SS-31

Overview

SS-31 (elamipretide) is a mitochondria-targeted tetrapeptide (D-Arg-Dmt-Lys-Phe-NH2) developed by Hazel Szeto (Cornell) and clinically advanced by Stealth BioTherapeutics. It concentrates in the inner mitochondrial membrane by binding cardiolipin. In September 2025, the FDA granted accelerated approval to elamipretide (brand name FORZINITY) as the first therapy for Barth syndrome — the first FDA-approved mitochondria-targeted drug. It remains investigational for other indications.

Mechanism of Action

SS-31 selectively binds cardiolipin in the inner mitochondrial membrane and stabilizes the cytochrome c / cardiolipin complex. This preserves cristae structure and electron transport chain supercomplex organization, improving ATP production and preventing cytochrome c peroxidase activity that generates ROS at the source. It is not a conventional free-radical scavenger — the mechanism is cardiolipin-binding and ETC stabilization.

Research Summary

FDA accelerated approval in Sep 2025 (FORZINITY) for Barth syndrome, based on the TAZPOWER trial (NCT03098797) and its 168-week open-label extension showing sustained improvement in knee-extensor strength and 6-minute walk test. Clinical results in other indications have been mixed: the Phase 3 MMPOWER-3 trial in primary mitochondrial myopathy FAILED its co-primary endpoints (6MWT and fatigue score) in 2023, though a post-hoc nuclear-DNA subgroup showed benefit. Phase 2 ReCLAIM-2 in dry AMD / geographic atrophy missed its primary endpoints but showed secondary signals on ellipsoid-zone preservation; a Phase 3 is underway. Earlier trials in heart failure (PROGRESS-HF) and LHON produced modest or mixed results.

Dosing Information

Reported Side Effects

• Injection site reactions (most common; can be managed with oral antihistamines or topical corticosteroids)
• Transient blurred vision (ocular)
• Headache
• Nausea
• Diarrhea

Research References

• Zhao K et al. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury (original SS-peptide report, J Biol Chem) (2004)
• Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics (Br J Pharmacol review) (2014)
• Karaa A et al. Efficacy and Safety of Elamipretide in Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial (Neurology) (2023)
• Thompson WR et al. Long-term efficacy and safety of elamipretide in Barth syndrome: 168-week open-label extension of TAZPOWER (Genet Med) (2024)
• Stealth BioTherapeutics announces FDA accelerated approval of FORZINITY (elamipretide) for Barth syndrome (press release, Sep 2025) (2025)