SS-31

SS-31 is the premium-tier mitochondrial peptide in the corpus and the molecule with the most ambitious — and most informative — clinical-development program. The trial chronology that anchors the evidence base:

• Karaa 2018 MMPOWER-2 — Phase 1/2 in primary mitochondrial myopathy. Positive signal on six-minute walk test distance at 40 mg dose; the result that motivated the Phase 3 program.
• Daubert 2017 — 44-patient acute-infusion trial in heart-failure-with-reduced-ejection-fraction. Acute hemodynamic signals; the broader PROGRESS-HF Phase 3 trial in heart failure subsequently failed and was discontinued.
• MMPOWER-3 (Karaa et al., Neurology 2023) — Phase III in primary mitochondrial myopathy. Across 27 sites in seven countries, 24 weeks of subcutaneous elamipretide 40 mg/day did not improve six-minute walk test distance or the primary fatigue endpoint compared to placebo. Class I evidence that elamipretide does not improve those endpoints in unselected primary mitochondrial myopathy patients, ending Stealth BioTherapeutics' lead-indication program. A prespecified subgroup of nuclear-DNA-mitochondrial-disease patients showed apparent response signals that were not the prespecified primary outcome but informed the subsequent NuPOWER program.

The story has a partial recovery in a different rare disease. In September 2025, the FDA approved elamipretide as Forzinity for Barth syndrome — a rare X-linked cardiolipin-remodeling disorder where the cardiolipin-stabilizing mechanism of SS-31 maps directly onto the disease pathophysiology. The pivotal trial is Thompson 2021 TAZPOWER / SPIBA-201: 12 subjects, randomized 12-week crossover that missed both primary endpoints, followed by an open-label extension that produced significant 36-week gains in six-minute walk distance (+95.9 m, p=0.024), patient-reported symptom burden, and knee extensor strength. SS-31 is now an FDA-approved peptide in a rare-disease indication, with a failed Phase III in the broader myopathy indication that originally drove the development program — and a Phase 2 ReCLAIM-2 trial in dry age-related macular degeneration that also missed both primary endpoints despite producing statistically significant secondary signals on ellipsoid zone preservation.

Recent mechanistic work continues to characterize the molecule across additional injury models. Song 2026 extended the protective signal into a mouse spinal-cord-injury model, showing improved locomotor recovery, attenuated early apoptosis, and preserved mitochondrial membrane potential — consistent with the broader pattern of robust preclinical signal across mitochondrial-stress models that has not consistently translated to large-trial clinical benefit outside the narrow Barth syndrome indication.

The biohacker and longevity-research interest in SS-31 rests on different evidence: mostly preclinical work in heart failure, age-related mitochondrial decline, and ischemia-reperfusion injury, plus the broader appeal of "mitochondrial health" as a category. The honest framing here is that SS-31 has more rigorous clinical evidence behind it than nearly any peptide on this list — but the rigorous evidence is mostly negative for the broad indication, positive for a narrow one, and absent for the longevity-focused use cases that drive most current interest. The mitochondrial peptides dossier walks the broader class context.