SS-31 (Elamipretide)

Elamipretide is a cell-permeable tetrapeptide (D-Arg-dimethyltyrosine-Lys-Phe-NH2) that concentrates approximately 1,000-fold in mitochondria due to its affinity for cardiolipin, a phospholipid found exclusively on the inner mitochondrial membrane. By stabilizing cardiolipin-cytochrome c interactions, elamipretide optimizes electron transfer in complexes III and IV of the respiratory chain, improving ATP production efficiency and reducing electron leak that generates superoxide. This mechanism is distinct from traditional antioxidants because it prevents ROS formation at the source rather than scavenging after production. Elamipretide also preserves cristae structure and inhibits the mitochondrial permeability transition pore.

The TAZPOWER Phase 2 trial in Barth syndrome (Thompson et al., 2021) showed trends toward improvement in 6-minute walk test but did not achieve statistical significance (n=12). The RESTORE-HF Phase 2 trial in HFpEF (Butler et al., 2023) did not meet its primary endpoint. A Phase 2 trial in AMD showed some signal for improvement in low-luminance visual acuity. The MMPOWER Phase 3 trial in primary mitochondrial myopathy also did not meet its primary endpoint. Despite these setbacks, open-label extension data suggest durable benefits in subsets of patients, and development continues.

Elamipretide is an investigational drug developed by Stealth BioTherapeutics (now Larimar Therapeutics). It has not received FDA or EMA approval. Multiple clinical trials have been conducted under IND. The FDA granted Fast Track designation for Barth syndrome. Development is ongoing despite mixed Phase 2/3 results. Grey-market versions are not available from the manufacturer.

Standard cardiac monitoring (echocardiography, BNP/NT-proBNP) for heart failure indications. Six-minute walk test for functional assessment. Ophthalmologic examination for AMD indications. Injection site assessment. No specific laboratory monitoring required based on trial data.

These are general considerations for clinical awareness and do not constitute prescriptive monitoring recommendations for any individual patient.

Investigational product supplied as a sterile solution for subcutaneous injection. Pharmaceutical-grade preparation. Store refrigerated at 2 to 8 degrees C. Protect from light. Do not freeze. Stability data are maintained in clinical trial documentation but not publicly available.

1. 1

   RCT

   Elamipretide in Patients with Barth Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial (TAZPOWER)

   Thompson WR, Hornby B, Manuel R, et al. (2021). Genetics in Medicine

   Key findings: Phase 2 trial in Barth syndrome patients showed improvement in 6-minute walk test distance and patient-reported outcomes. Statistical significance was not achieved on the primary endpoint but trends were favorable.

   Limitations: Small sample size due to rare disease (n=12). Did not meet primary endpoint. Open-label extension ongoing.

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2. 2

   RCT

   Elamipretide in Heart Failure with Preserved Ejection Fraction: Results of the RESTORE-HF Trial

   Butler J, Khan MS, Anker SD, et al. (2023). European Heart Journal

   Key findings: Phase 2 trial of elamipretide in HFpEF did not meet the primary endpoint of change in left ventricular end-diastolic volume. Some secondary endpoints trended favorably.

   Limitations: Failed primary endpoint. Moderate sample size. Questions about patient selection and dosing.

3. 3

   review

   Mitochondria-Targeted Peptide SS-31 (Elamipretide): Pharmacology and Clinical Development

   Szeto HH, Birk AV. (2014). British Journal of Pharmacology

   Key findings: Review of SS-31 mechanism including selective binding to cardiolipin on the inner mitochondrial membrane, stabilization of electron transport chain complexes, and reduction of reactive oxygen species generation.

   Limitations: Early clinical development review. Most data preclinical at time of publication.

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