Elamipretide (SS-31)

Elamipretide is a Szeto-Schiller (SS) peptide, one of a family of short peptides that alternate aromatic and basic amino acids. Its dimethyltyrosine residue gives it antioxidant properties, and the peptides concentrate about 1,000-fold in the inner mitochondrial membrane [1]. It is developed by Stealth BioTherapeutics [3].

Barth syndrome. This rare genetic disorder of cardiolipin was where it was finally approved. In TAZPOWER, 12 patients took 40 mg a day or placebo for 12 weeks each, and neither primary endpoint improved. In the open-label extension, walking distance improved by 95.9 m at 36 weeks [4], an improvement that was sustained to 168 weeks in the 8 patients who got that far [8]. It then received US accelerated approval in September 2025 to improve muscle strength, the first treatment specific to Barth syndrome [3].

Primary mitochondrial myopathy. A 5-day intravenous trial showed a dose-dependent gain in walking distance [9]. A 4-week subcutaneous crossover trial missed its walking endpoint but improved fatigue scores [10]. The pivotal phase 3 trial, MMPOWER-3 (218 patients, 24 weeks), found no effect on walking distance (-3.2 m vs placebo) or fatigue [5].

Heart and kidney. In the EMBRACE STEMI trial, an infusion during primary angioplasty did not reduce infarct size or improve imaging or clinical outcomes [6]. A single high-dose infusion in heart failure with reduced ejection fraction briefly shrank left-ventricular volumes [11]. In a 14-patient pilot, adding it to renal artery stenting improved kidney blood flow and function at 3 months [12].

Eye. In dry macular degeneration (ReCLAIM-2, 176 patients, 48 weeks), it missed both primary endpoints but slowed loss of the ellipsoid zone, a marker of photoreceptor damage [7]. Phase 3 trials in macular degeneration and mitochondrial myopathy are under way [3].

Cardiolipin is a phospholipid of the inner mitochondrial membrane, and cristae need it to form. Elamipretide binds it with high affinity. The complex blocks the peroxidase activity of cytochrome c, which would otherwise damage cardiolipin during ischaemia. In rats, pretreatment preserved cristae in the kidney during ischaemia, and ATP recovered promptly on reperfusion [2]. Biophysical work suggests that it also sits at the membrane surface, changes its electrical charge and eases calcium stress [13].

In the original cell studies, the SS peptides reduced mitochondrial reactive oxygen species and prevented mitochondrial swelling and cytochrome c release. Versions without dimethyltyrosine did not work [1].

Given intravenously, it was safe and well tolerated in heart-attack and heart-failure trials, with stable blood pressure and heart rate [6][11]. Daily subcutaneous injections cause frequent injection-site reactions: 80% of participants in MMPOWER-2 [10], and redness in all 12 Barth patients on the drug, with 2 dropping out of the extension because of them [4]. In MMPOWER-3, 98% on elamipretide and 76% on placebo reported adverse events, mostly mild to moderate [5]. The MMPOWER-3 authors described it as generally well tolerated [5], as did the 168-week Barth extension [8].