SS-31 dosage protocol

What Elamipretide is

Elamipretide, also known as SS-31 or MTP-131, is a mitochondria-targeted tetrapeptide (PMID 39940712). Peptides are short chains of amino acids (PMID 41966639). It is currently being investigated for its therapeutic potential (PMID 39940712).

Elamipretide is identified as a potential therapeutic candidate for conditions like Age-related Macular Degeneration (AMD) and is among peptides marketed in a 'gray market' alongside approved and unapproved compounds for musculoskeletal injuries and athletic performance (PMID 34572131, PMID 41966639).

How it is thought to work

Elamipretide has a structure that allows for uptake into various cell types and highly selective targeting of mitochondria (PMID 39940712). Within mitochondria, it selectively binds to cardiolipin (CL), a lipid in the inner mitochondrial membrane (PMID 39940712).

This binding helps stabilize the structure of mitochondrial cristae, which are inner folds of the mitochondria. This action reduces oxidative stress and enhances the production of adenosine triphosphate (ATP), an energy-carrying molecule (PMID 39940712). It is also thought to prevent reactive oxygen species-induced cell damage by stabilizing the cardiolipin-cytochrome c supercomplex (PMID 35037146).

What laboratory and animal studies report

Preclinical studies have indicated protective and restorative effects of elamipretide in animal models of heart failure, neurodegeneration, ischemia-reperfusion injury, metabolic syndromes, and muscle atrophy and weakness (PMID 39940712).

In dog models of heart failure with reduced ejection fraction, elamipretide increased left ventricular ejection fraction (PMID 35037146). In rats, it prevented left ventricular remodeling (PMID 35037146).

Studies in mice showed that elamipretide significantly ameliorated lipopolysaccharide (LPS)-induced learning and memory impairment (PMID 31747905). This was associated with protective effects against mitochondrial dysfunction and oxidative stress, and facilitated the regulation of brain-derived neurotrophic factor (BDNF) signaling, reversing synaptic-signaling proteins and increasing synaptic structural complexity (PMID 31747905). LPS-treated mice exhibited mitochondrial dysfunction, oxidative stress, inflammation, neural cell apoptosis, and loss of dendritic spines in the hippocampus (PMID 31747905).

Human evidence so far

Early-phase clinical trials in humans have shown that elamipretide administration did not result in any severe adverse events (PMID 35037146). These trials also indicated promising improvements in cardiac hemodynamics at the highest doses (PMID 35037146).

However, a phase-3 clinical trial (MMPOWER-3) evaluating elamipretide for primary mitochondrial myopathy (PMM) did not meet its primary endpoints, which were changes in the 6-minute walk test (6MWT) distance and total fatigue score on the PMM Symptom Assessment (PMMSA) (PMID 37268435). The study randomized 218 participants to receive 40 mg/d elamipretide or placebo subcutaneously for 24 weeks (PMID 37268435). While well-tolerated, the difference in 6MWT distance and total fatigue score between elamipretide and placebo groups was not statistically significant (PMID 37268435).

Open questions and limitations

Additional studies are necessary to describe the long-term safety and efficacy of elamipretide (PMID 35037146). While preclinical animal models show promising outcomes, rigorous human safety data for many unapproved peptides, including elamipretide, are scarce (PMID 41966639).

The MMPOWER-3 trial highlighted that despite preclinical findings, efficacy in human trials for specific conditions like PMM requires further investigation (PMID 37268435). Further research may expand its application to other diseases involving mitochondrial dysfunction as well as investigate long-term efficacy and safety of the drug (PMID 39940712).

Key terms explained

Mitochondrial dysfunction: This refers to when mitochondria, the cell's powerhouses, do not work properly, impairing the cell's ability to produce energy (ATP) and contributing to oxidative stress (PMID 39940712, PMID 40497970).

Oxidative stress: An imbalance between the production of reactive oxygen species (ROS) and the body's ability to detoxify them, leading to cellular damage (PMID 31747905, PMID 39940712).

Cardiolipin: A lipid found in the inner mitochondrial membrane, crucial for mitochondrial function (PMID 39940712).

Left ventricular ejection fraction: A measure of how much blood the left ventricle of the heart pumps out with each contraction, used as an indicator of heart function (PMID 35037146).

Primary mitochondrial myopathy (PMM): A group of genetic disorders that impair mitochondrial oxidative phosphorylation, affecting physical function, exercise capacity, and quality of life (PMID 37268435).