SS-31 (Elamipretide) in Human Clinical Trials: Populations, Endpoints and Findings

Elamipretide, the compound also known as SS-31, has been tested in randomised trials in primary mitochondrial myopathy, Barth syndrome and dry age-related macular degeneration. This article sets out each trial, its primary endpoint, and what was and was not met.

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SS-31 is the laboratory designation of a mitochondria-targeted tetrapeptide developed clinically as elamipretide, and also coded MTP-131. The two names describe one molecule, and the split between them maps neatly onto the split in its literature: the preclinical work is published under SS-31, and the clinical trials under elamipretide.

That clinical record is substantial by the standards of this library. It includes a randomised crossover trial, a 218-participant phase 3 trial with a Class I evidence classification, a 176-participant phase 2 trial in an eye disease, and a randomised trial with a 168-week open-label extension in an ultra-rare genetic disorder. It is also, on its prespecified primary endpoints, largely negative — and the way its positive findings have been generated, through subgroups, open-label extensions and external controls, is the most instructive thing about it.

This article sets out each trial: population, design, duration, primary endpoint, results as reported, adverse events, limitations. It describes published research and contains no guidance of any kind on handling any material.

What SS-31 is, and how it is thought to act

In vitro research

SS-31 is a four-residue peptide that concentrates in the inner mitochondrial membrane. The mechanism reported for it is interaction with cardiolipin, the phospholipid of that membrane: a 2013 study described SS-31 interacting with cardiolipin in ischaemic mitochondria [1], and the compound was characterised as a first-in-class cardiolipin-protective agent intended to restore mitochondrial bioenergetics [2].

Later biophysical work refined the account. A 2020 study described binding to lipid bilayers and modulation of surface electrostatics as a key component of the mechanism rather than a specific protein interaction [4], and a 2022 study mapped structure-activity relationships across a series of mitochondria-targeted tetrapeptides [5].

Two things follow. The mechanism is a membrane-level one, which is unusual among the compounds in this library and which makes it hard to define a conventional target-engagement biomarker. And the mechanism is plausible across a wide range of conditions involving mitochondrial dysfunction, which is why the clinical programme below spans skeletal, cardiac and retinal disease — breadth that reflects a mechanistic hypothesis rather than evidence in each of those tissues.

Primary mitochondrial myopathy: the MMPOWER programme

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

MMPOWER-2, the crossover trial. 30 participants with genetically confirmed primary mitochondrial myopathy were randomly assigned 1:1 to 40 mg/day subcutaneous elamipretide for four weeks then placebo for four weeks, separated by a four-week washout, or the reverse sequence. The primary endpoint was distance walked on the six-minute walk test [3, 12].

Distance walked was 398.3 ± 134.16 m on elamipretide against 378.5 ± 125.10 m on placebo — a difference of 19.8 m (95% CI −2.8 to 42.5; P=0.0833), which did not reach statistical significance. Several patient-reported secondary measures did reach nominal significance: total fatigue and total fatigue during activities (P=0.0006 and P=0.0018), a fatigue short form (P=0.0115) and patient global assessment (P=0.0421). Physician global assessment, a timed up-and-go test and wrist and hip accelerometry showed no significant change. Injection-site reactions were the most common adverse event, in 80% of participants, mostly mild, with no serious adverse events or deaths [3].

MMPOWER-3, the phase 3 trial. 218 participants with genetically confirmed primary mitochondrial myopathy, randomised 1:1 to 24 weeks of elamipretide 40 mg/day subcutaneously or placebo. Mean age was 45.6 years; 64% were women and 94% were White; 162 (74%) had a mitochondrial DNA alteration and the remainder nuclear DNA defects. Mean baseline six-minute walk distance was 336.7 ± 81.2 m. Primary efficacy endpoints were change to week 24 in six-minute walk distance and in total fatigue on a disease-specific symptom assessment [7, 13].

The study did not meet either primary endpoint. The difference in least-squares mean change in walk distance was −3.2 m (95% CI −18.7 to 12.3; p=0.69) and in total fatigue score −0.07 (95% CI −0.10 to 0.26; p=0.37). Elamipretide was well tolerated, with most adverse events mild to moderate. The publication classifies its own result as Class I evidence that elamipretide does not improve the six-minute walk test or fatigue at 24 weeks in this population [7].

The genotype analyses. A prespecified subgroup with nuclear DNA pathogenic variants showed improvement on the walk test while the mitochondrial DNA cohort did not, and that observation prompted post hoc analyses. In the mitochondrial DNA replisome cohort — mostly POLG and TWNK variants — the elamipretide group walked 25.2 ± 8.7 m further against 2.0 ± 8.6 m for placebo (p=0.06). Among participants with chronic progressive external ophthalmoplegia the difference was 37.3 ± 9.5 m against −8.0 ± 10.7 m (p=0.0024). Exposure-response analysis in the nuclear DNA cohort showed a weak positive correlation between plasma concentration and walk-test change. The authors present these as the foundation for a follow-up phase 3 trial in likely responders [9].

Limitations. A post hoc subgroup analysis of a trial that missed both primary endpoints is hypothesis-generating by construction, and the authors describe it that way. The cohorts involved are small fractions of 218 participants, the comparisons are numerous, and the p-values are not adjusted for that. The correct reading is that the trial was negative and identified a subgroup worth testing prospectively — which is exactly what the authors say and exactly what is lost in summary.

Barth syndrome: TAZPOWER and its extension

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Design. TAZPOWER was a 28-week randomised, double-blind, placebo-controlled trial in patients with Barth syndrome, an ultra-rare X-linked disorder of cardiolipin remodelling, followed by a 168-week open-label extension in which all participants received elamipretide 40 mg subcutaneously daily. The extension's primary endpoints were safety and tolerability; secondary endpoints included change in six-minute walk distance and a disease-specific total fatigue score, with strength, echocardiographic parameters and cardiolipin biomarkers also assessed [8, 11].

Results as reported. Ten patients entered the extension and eight reached the week-168 visit. Elamipretide was well tolerated, with injection-site reactions the most common adverse event. Six-minute walk distance improved significantly from extension baseline at all time points, cumulatively 96.1 m at week 168 (P=0.003). Total fatigue scores were below baseline at all extension time points. Three-dimensional left ventricular stroke, end-diastolic and end-systolic volumes improved, with significant trends from baseline to week 168. The ratio of monolysocardiolipin to cardiolipin improved [8].

The natural-history comparison. Because the randomised phase was small and short, a separate retrospective, non-interventional phase 3 study built an external control cohort. A propensity-score model compared 8 patients from the open-label extension with 19 untreated natural-history controls, 12 of whom had serial echocardiographic assessments. For the six-minute walk test, the least-squares mean difference was 79.7 m at week 64 (P=0.0004) and 91.0 m at week 76 (P=0.0005) in favour of elamipretide. Strength by handheld dynamometry differed by 40.8 N at 64 weeks (P=0.0002) and 56.7 N at 76 weeks (P=0.0005), with significant differences also on a sit-to-stand measure and a multi-domain responder index. Left ventricular stroke volume increased in treated patients and decreased in controls [6].

Limitations, which are structural rather than incidental. Eight patients contributed the treated data in both analyses. An open-label extension has no control group: every participant knows they are receiving the drug, the six-minute walk test is effort-dependent, and improvement from extension baseline over 168 weeks is not a controlled comparison. The natural-history study supplies a comparison group, but retrospectively, non-randomised, and matched by a propensity model on a cohort of 19 — a design whose value in ultra-rare disease is genuine and whose inferential strength is well below that of randomisation. Barth syndrome is a disorder of cardiolipin remodelling, so this is the indication in which the compound's proposed mechanism is most directly relevant; that makes the finding interesting, and does not make the design stronger.

What the evidence base does not establish

Efficacy on a prespecified primary endpoint in a randomised trial. MMPOWER-2 missed its primary endpoint [3]. MMPOWER-3 missed both of its primary endpoints and classified the result as Class I evidence of no effect [7]. ReCLAIM-2 missed both of its coprimary endpoints [10]. That is three randomised trials, three negative primary results.

That the positive findings survive the transition to a controlled design. Every favourable result in this literature comes from an open-label extension [8], an external retrospective control [6], a post hoc subgroup [9], or an unadjusted secondary endpoint [10, 3]. Each of these is a legitimate way to generate a hypothesis and none is a way to confirm one.

Anything outside rare mitochondrial and retinal disease. The trials enrolled genetically confirmed primary mitochondrial myopathy, Barth syndrome, and geographic atrophy. There is no randomised trial of this compound in any common condition, and no trial in a healthy population.

Anything in a population that is not ill. No published trial administered elamipretide to healthy volunteers for an efficacy endpoint. Claims about general mitochondrial function in people without mitochondrial disease have no trial evidence behind them in this record.

Long-term controlled safety. The longest exposure reported is 168 weeks, in eight patients, open-label [8]. Injection-site reactions are frequent and well documented; everything else about long-term safety rests on small numbers.

Any route other than subcutaneous. Every clinical trial above administered the compound subcutaneously at 40 mg daily [3, 7, 10, 8].

All of the research described in this article is research into a pharmaceutical product candidate, conducted by its sponsor under registered protocols, using investigational material manufactured to a regulatory standard and administered under clinical supervision in defined populations. None of it is research into, or evidence about, research-grade material supplied for laboratory use.

Frequently Asked Questions

Is SS-31 the same as elamipretide?
Yes. SS-31 is the laboratory designation for the mitochondria-targeted tetrapeptide developed clinically as elamipretide, also coded MTP-131. The preclinical literature uses SS-31 [1, 2] and the clinical literature uses elamipretide [7, 8].
What did the phase 3 trial of elamipretide in mitochondrial myopathy find?
MMPOWER-3 randomised 218 participants with genetically confirmed primary mitochondrial myopathy 1:1 to elamipretide 40 mg daily subcutaneously or placebo for 24 weeks. It did not meet either primary endpoint. The difference in six-minute walk distance was −3.2 m (95% CI −18.7 to 12.3; p=0.69) and the difference in total fatigue score was −0.07 (95% CI −0.10 to 0.26; p=0.37). The paper classifies its own finding as Class I evidence of no improvement [7].
Did any subgroup respond in the mitochondrial myopathy trial?
A prespecified subgroup with nuclear DNA pathogenic variants showed improvement on the six-minute walk test while the mitochondrial DNA cohort did not, and post hoc analyses reported a trend in the mitochondrial DNA replisome cohort (25.2 m against 2.0 m; p=0.06) and a significant change in participants with chronic progressive external ophthalmoplegia (37.3 m against −8.0 m; p=0.0024) [9]. These are post hoc analyses of a trial that missed its primary endpoints.
What happened in the Barth syndrome trials?
TAZPOWER was a 28-week randomised, double-blind, placebo-controlled trial followed by a 168-week open-label extension. Ten patients entered the extension and eight reached week 168, with a cumulative six-minute walk improvement of 96.1 m from extension baseline (P=0.003) and improvements in cardiac volumes [8]. A separate retrospective study compared 8 treated patients with 19 untreated natural-history controls using a propensity score model, reporting a 79.7 m difference at week 64 (P=0.0004) [6].
Did the elamipretide eye trial meet its endpoints?
No. ReCLAIM-2 randomised 176 patients with dry age-related macular degeneration and non-central geographic atrophy to daily subcutaneous elamipretide 40 mg or placebo for 48 weeks. Neither primary endpoint was met — low-luminance best-corrected visual acuity and square-root-converted geographic atrophy area. Nominally significant differences were reported on ellipsoid zone measures [10].
Is elamipretide approved by the FDA?
The compound has been through phase 2 and phase 3 trials in several rare diseases, with the outcomes described in this article. No trial summarised here met its prespecified primary endpoints except in open-label or externally controlled settings [7, 10, 8].
What adverse events are reported in elamipretide trials?
Injection-site reactions dominate. They were the most common adverse event in the crossover trial, affecting 80% of participants and mostly mild [3], the most common in the Barth syndrome extension [8], and the most common in the eye trial, where adverse events were reported by 86% on elamipretide against 71% on placebo [10]. The phase 3 myopathy trial described elamipretide as well tolerated with most events mild to moderate [7].
How does SS-31 act at the molecular level?
It concentrates in the inner mitochondrial membrane and interacts with cardiolipin. Preclinical work describes interaction with cardiolipin in ischaemic mitochondria [1] and characterises the compound as cardiolipin-protective [2]. Later biophysical work describes binding to lipid bilayers and modulation of surface electrostatics as a key component of the mechanism [4], with structure-activity relationships mapped across related tetrapeptides [5].

References

  1. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin Journal of the American Society of Nephrology; 2013. PMID 23813215 doi:10.1681/ASN.2012121216
  2. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics British Journal of Pharmacology; 2014. PMID 24117165 doi:10.1111/bph.12461
  3. A randomized crossover trial of elamipretide in adults with primary mitochondrial myopathy Journal of Cachexia, Sarcopenia and Muscle; 2020. PMID 32096613 doi:10.1002/jcsm.12559
  4. The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of action The Journal of Biological Chemistry; 2020. PMID 32273339 doi:10.1074/jbc.RA119.012094
  5. Structure-activity relationships of mitochondria-targeted tetrapeptide pharmacological compounds eLife; 2022. PMID 35913044 doi:10.7554/eLife.75531
  6. Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome Orphanet Journal of Rare Diseases; 2022. PMID 36056411 doi:10.1186/s13023-022-02469-5
  7. Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial Neurology; 2023. PMID 37268435
  8. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER Genetics in Medicine; 2024. PMID 38602181 doi:10.1016/j.gim.2024.101138
  9. Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial Orphanet Journal of Rare Diseases; 2024. PMID 39574155 doi:10.1186/s13023-024-03421-5
  10. ReCLAIM-2: A Randomized Phase II Clinical Trial Evaluating Elamipretide in Age-related Macular Degeneration, Geographic Atrophy Growth, Visual Function, and Ellipsoid Zone Preservation Ophthalmology Science; 2025. PMID 39605874 doi:10.1016/j.xops.2024.100628
  11. A Trial to Evaluate Safety, Tolerability and Efficacy of Elamipretide in Subjects With Barth Syndrome. NCT03098797
  12. Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study. NCT02805790
  13. A Trial to Evaluate Safety and Efficacy of Elamipretide Primary Mitochondrial Myopathy Followed by Open-Label Extension. NCT03323749
  14. ReCLAIM-2 Study to Evaluate Safety,Efficacy & Pharmacokinetics of Elamipretide in Subjects With AMD With Non-central GA. NCT03891875

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