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

A molecule aimed at 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 peroxidase².

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 Szeto-Schiller peptide 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 phosphorylation². 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 endurance¹¹.

Barth syndrome: 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 intolerance¹. It is caused by defects in the TAZ gene that disrupt cardiolipin: the exact target of SS-31³.

The TAZPOWER trial began with a randomized, double-blind, placebo-controlled crossover in 12 study subjects (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 event⁴.

What exactly the FDA approved

On 19 September 2025 the 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, the FDA requires a post-approval randomized, double-blind, placebo-controlled trial¹. That trial, 4TAZPower (phase 3b/4, 72 weeks), started in July 2026, with 48 planned participants and estimated primary completion in 2029⁵.

Primary mitochondrial myopathy: 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 tolerated⁷.

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 population⁸.

Eye and heart: what the trials showed

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% vs 2.1%). Adverse events occurred in 86% vs 71% on placebo, mostly injection-site reactions⁹. That photoreceptor loss is the primary endpoint of the phase 3 ReNEW trial, with 313 participants and estimated primary completion in 2027¹⁰.

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 events¹². However, the phase 2 PROGRESS-HF trial (71 patients, 4 weeks of daily subcutaneous dosing) did not improve end-systolic volume¹³. In ST-elevation myocardial infarction, the EMBRACE STEMI trial did not reduce infarct size, although it was safe and well tolerated¹⁴.

Where the evidence ends

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 negative¹³⁵. Outside Barth syndrome, the controlled trials in mitochondrial myopathy (phase 3), heart failure and myocardial infarction (phase 2) missed their primary endpoints⁷¹³¹⁴. The muscle and cardiac aging data come from mice¹¹. How it compares with other longevity compounds is covered in Epitalon, MOTS-c, NAD+ and SS-31: longevity between promise and proof.

What is established is that SS-31 is the first cardiolipin-directed drug with FDA approval¹⁵, with a well-characterized laboratory mechanism and a consistent tolerability profile across several research protocols, where injection-site reaction was the most common event; the FDA also notes that serious reactions have been reported¹²⁴⁷. For investigators interested in bioenergetics, the product page is at SS-31.