NAD+ and SS-31 — two routes to the mitochondrion, two very different evidence bases
Both are pitched at the mitochondrion, and there the resemblance ends. Almost every human figure quoted for NAD+ comes from a trial of an oral precursor, while SS-31 has a Phase 3 trial that missed both its primary endpoints — and that miss is the more informative result.
Two compounds in this catalogue are aimed at the same organelle. NAD+ and SS-31 are both discussed in terms of mitochondrial function and ageing, and past that they have almost nothing in common — not their chemistry, not their proposed mechanism, and least of all the kind of evidence that exists about them.
SS-31, known by its international nonproprietary name elamipretide, has been through a placebo-controlled Phase 3 trial in 218 adults with primary mitochondrial myopathy. The trial met neither of its two primary endpoints (1). Nothing of that shape exists for NAD+, and the reason is stranger than it first looks: almost the entire human literature on NAD+ studies something else — the oral precursors nicotinamide riboside and nicotinamide mononucleotide.
That asymmetry is the subject of this post. A failed Phase 3 trial and an untested mechanism are not two grades of the same thing. They sit on different axes, and the failed trial is by a distance the more informative of the two.
218
Adults randomised in the Phase 3 myopathy trial
elamipretide 40 mg/day · 24 weeks (1)
−3.2 m
Difference from placebo, six-minute walk test
primary endpoint · p = 0.69 (1)
142%
Whole-blood NAD+ rise on an oral precursor
nicotinamide riboside 1000 mg · 2 weeks (5)
2025
First approval for elamipretide, in Barth syndrome
accelerated approval · United States (10, 12)
NAD+ is a coenzyme, not a peptide
The catalogue lists NAD+ beside a shelf of peptides, and it is worth saying plainly that it does not belong to that class. Nicotinamide adenine dinucleotide is a dinucleotide coenzyme present in every cell. Nobody designed it against a target.
It carries electrons through redox reactions, and separately it is consumed as a substrate by sirtuins and the other NAD+-dependent enzymes. It is not an agonist of anything. It is part of the machinery rather than a signal sent to it.
That distinction changes how the literature should be read. Of a peptide, the question is what it binds. Of NAD+, the question is whether its concentration can be moved at all, and whether moving it changes anything downstream.
What the human work actually administered
NR
Nicotinamide riboside
An oral precursor. In an 8-week placebo-controlled trial in healthy overweight adults, 100 mg, 300 mg and 1000 mg daily raised whole-blood NAD+ by 22%, 51% and 142% respectively within two weeks (5). A crossover trial gave 12 aged men 1 g daily for 21 days and reported a raised skeletal-muscle NAD+ metabolome with no change in muscle bioenergetics (6). A 12-week trial at 2000 mg daily in obese, insulin-resistant men reported no improvement in insulin sensitivity or whole-body glucose metabolism (7).
NMN
Nicotinamide mononucleotide
The other oral precursor. In a 60-day trial, 80 healthy middle-aged adults took placebo, 300 mg, 600 mg or 900 mg daily; blood NAD concentrations rose in every NMN group at day 30 and day 60 against both placebo and baseline, all at p ≤ 0.001 (8). The read-out there is a concentration, and a concentration is not an outcome.
NAD+
NAD+ itself
Far less. A pilot study infused NAD+ intravenously at 3 μmol/min over six hours and reported no change in plasma NAD+ or its metabolites until after the second hour, a pattern the authors read as rapid and complete removal from plasma (9). That is a pharmacokinetic observation, not a trial with clinical endpoints.
Check which molecule was in the trial
Almost every human figure quoted for NAD+ comes from a trial of nicotinamide riboside or nicotinamide mononucleotide taken by mouth, not from NAD+ given directly. The three are related but they are not the same compound, and a precursor trial cannot answer what NAD+ itself does. Every NAD+ figure on this page names the compound that was actually administered.
SS-31 binds a lipid, not a receptor
SS-31 is a tetrapeptide built from alternating cationic and aromatic residues, and its proposed mechanism is unusual. Rather than docking into a receptor, it concentrates in the inner mitochondrial membrane and binds cardiolipin, the phospholipid that gives that membrane its folded shape.
Birk and colleagues reported in 2013 that SS-31 binds cardiolipin with high affinity, inhibits cytochrome c peroxidase activity and prevents cardiolipin peroxidation, and that pretreatment protected cristae membranes and preserved ATP recovery on reperfusion in a renal ischaemia model (4).
A lipid target rather than a receptor target is a genuinely different design, and it is the part of the SS-31 story told most often. It is also the part that carries the least weight, because a mechanism describes what a molecule might do, while only a trial reports what happened when it was given.
What elamipretide has been tested in
- Primary mitochondrial myopathy — MMPOWER-3
- Phase 3, randomised, double-blind, placebo-controlled. 218 participants with genetically confirmed disease, 40 mg/day subcutaneously for 24 weeks. Neither primary endpoint was met: −3.2 m on the six-minute walk test (p = 0.69) and −0.07 on the total fatigue score (p = 0.37) (1).
- Barth syndrome — TAZPOWER
- Phase 2/3 crossover, 12 subjects, 40 mg/day for 12 weeks per arm with a 4-week washout. The randomised part did not meet its primary endpoints; the open-label part reported +95.9 m on the six-minute walk test (p = 0.024) and −2.1 points on the symptom assessment at 36 weeks (2).
- Dry age-related macular degeneration — ReCLAIM-2
- Phase 2, 176 randomised — 117 elamipretide, 59 placebo. The primary endpoints on visual acuity and atrophy area were not met; the trial reported a 43% reduction in mean progression of ellipsoid zone loss and a 47% reduction on partial attenuation, the latter at a nominal p = 0.0040 (3).
- After MMPOWER-3 — post hoc analysis
- In participants carrying mtDNA replisome variants together with chronic progressive external ophthalmoplegia, the same trial's post hoc analysis reported 37.3 m on the six-minute walk test at week 24 against −8.0 m for placebo (p = 0.0024). It is a subgroup finding from a trial that missed its primary endpoints, and it was used to design a further trial rather than to claim a result (11).
NAD+ and SS-31 side by side
The two have never been compared in the same trial, and nothing in this table is a head-to-head result. Each column reports what has been published about that compound on its own, and the two literatures differ so much in kind that most rows are descriptions rather than numbers.
| Parameter | NAD+ | SS-31 (elamipretide) |
|---|---|---|
| What it is | A dinucleotide coenzyme present in every cell — not a peptide, and not designed against a target | A synthetic tetrapeptide of alternating cationic and aromatic residues, also called elamipretide |
| Proposed mechanism | Substrate and electron carrier: consumed in redox reactions and by sirtuins and other NAD+-dependent enzymes | Binds cardiolipin in the inner mitochondrial membrane rather than acting at a receptor (4) |
| What has actually been tested in humans | Almost entirely the oral precursors nicotinamide riboside and nicotinamide mononucleotide; NAD+ given directly appears mainly as small pharmacokinetic work (5, 6, 7, 8, 9) | The compound itself, given subcutaneously, in randomised placebo-controlled trials in three separate conditions (1, 2, 3) |
| Highest trial phase reached | No trial of NAD+ itself past small pharmacokinetic work; the precursor trials cited here are small randomised trials in healthy volunteers and metabolic populations (5, 6, 7, 8, 9) | Phase 3, in primary mitochondrial myopathy — 218 adults over 24 weeks (1) |
| Outcome at that level | Blood NAD+ rises on precursor dosing; functional and metabolic read-outs are mixed, with a 12-week trial at 2000 mg NR daily reporting no improvement in insulin sensitivity (5, 7, 8) | Neither primary endpoint met at 24 weeks — −3.2 m on the six-minute walk test (p = 0.69) and −0.07 on total fatigue (p = 0.37) (1) |
| Regulatory status | Research use only. None of the work cited above supports a marketing authorisation, and Peptio is not a pharmacy. | Approved in the United States on 19 September 2025 under accelerated approval as FORZINITY, to improve muscle strength in adult and paediatric patients with Barth syndrome weighing at least 30 kg, on the basis of knee extensor muscle strength as an intermediate endpoint; continued approval is contingent on verification of clinical benefit in a confirmatory trial (10, 12). |
Sources. (1) Karaa A, Bertini E, Carelli V, et al. Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial. Neurology. 2023;101(3):e238–e252. (2) Reid Thompson W, Hornby B, Manuel R, et al. A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome. Genet Med. 2021;23(3):471–478. (3) Ehlers JP, Hu A, Boyer D, et al. ReCLAIM-2: A Randomized Phase II Clinical Trial Evaluating Elamipretide in Age-related Macular Degeneration, Geographic Atrophy Growth, Visual Function, and Ellipsoid Zone Preservation. Ophthalmol Sci. 2024;5(1):100628. (4) Birk AV, Liu S, Soong Y, et al. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol. 2013;24(8):1250–1261. (5) Conze D, Brenner C, Kruger CL. Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Sci Rep. 2019;9(1):9772. (6) Elhassan YS, Kluckova K, Fletcher RS, et al. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Cell Rep. 2019;28(7):1717–1728.e6. (7) Dollerup OL, Christensen B, Svart M, et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Am J Clin Nutr. 2018;108(2):343–353. (8) Yi L, Maier AB, Tao R, et al. The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. Geroscience. 2023;45(1):29–43. (9) Grant R, Berg J, Mestayer R, et al. A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD+. Front Aging Neurosci. 2019;11:257. (10) FORZINITY (elamipretide) prescribing information. Stealth BioTherapeutics Inc.; 2025. (11) Karaa A, Bertini E, Carelli V, et al. Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial. Orphanet J Rare Dis. 2024;19(1):431. (12) Zhao C, Zhuang X, Gao J. Elamipretide: The first cardiolipin-directed mitochondrial therapeutic for Barth syndrome approved under accelerated approval. Drug Discov Ther. 2026;19(6):435–436. The approved product named above is a prescription medicine and is not the material Peptio supplies.
Reading the two evidence bases
| Correct | Common mistake |
|---|---|
| Name the compound a figure came from — nicotinamide riboside, nicotinamide mononucleotide, or NAD+ itself. | Quote a precursor result as though NAD+ had been administered. It is the single most blurred point in this category. |
| Read a missed primary endpoint as a result: a well-powered trial answered the question it asked. | Read it as an absence of evidence, or as a trial still waiting to happen. |
| Treat a post hoc subgroup finding as a hypothesis for the next trial. | Treat it as the trial's conclusion — MMPOWER-3 reported its subgroup analyses alongside primary endpoints it did not meet (1, 11). |
| Check the population, the endpoint and the duration before setting two figures beside each other. | Compare a walk-test distance in mitochondrial myopathy with a blood NAD+ percentage in healthy volunteers as though they measured the same thing. |
| Note how narrow an approval can be: one ultra-rare disease, one weight threshold, one intermediate endpoint (10). | Read an accelerated approval in Barth syndrome as evidence about mitochondrial ageing in general. |
More mechanism is not more evidence
The two compounds invert each other. SS-31 has the tidier mechanism story and the worse headline result. NAD+ has the more intuitive premise — a coenzyme that falls with age, topped back up — and almost no direct human data standing behind it.
It is worth being exact about what MMPOWER-3 bought. A randomised, placebo-controlled Phase 3 trial in 218 adults returned a difference of −3.2 m on a six-minute walk, at p = 0.69 (1). That figure closes a question. It says that at 40 mg/day over 24 weeks, in a genetically mixed myopathy population, the compound did not move the endpoints the trial was built to move. Nothing in the NAD+ literature answers a question of that shape, because no trial of that shape has been run on NAD+ itself.
The convenient reading — that a compound with no failures behind it is doing better than one with a public failure — has it backwards. An untested compound has no failures because it has no results. Mechanism and evidence are different axes, and only one of them can be wrong in a way that anyone finds out about.
Research use only
Peptio supplies NAD+ in 100 mg and 500 mg vials and SS-31 in 10 mg and 20 mg vials, for research use only — not for human or veterinary consumption, and not as medicines. Elamipretide holds an accelerated approval in the United States for one ultra-rare indication under a prescription brand name; the material shipped here is a research compound and is not that product. Peptio is not a pharmacy. Every figure above describes participants in a published trial, and none of it is guidance for use in people.