Elamipretide (DB11981): A Comprehensive Monograph on a First-in-Class Mitochondrial-Targeted Tetrapeptide

Executive Summary

Elamipretide (DrugBank ID: DB11981) is an investigational, first-in-class, mitochondria-targeted therapeutic agent representing a novel paradigm in addressing diseases rooted in cellular bioenergetic failure. A synthetic aromatic-cationic tetrapeptide, Elamipretide was engineered to selectively target and interact with cardiolipin, a phospholipid unique to the inner mitochondrial membrane that is critical for maintaining mitochondrial structure and function. Its mechanism of action is fundamentally restorative; by binding to and stabilizing cardiolipin, Elamipretide improves the integrity of the electron transport chain, enhances adenosine triphosphate (ATP) production, and reduces the generation of damaging reactive oxygen species (ROS). This action is most pronounced in dysfunctional mitochondria, with minimal effect on healthy organelles, conferring a favorable safety profile.

The therapeutic rationale for Elamipretide is exceptionally broad, leading to an ambitious and complex clinical development program spanning multiple indications. These include ultra-rare genetic disorders such as Barth syndrome (BTHS) and primary mitochondrial myopathy (PMM), as well as common, age-related diseases like dry age-related macular degeneration (dry AMD) and heart failure. Across these varied conditions, the clinical trial results have been mixed. While the drug has consistently demonstrated excellent safety and tolerability, it has often failed to meet primary endpoints in large, heterogeneous patient populations. A recurring theme in its development has been the post-hoc identification of responsive patient subgroups or alternative endpoints that have justified continued, more targeted investigation.