SS-31

What SS-31 is

SS-31 — also called elamipretide, MTP-131, or Bendavia — is a synthetic, cell-permeable, mitochondria-targeted tetrapeptide: four residues, alternating aromatic and cationic, with a D-arginine at the N-terminus and a C-terminal amide^[1]. It belongs to the Szeto-Schiller peptide series, developed in the laboratory of Hazel H. Szeto.

Its defining property is that it concentrates in the inner mitochondrial membrane and binds cardiolipin, a phospholipid found almost nowhere else in the cell^[1]. That is a genuinely distinctive mechanism, and it is the thing that makes SS-31 interesting. It is also — as this page will show at length — a mechanism that has repeatedly failed to convert into a positive human clinical result.

Structure and identity

SS-31 · C32H49N9O5 · 639.8 g/mol · CAS 736992-21-5 · Source: PubChem CID 11764719

Molecular formula, molecular weight, CAS registry number, sequence and structure above were retrieved directly from the PubChem PUG-REST API^[10]. One practical note: 736992-21-5 is the CAS number PubChem records for the free base. Salt forms carry different registry numbers, and vendors routinely quote them interchangeably. If a CAS number you see elsewhere does not match this one, that is not necessarily an error — but it is a difference worth asking about.

The 2,6-dimethyltyrosine (Dmt) residue is not decorative. The alternating aromatic-cationic motif is what drives the peptide’s mitochondrial partitioning, and it is the structural basis of the entire SS series^[1].

Every batch we supply is assayed by an independent laboratory using HPLC-UV-MS: mass spectrum against an authentic reference standard for identity, peak area against total chromatogram area for chromatographic purity, and total peptide mass against the stated label claim. Measured values for the current lot are pending. We do not print numbers we do not have.

Where the evidence stands

This is the section most vendors skip. It is the most important one on the page.

Mechanism — cardiolipin in vitro

Szeto’s 2014 review in the British Journal of Pharmacology is the canonical mechanistic account. SS-31 selectively concentrates in the inner mitochondrial membrane and associates with cardiolipin. Cardiolipin is required for cristae architecture and for the assembly and function of the respiratory supercomplexes; it is also the phospholipid that, when it complexes with cytochrome c, converts cytochrome c into a peroxidase and initiates lipid peroxidation^[1].

The companion paper by Birk et al. in the same issue is the biophysical demonstration: SS-31 interacts with the cytochrome c/cardiolipin complex, suppresses the peroxidase activity of that complex, and thereby preserves electron transport and mitochondrial ATP synthesis^[2]. This is isolated-mitochondria and cell-free work. It is elegant, it is well-replicated, and it is not a claim about a living organism.

Szeto’s 2018 review in Protein and Peptide Letters extends the framing to age-related mitochondrial dysfunction generally^[3]. Note that reviews are reviews. They summarise a hypothesis; they do not test it.

Animal models rodent

Siegel et al., Aging Cell 2013. Young (5-month) and old (27-month) mice were injected intraperitoneally with saline or 3 mg/kg SS-31. In the aged mice, resting and maximal mitochondrial ATP production, oxidative phosphorylation coupling (P/O), and cell energy state (PCr/ATP) were measured in vivo one hour after a single injection and were restored toward the values seen in young animals. Skeletal muscle of the aged mice was more fatigue-resistant in situ one hour after treatment, and eight days of treatment was associated with increased whole-animal endurance capacity^[4].

Two details that vendors leave out:

• SS-31 had no observable effect on young muscle. The effect was specific to the aged, dysfunctional state^[4].
• This is a mouse. A single intraperitoneal injection in a 27-month-old mouse is not a protocol, an indication, or an outcome. It is a rodent result, and it is the single most-misquoted finding in the SS-31 literature.

The human trials — all of them

Elamipretide has been through more randomised human testing than almost anything else in this catalogue. Here is what happened.

MMPOWER-3 — phase 3, primary mitochondrial myopathy human

A pivotal, phase 3, randomised, double-blind, placebo-controlled trial. 218 participants with genetically confirmed primary mitochondrial myopathy were randomised 1:1 to subcutaneous elamipretide 40 mg/day or placebo for 24 weeks. Co-primary endpoints: distance walked on the six-minute walk test, and total fatigue score^[5].

The trial did establish that subcutaneous elamipretide was well tolerated, with most adverse events mild to moderate^[5]. A later post-hoc analysis in Orphanet Journal of Rare Diseases explored genotype-specific subgroups of the same failed trial^[9] — which is what investigators do after a primary endpoint misses, and which is hypothesis-generating, not confirmatory.

PROGRESS-HF — phase 2, heart failure human

71 patients with heart failure and reduced ejection fraction were randomised 1:1:1 to placebo, 4 mg, or 40 mg elamipretide daily for 28 days, with cardiac MRI endpoints. The change in left ventricular end-systolic volume was not significantly different from placebo in either dose arm (4 mg vs placebo: difference of means −0.3, 95% CI −4.6 to 4.0, p = 0.90; 40 mg vs placebo: 2.3, 95% CI −1.9 to 6.5, p = 0.28). No significant differences in ejection fraction either. Adverse event rates were similar across the three groups^[6].

ReCLAIM-2 — phase 2, dry age-related macular degeneration human

176 patients randomised to daily subcutaneous elamipretide 40 mg or placebo for 48 weeks. The trial did not meet statistical significance for either primary endpoint (mean change in low-luminance best-corrected visual acuity; mean change in square-root-converted geographic atrophy area)^[7].

Secondary and exploratory analyses reported a 43% reduction in progression of ellipsoid zone attenuation versus placebo (nominal p = 0.0034) — the authors state this surrogate endpoint will serve as the primary endpoint in a subsequent phase 3 programme^[7]. Read that carefully: a nominal p-value on a secondary endpoint, in a trial whose primary endpoints failed, is a hypothesis. It is not a result. Adverse events were reported in 86% of the elamipretide group versus 71% of placebo, most commonly injection site reactions^[7].

TAZPOWER — Barth syndrome human

The one place elamipretide has produced sustained positive human data is Barth syndrome, a rare genetic disorder of cardiolipin remodelling — i.e. the one condition where the drug’s exact molecular target is the thing that is broken. TAZPOWER was a 28-week randomised, double-blind, placebo-controlled trial followed by a 168-week open-label extension. Ten patients entered the extension; eight reached week 168. Cumulative improvement on the six-minute walk test was 96.1 metres at week 168 (p = 0.003), with improvements in fatigue scores and echocardiographic parameters^[8].

The trials that failed

Set out plainly, because nobody selling this compound will:

• MMPOWER-3 (phase 3, n=218) — both co-primary endpoints missed. Class I evidence of no effect^[5].
• PROGRESS-HF (phase 2, n=71) — primary imaging endpoint missed at both doses^[6].
• ReCLAIM-2 (phase 2, n=176) — both primary endpoints missed^[7].

Three randomised, placebo-controlled trials, in three different conditions, all missing their pre-specified primary endpoints. The mechanism is real and well-characterised. The clinical translation has, so far, largely not happened. Those are not contradictory statements — they are the normal state of drug development, and this compound is a textbook illustration of it.

Limitations of the literature

The mechanistic literature is concentrated. The foundational mechanistic work — including both 2014 British Journal of Pharmacology papers and the 2018 review — originates from Hazel Szeto’s group^[1][2][3]. That does not make the work wrong. It does mean the mechanism has had less fully independent replication than the volume of citations suggests.

The clinical trials share a sponsor. MMPOWER-3, PROGRESS-HF, ReCLAIM-2 and TAZPOWER were all run with Stealth BioTherapeutics involvement, with company employees appearing as co-authors and named in conflict-of-interest statements on all four^[5][6][7][8]. Note that this sponsor published its own failures. That is to its credit, and it is why this page can be written at all.

Preclinical breadth is not clinical depth. A compound showing an effect in twenty different rodent models is showing you twenty rodent results, not mounting human evidence. In elamipretide’s case, the human evidence exists — and it is largely negative.

Regulatory and anti-doping status

Regulatory status has changed recently and you should verify it yourself. PubChem’s synonym record for CID 11764719 now includes a trade name (Forzinity) alongside the development codes, which is consistent with elamipretide having received a narrow regulatory approval for Barth syndrome — the one indication where its randomised and open-label data are positive^[10]. We have not independently confirmed the scope, date, or conditions of that approval, and we are not going to characterise it beyond what we can verify. Check Drugs@FDA directly^[11].

What is unambiguous: elamipretide has not been approved for mitochondrial myopathy, heart failure, or macular degeneration — the three indications where its trials read out negative^[5][6][7]. And whatever the approval status of the branded product, the material sold on this page is not it: it is bulk research material with no NDA, no pharmacy chain of custody, and no prescribing information.

WADA status appears as a neutral data line in the specification block above — Not listed — in the same register as the CAS number. Anti-doping lists change annually and by governing body. If you compete under any tested organisation, the only reliable source is that organisation’s current prohibited list — not this page, and not any vendor’s.

What we don’t know

• Why a mechanism this well-characterised failed in three randomised trials. Nobody has answered that.
• Whether the ellipsoid-zone surrogate endpoint from ReCLAIM-2 will replicate as a primary endpoint in phase 3^[7].
• Whether anything observed in Barth syndrome — a disorder of the drug’s exact molecular target, in eight open-label patients — generalises to any other population. There is no evidence that it does^[8].
• Long-term safety outside the trial populations above.
• Per-kilogram dosing in rodents does not scale to humans, and nothing on this page should be read as implying that it does.

We supply this compound for laboratory research. The cardiolipin mechanism is one of the most interesting stories in mitochondrial pharmacology. It is also a story whose human chapters have mostly ended in a null result, and we are not going to pretend otherwise.