SS-31 (elamipretide): the mitochondrial peptide that reached FDA

Key points

• SS-31 binds selectively to cardiolipin and, in experimental models, protects mitochondrial cristae and oxidative phosphorylation [2].
• On September 19, 2025, FDA granted accelerated approval to Forzinity (elamipretide) as the first treatment for Barth syndrome, in patients weighing at least 30 kg [1].
• In the TAZPOWER open-label extension, 8 of 10 patients reached week 168, with a cumulative 96.1 m improvement in the 6-minute walk test [4].
• The phase 3 MMPOWER-3 trial in primary mitochondrial myopathy (218 participants) missed its primary endpoints [7].
• In dry macular degeneration, the phase 2 ReCLAIM-2 trial missed its primary endpoints but was associated with less photoreceptor loss, now the primary endpoint of the phase 3 ReNEW trial [9][10].

US status (October 2026): Elamipretide is FDA-approved as Forzinity under accelerated approval, for Barth syndrome in patients weighing at least 30 kg, with a confirmatory trial required [1]. See the peptide status tracker.

SS-31 targets cardiolipin

Cardiolipin is a phospholipid found only in the inner mitochondrial membrane. It shapes the cristae and organizes the respiratory complexes into supercomplexes for efficient oxidative phosphorylation. Its interaction with cytochrome c decides whether cytochrome c acts as an electron carrier or as a membrane-damaging peroxidase [2].

SS-31 (elamipretide, formerly MTP-131 or Bendavia) is a tetrapeptide of the Szeto-Schiller family that concentrates in the inner mitochondrial membrane. According to a review by Hazel Szeto, whose name the family carries, it binds cardiolipin through electrostatic and hydrophobic interactions, prevents cytochrome c from turning into a peroxidase and preserves its electron-carrying function. As a result, it protects the cristae and promotes oxidative phosphorylation [2]. In 27-month-old mice, a single dose restored muscle mitochondrial energetics to young levels within one hour, and 8 days of treatment increased exercise endurance [11].

“SS-31 represents a new class of compounds that can recharge the cellular powerhouse and restore bioenergetics.” (Hazel H. Szeto, Br J Pharmacol, 2014 [2])

Barth syndrome went from a negative crossover to approval

Barth syndrome is a rare, serious mitochondrial disease that mainly affects males. It typically starts with heart failure in infancy, and those who reach adolescence and adulthood live with fatigue, poor stamina and exercise intolerance [1]. It is caused by defects in the TAZ gene that disrupt cardiolipin, the exact target of SS-31 [3].

The TAZPOWER trial began with a randomized, double-blind, placebo-controlled crossover in 12 participants (40 mg/day for 12 weeks per arm). In that first part neither primary endpoint was met. In the open-label extension, at 36 weeks there were significant improvements in the 6-minute walk test (+95.9 m, p = 0.024) and in the BTHS-SA symptom scale (-2.1 points, p = 0.031) [3]. Long-term follow-up was consistent: 8 of 10 patients reached week 168, with a cumulative +96.1 m (P = .003), improvements in left ventricular volumes and in the monolysocardiolipin/cardiolipin ratio, and good tolerability. Injection-site reactions were the most common adverse event [4].

• +96.1 m: 6-minute walk at week 168 in TAZPOWER [4]
• 218: participants in MMPOWER-3, which missed its primary endpoints [7]
• 43%: less progression of ellipsoid zone loss in ReCLAIM-2 (nominal P) [9]

FDA approved a narrow indication on a surrogate measure

On September 19, 2025, FDA granted accelerated approval to Forzinity (elamipretide) injection as the first treatment for Barth syndrome, in patients weighing at least 30 kg. It is given subcutaneously once daily. The approval was based on improved strength of the knee extensor muscle, a measure the agency considers reasonably likely to predict clinical benefit, such as standing more easily or walking farther. As a condition, FDA requires a post-approval randomized, double-blind, placebo-controlled trial [1]. That trial, 4TAZPower (phase 3b/4, 72 weeks), started in July 2026, with 48 planned participants and estimated primary completion in 2029 [5].

Elamipretide is the first cardiolipin-directed drug approved by FDA [15]. For mitochondrial peptides as a class, Barth syndrome served as proof of concept: a disease caused by abnormal cardiolipin responded to a peptide that binds cardiolipin [1][3][4].

Mitochondrial myopathy produced a negative phase 3 and a genetic clue

In primary mitochondrial myopathy, the MMPOWER-2 crossover (30 participants, 4 weeks per arm) showed a 19.8 m difference in the 6-minute walk that was not significant (P = 0.0833), although participants reported less fatigue (P = 0.0006) [6]. The phase 3 MMPOWER-3 trial randomized 218 adults for 24 weeks and missed its primary endpoints: the difference versus placebo was -3.2 m on the walk test (p = 0.69). Treatment was well tolerated [7].

A post hoc analysis found a signal in one subgroup. In patients with mitochondrial DNA replisome variants (mainly POLG and TWNK), the walk improved by 25.2 m versus 2.0 m on placebo (p = 0.06), and in those who also had chronic progressive external ophthalmoplegia, by 37.3 m versus -8.0 m (p = 0.0024) [8]. Being post hoc, it generates hypotheses. The authors used it to design the NuPOWER trial in that population [8].

The eye and heart trials missed their primary endpoints

In dry age-related macular degeneration with geographic atrophy, the phase 2 ReCLAIM-2 trial randomized 176 patients for 48 weeks. It did not reach significance on its primary endpoints (low-luminance visual acuity and atrophy growth), but was associated with 43% less progression of total ellipsoid zone loss (nominal P = 0.0034) and more patients gaining 10 or more letters (14.6% versus 2.1%). Adverse events occurred in 86% versus 71% on placebo, mostly injection-site reactions [9]. That photoreceptor loss is the primary endpoint of the phase 3 ReNEW trial, with 313 participants and estimated primary completion in 2027 [10].

In heart failure with reduced ejection fraction, a single 4-hour infusion at the highest dose was associated with reductions in left ventricular end-diastolic (-18 mL) and end-systolic (-14 mL) volume versus placebo, with no serious adverse events [12]. The phase 2 PROGRESS-HF trial (71 patients, 4 weeks of daily subcutaneous dosing) did not improve end-systolic volume [13]. In ST-elevation myocardial infarction, the EMBRACE STEMI trial did not reduce infarct size, although it was safe and well tolerated [14].

The evidence ends at Barth syndrome

The approval is narrow (one ultra-rare disease, patients of at least 30 kg), provisional (accelerated, based on a muscle-strength measure, with a confirmatory trial pending) and rests on small trials whose initial controlled part was negative [1][3][5]. Outside Barth syndrome, the controlled trials in mitochondrial myopathy (phase 3), heart failure and myocardial infarction (phase 2) missed their primary endpoints [7][13][14]. The muscle and cardiac aging data come from mice [11].

What is established: SS-31 is the first cardiolipin-directed drug with FDA approval [15], with a well-characterized laboratory mechanism and a consistent tolerability profile across several trials, where injection-site reaction was the most common event. FDA also notes that serious reactions have been reported [1][2][4][7].

What this means for you

When a patient asks about SS-31 for energy or aging, the approval does not cover that use, and the trials outside Barth syndrome were negative. A vial sold as “SS-31” under a research use only label is not Forzinity. How it compares with other longevity compounds, including MOTS-c, is covered in Epitalon, MOTS-c, NAD+ and SS-31. For how MDside reviews peptide requests, see peptide programs.

References

1. U.S. Food and Drug Administration. FDA grants accelerated approval to first treatment for Barth syndrome. 19 September 2025. Link
2. Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014;171(8):2029-50. PMID 24117165. Link
3. Reid Thompson W, et al. A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism. Genet Med. 2021;23(3):471-478. PMID 33077895. Link
4. Thompson WR, et al. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. Genet Med. 2024;26(7):101138. PMID 38602181. Link
5. ClinicalTrials.gov. NCT07531251. Phase 3b/4 trial of elamipretide in genetically confirmed Barth syndrome (4TAZPower). Link
6. Karaa A, et al. A randomized crossover trial of elamipretide in adults with primary mitochondrial myopathy. J Cachexia Sarcopenia Muscle. 2020;11(4):909-918. PMID 32096613. Link
7. Karaa A, 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. PMID 37268435. Link
8. Karaa A, 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. PMID 39574155. Link
9. Ehlers JP, 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. 2025;5(1):100628. PMID 39605874. Link
10. ClinicalTrials.gov. NCT06373731. ReNEW: phase 3 study of subcutaneous elamipretide in dry age-related macular degeneration. Link
11. Siegel MP, et al. Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell. 2013;12(5):763-71. PMID 23692570. Link
12. Daubert MA, et al. Novel mitochondria-targeting peptide in heart failure treatment: a randomized, placebo-controlled trial of elamipretide. Circ Heart Fail. 2017;10(12). PMID 29217757. Link
13. Butler J, et al. Effects of elamipretide on left ventricular function in patients with heart failure with reduced ejection fraction: the PROGRESS-HF phase 2 trial. J Card Fail. 2020;26(5):429-437. PMID 32068002. Link
14. Gibson CM, et al. EMBRACE STEMI study: a phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention. Eur Heart J. 2016;37(16):1296-303. PMID 26586786. Link
15. Zhao C, et al. Elamipretide: the first cardiolipin-directed mitochondrial therapeutic for Barth syndrome approved under accelerated approval. Drug Discov Ther. 2026;19(6):435-436. PMID 41260682. Link

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