid and is required for assembly of ETC supercomplexes and for cytochrome c tethering. Unlike conventional mito-targeted drugs, SS-31 uptake does not depend on membrane potential — which matters in dysfunctional mitochondria where ΔΨm is already depolarized.

  2. 02

    Electron transport chain supercomplex stabilization

    Mitchell (2020, PNAS — the chemical cross-linking / mass spectrometry 'interaction landscape' paper cited in Stealth's Barth submission) identified the proteomic neighborhood of SS-31 at the inner membrane: ATP synthase subunits, Complex I/III/IV components, and the 2-oxoglutarate dehydrogenase complex — all cardiolipin-dependent. SS-31 improves coupling efficiency, preserves supercomplex formation, and restores ATP production in aged and diseased mitochondria without inhibiting normal respiration.

  3. 03

    Reduction of mitochondrial ROS without blunting physiological redox signaling

    The 2',6'-dimethyltyrosine residue scavenges hydroxyl and peroxynitrite radicals by forming stable tyrosyl radicals that couple to di-tyrosine — a mechanism that targets pathologic mitochondrial ROS without disrupting cytosolic redox tone. This is the pharmacological case for 'mitochondrial antioxidant' activity separate from broad antioxidant supplementation, which has failed repeatedly in clinical trials. Dai (2014, Aging Cell) showed reversal of age-related cardiac dysfunction in mice via this mechanism.

  4. 04

    Cytochrome c peroxidase inhibition and apoptosis-threshold raising

    Cardiolipin-bound cytochrome c acquires peroxidase activity under oxidative stress; peroxidation of cardiolipin releases cytochrome c from the inner membrane and triggers intrinsic apoptosis. Birk (2014) showed SS-31 inhibits cyt-c peroxidase activity at sub-micromolar concentrations and prevents cardiolipin peroxidation, raising the threshold for apoptotic cascade activation in ischemia-reperfusion and in aged or tafazzin-deficient cells.

  5. 05

    Barth-specific rationale — tafazzin deficiency and cardiolipin remodeling

    Barth syndrome is caused by loss-of-function mutations in TAZ (tafazzin), the transacylase that remodels immature monolysocardiolipin into mature tetralinoleoyl-cardiolipin. In tafazzin-deficient cells, SS-31 binds residual cardiolipin and restores supercomplex assembly even without normalizing the cardiolipin-species profile (Allen 2022, JAHA). This is the one indication where the drug-target biology is a close mechanistic fit, and it is the one indication where elamipretide has reached FDA approval.

  6. 06

    What is still unresolved

    Why the preclinical-to-clinical translation has repeatedly failed outside Barth is not mechanistically explained. Candidate reasons include dosing regimen (40 mg SC daily may under-expose tissue compared to the continuous IV infusion protocols used in early trials), disease heterogeneity (PMM encompasses many distinct genotypes with differing cardiolipin dependence), trial duration (24–28 weeks may be too short for structural mitochondrial remodeling), and insufficient baseline mitochondrial dysfunction in the enrolled populations. None of these has been resolved by a follow-up positive trial.

§ Investigated uses

What it’s
been studied for.

Investigated does not mean proven. This list shows every use that appears in the published literature, regardless of evidence strength. See the grade matrix above for which ones have actually held up.

  • Barth syndrome (TAZ-mutation cardiolipin remodeling disorder)

    FDA accelerated approval September 2025 (Forzinity, 40 mg SC daily, ≥1 year old); TAZPOWER Phase 2/3 n=12 + open-label extension + natural-history comparator

  • Primary mitochondrial myopathy (MELAS, KSS, PEO, mtDNA deletions)

    MMPOWER-3 Phase 3 (Karaa 2023) negative on 6MWD and fatigue; program terminated 2020

  • Dry AMD / geographic atrophy

    ReCLAIM-2 Phase 2b (Allingham 2024) missed co-primary endpoints; ReGAIN Phase 3 initiated but not reported

  • Heart failure with reduced ejection fraction

    PROGRESS-HF Phase 2 (Butler 2020) negative on LV end-systolic volume change

  • Heart failure with preserved ejection fraction (HFpEF)

    Small mechanistic studies; no Phase 3

  • Ischemia-reperfusion injury in STEMI

    EMBRACE-STEMI Phase 2 (Gibson 2016) negative on infarct size by CMR

  • Leber hereditary optic neuropathy (LHON)

    ReSIGHT Phase 2 open-label, limited data; no controlled trial published

  • Friedreich's ataxia

    Small mechanistic studies; no Phase 3

  • Contrast-induced and ischemic acute kidney injury

    Small Phase 2 (Saad 2017) cortical-perfusion endpoint only

  • Age-related skeletal muscle dysfunction

    Phase 1/2 (Roshanravan 2021, Sweetwyne 2017) short-duration ATP and fatigue signals

§ The honest gaps

What we don’t
know yet.

Every peptide page on this site is required to include this section. Absence of evidence is information. If we don’t flag the gaps, we’re lying by omission.

  • !

    Why preclinical-to-clinical translation has failed outside Barth syndrome despite a well-characterized and replicated mechanism. Three consecutive negative Phase 2/3 trials (EMBRACE-STEMI, PROGRESS-HF, MMPOWER-3) is a pattern, not noise.

  • !

    Whether the subcutaneous 40 mg once-daily regimen (approved in Barth) achieves tissue exposure comparable to the continuous or intermittent IV regimens used in the positive preclinical work. No head-to-head PK/PD study exists.

  • !

    Whether the Barth syndrome accelerated-approval efficacy signal replicates in the confirmatory post-marketing trial Stealth is required to complete. The core TAZPOWER n is 12 and the external natural-history comparator is non-randomized.

  • !

    Long-term (>2 year) safety and immunogenicity data in pediatric patients chronically dosed for Barth syndrome. The approval pathway was accelerated on open-label extension data.

  • !

    Dose-response in primary mitochondrial myopathy — MMPOWER-3 tested only one dose (40 mg SC daily) and was negative; no higher-dose arm was ever taken to Phase 3.

  • !

    Whether any predictive biomarker (cardiolipin species profile, mitochondrial DNA copy number, ATP synthase activity) can pre-select responders. Without one, heterogeneous trial populations will likely continue to be underpowered.

  • !

    Whether oral or intranasal formulations under exploratory development can match subcutaneous exposure. Oral bioavailability of the parent peptide is negligible.

  • !

    Drug–drug interaction profile for chronic use in elderly heart-failure or AMD populations with extensive polypharmacy is not systematically characterized.

§ On YouTube

What experts and
influencers say.

We index YouTube content discussing SS-31 (Elamipretide)and tag every speaker by credential and trust level. The goal is not to summarize the internet — it’s to tell you which voices to weight.

  • SS-31 / Elamipretide: Mitochondrial Medicine Explained

    NIH VideoCast·Hazel Szeto, MD, PhD — co-inventor, Weill Cornell

    Original co-inventor walks through the cardiolipin-binding mechanism and the distinction between SS-31 and triphenylphosphonium-conjugated mito-targeted drugs. Honest about the clinical failures outside Barth.

    Verified credentials

  • The MMPOWER-3 Trial: What Went Wrong with Elamipretide in Primary Mitochondrial Myopathy

    United Mitochondrial Disease Foundation·Amel Karaa, MD — MMPOWER-3 principal investigator, Mass General

    PI of the negative Phase 3 trial discusses why the drug missed its primary endpoints and what the data imply about trial design in heterogeneous mitochondrial disease populations.

    Verified credentials

  • FDA AdCom on Elamipretide for Barth Syndrome — October 2024 Briefing

    FDA — CDER·FDA Peripheral and Central Nervous System Drugs Advisory Committee

    Full advisory committee session (10–6 vote against accelerated approval) covering the TAZPOWER data, the natural-history comparator methodology, and the statistical objections that preceded the eventual 2025 approval.

    Verified credentials

§ Citations

Every claim,
linked to source.

All 19 sources informing this page, with DOI or PubMed identifiers. Click through to the primary literature.

  1. [01]

    A phase 2/3 randomized trial of elamipretide in Barth syndrome (TAZPOWER)

    Reid Thompson W, Hornby B, Manuel R, et al. · Genet Med · 2021

    RCTPMID 34758060
  2. [02]

    Randomized trial of elamipretide for primary mitochondrial myopathy (MMPOWER-3)

    Karaa A, Bertini E, Carelli V, et al. · Neurology · 2023

    RCTPMID 37019666
  3. [03]

    Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy (MMPOWER)

    Karaa A, Haas R, Goldstein A, et al. · Neurology · 2018

    RCTPMID 30404833
  4. [04]

    Effects of elamipretide on left ventricular function in patients with heart failure with reduced ejection fraction: the PROGRESS-HF phase 2 trial

    Butler J, Khan MS, Anker SD, et al. · Eur J Heart Fail · 2020

    RCTPMID 32558998
  5. [05]

    EMBRACE STEMI study: a Phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous Bendavia on reperfusion injury in patients treated with primary PCI for ST-elevation myocardial infarction

    Gibson CM, Giugliano RP, Kloner RA, et al. · Eur Heart J · 2016

    RCTPMID 26912803
  6. [06]

    Elamipretide for age-related macular degeneration with geographic atrophy: the ReCLAIM-2 phase 2b randomized trial

    Allingham MJ, Mettu PS, Cousins SW · Ophthalmol Retina · 2024

    RCTPMID 38462196
  7. [07]

    The mitochondrial protein interaction landscape of SS-31

    Chavez JD, Tang X, Campbell MD, et al. · Proc Natl Acad Sci USA · 2020

    In vitroPMID 32554492
  8. [08]

    The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin

    Birk AV, Liu S, Soong Y, et al. · J Am Soc Nephrol · 2014

    AnimalPMID 24697750
  9. [09]

    First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics

    Szeto HH · Br J Pharmacol · 2014

    Systematic reviewPMID 24116825
  10. [10]

    Elamipretide (SS-31) reverses mitochondrial dysfunction and cardiac hypertrophy in aged mice

    Dai DF, Chiao YA, Marcinek DJ, et al. · Aging Cell · 2014

    AnimalPMID 24688093
  11. [11]

    Targeting mitochondrial dysfunction with elamipretide in older adults: results from a phase 2 clinical trial

    Roshanravan B, Liu SZ, Ali AS, et al. · Aging Cell · 2021

    RCTPMID 33512760
  12. [12]

    Phase 2a safety and efficacy of MTP-131 (Bendavia) in subjects with renovascular hypertension

    Saad A, Herrmann SMS, Eirin A, et al. · Clin J Am Soc Nephrol · 2017

    RCTPMID 28794261
  13. [13]

    Novel mitochondria-targeting peptide in heart failure treatment: a randomized, placebo-controlled trial of elamipretide

    Daubert MA, Yow E, Dunn G, et al. · Circ Heart Fail · 2017

    RCTPMID 28232424
  14. [14]

    SS-31 rejuvenates mitochondria and improves renal function in aged mice via improved mitochondrial bioenergetics

    Sweetwyne MT, Pippin JW, Eng DG, et al. · Kidney Int · 2017

    AnimalPMID 28923537
  15. [15]

    Efficacy and safety of elamipretide in subjects with primary mitochondrial myopathy followed by an open-label treatment extension (MMPOWER-3)

    Stealth BioTherapeutics · ClinicalTrials.gov · 2023

    RegistrationTrial
  16. [16]

    A study to evaluate the safety, tolerability, and efficacy of elamipretide in subjects with Barth syndrome (TAZPOWER)

    Stealth BioTherapeutics · ClinicalTrials.gov · 2021

    RegistrationTrial
  17. [17]

    A study to evaluate the efficacy and safety of elamipretide in subjects with dry age-related macular degeneration with non-central geographic atrophy (ReCLAIM-2)

    Stealth BioTherapeutics · ClinicalTrials.gov · 2024

    RegistrationTrial
  18. [18]

    FDA grants accelerated approval to Forzinity (elamipretide) for Barth syndrome

    U.S. Food and Drug Administration · FDA · 2025

    RegulatoryLink
  19. [19]

    Stealth BioTherapeutics receives Complete Response Letter from FDA for elamipretide NDA in Barth syndrome

    Stealth BioTherapeutics · Press release · 2024

    RegulatoryLink

§ Adjacent peptides

Worth reading
alongside this.

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MOTS-c

Mitochondrial-derived peptide targeting the same organelle — very different mechanism (AMPK activation, mitokine signaling) but the same therapeutic category. Useful contrast: MOTS-c is endogenous and has no approved indication; SS-31 is exogenous and has one.

Read its grades

Compare

Epitalon

Often grouped with SS-31 in longevity / anti-aging peptide discussions on the basis of mitochondrial and telomerase claims. The evidence base is incomparable — epitalon has no Phase 3 data; SS-31 has four and one approval. Worth reading side-by-side.

Read its grades

Compare

BPC-157

Opposite evidence profile: BPC-157 has deep preclinical data but no Phase 3 and no approvals. SS-31 illustrates what it looks like when a peptide actually reaches late-stage trials — and how hard the translation is even with a well-characterized mechanism.

Read its grades

Where to research further

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for laboratory research?

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