SS-31 (elamipretide): what a decade of human trials found

SS-31, now called elamipretide, is the rare peptide on longevity forums that has been through the full drug-development mill. On 19 September 2025 the FDA granted it accelerated approval, as Forzinity, to improve muscle strength in people with Barth syndrome, an ultra-rare inherited mitochondrial disease. That approval rests on a small open-label extension, and the drug’s larger placebo-controlled trials, in mitochondrial myopathy, heart failure, heart attack and macular degeneration, all missed their primary endpoints.

What it is

Elamipretide is a four-amino-acid peptide with two unusual building blocks: D-arginine, dimethyltyrosine, lysine and phenylalanine, with an amidated end. It came out of a series of small “Szeto–Schiller” peptides developed by Hazel Szeto and Peter Schiller, first described in 2004 as cell-permeable antioxidants that concentrate in the inner membrane of mitochondria [1]. It has also been known as MTP-131 and Bendavia.

The working theory is that it binds cardiolipin, a four-tailed lipid found almost only in the inner mitochondrial membrane, which holds the energy-making protein complexes in place. By binding cardiolipin, elamipretide is thought to keep the complexes organised, help electrons flow and reduce the leak of damaging oxidants [2]. Most of that evidence comes from isolated mitochondria and animal models, so treat it as a well-developed mechanism theory. Barth syndrome, caused by faults in the tafazzin gene, is a disease of abnormal cardiolipin, which is why it was always the most logical target.

The human evidence

Barth syndrome: the trial behind the approval

TAZPOWER randomised 12 people with Barth syndrome aged 12 and over to 12 weeks of 40 mg a day of subcutaneous elamipretide or placebo, then swapped them over [3]. Neither primary endpoint, the six-minute walk test and a Barth symptom score, improved. Ten people then continued on open-label elamipretide. At 36 weeks their walk distance was 95.9 metres further than at the start, and knee muscle strength and some heart measures had improved [3]. Eight people reached 168 weeks, with a cumulative walk-distance gain of 96.1 metres and improved heart volumes on 3D echocardiography [4].

Because the randomised phase failed, the company built a comparison group from untreated Barth patients’ records. Against 19 such patients, the eight treated patients walked 79.7 metres further at week 64 and gained strength by propensity-matched analysis [5]. That is a legitimate method for an ultra-rare disease, but it is not a randomised comparison.

The FDA’s label is candid about all this. It states that elamipretide was not superior to placebo on the trial’s primary endpoints, that knee strength did not improve during the randomised phase, and that approval is based on strength gains seen in the open-label extension, an “intermediate clinical endpoint” [14]. Median knee strength rose by 63 newtons from a baseline of 124 by week 168 in the eight remaining patients [14]. Continued approval may depend on a confirmatory trial [14]. Several trial authors are employees of, or received funding from, Stealth BioTherapeutics, which makes the drug [3,4].

Primary mitochondrial myopathy

The first mitochondrial myopathy trial, MMPOWER, gave 36 adults two-hour IV infusions for five days at three doses or placebo [6]. At the top dose, people walked 64.5 metres further versus 20.4 on placebo (p = 0.053), with a significant dose trend. MMPOWER-2, a crossover in 30 adults using 40 mg a day under the skin for four weeks, found a 19.8-metre walk difference that was not significant (p = 0.08), though fatigue scores improved [7].

Then the definitive test. MMPOWER-3 randomised 218 adults to 40 mg a day or placebo for 24 weeks [8]. It missed both primary endpoints: the walk-test difference was −3.2 metres (95% CI −18.7 to 12.3; p = 0.69), and fatigue scores didn’t differ [8].

The arc from MMPOWER to MMPOWER-3 is a familiar one in drug development. Small early trials, with short treatment periods and walking tests that vary a lot from day to day, produced encouraging numbers with wide uncertainty. When the trial was made ten times larger and six months long, the average effect was indistinguishable from zero. That doesn’t prove elamipretide does nothing in anyone with mitochondrial myopathy, but it does mean the early signals can’t be quoted as evidence of benefit.

A post hoc reanalysis found a possible signal in people whose disease stems from faults in the genes that copy mitochondrial DNA, mostly POLG and TWNK: 25.2 versus 2.0 metres (p = 0.06), and a significant gain in a smaller subgroup with a condition affecting eye movement [9]. Subgroups picked after a trial fails are hypotheses, not results; the authors present them as the basis for a new trial.

Heart and eye trials

ReCLAIM-2 did show slower loss of a retinal photoreceptor layer (the ellipsoid zone) on imaging, and more people gaining 10 or more letters in low light (14.6% vs 2.1%), both with nominal p values [12]. The company has adopted the imaging measure as the main endpoint for its next eye trial.

What the animal and lab work suggests

The lab record is broad. In tissue taken from failing human hearts at transplant, elamipretide improved mitochondrial function in the dish [13]. The original 2004 paper showed the peptides prevented mitochondrial swelling and oxidant-driven death in cultured cells, and improved contractile force in an isolated-heart model of reperfusion [1]. Later rodent studies reported better function in aged heart and muscle. None of this has so far translated into a positive large trial outside Barth syndrome.

Safety and side effects reported

Safety is the strongest part of the record. In the Barth trial, all 12 people had injection-site reactions on elamipretide versus eight of 12 on placebo; redness, hardening, itching and pain were common [14]. MMPOWER-3 described elamipretide as well tolerated, with mostly mild events [8]. In ReCLAIM-2, 86% on elamipretide and 71% on placebo reported adverse events, led by injection-site reactions [12].

The label lists hypersensitivity as a contraindication, warns against use in newborns because the product contains benzyl alcohol as a preservative, and halves the dose in severe kidney impairment, where breakdown products build up [14].

What this means for “SS-31” as a longevity peptide

Elamipretide is often sold online as a general anti-ageing or energy product. No human trial has tested it in healthy people for that purpose. The human evidence comes from people with specific diseases of the mitochondria, heart or retina, and in all of them except Barth syndrome the controlled result was null. The trials also used a pharmaceutical product at a fixed dose under medical supervision, with safety monitoring. The positive animal work in aged hearts and muscle is the only basis for the ageing claim, and it has not been tested in people.

Legal and regulatory status

In the US, elamipretide is a prescription drug approved for one use: improving muscle strength in adults and children with Barth syndrome who weigh at least 30 kg, at 40 mg once daily under the skin [14,15]. The approval is accelerated. That pathway lets the FDA approve a drug for a serious condition on an endpoint thought reasonably likely to predict real benefit, here muscle strength, on condition that the benefit is later confirmed; if confirmation fails, approval can be withdrawn [14]. Any other use is off-label, and research-grade “SS-31” sold online is not the approved product. We found no marketing authorisation from the MHRA or the European Medicines Agency as of September 2026.

What we still don’t know

• Whether the Barth syndrome benefit is real at the level of a randomised comparison, which the confirmatory trial is meant to show.
• Whether any genetic subgroup of mitochondrial myopathy benefits, as the post hoc analysis suggests.
• Whether slowing photoreceptor loss on scans translates into better sight.
• Whether it does anything for healthy ageing. It has never been tested for that in a human trial.
• Long-term safety beyond the eight Barth patients followed for three years.

Educational content only — not medical advice. Many peptides discussed on HPR are not approved for human use. Talk to a qualified clinician before making any decision about your health.

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