Elamipretide

Mechanism (as reported)

Research describing elamipretide as selectively targeting mitochondria reports that it binds cardiolipin in the inner mitochondrial membrane, with downstream findings reported to include stabilization of mitochondrial cristae structure, reduction of oxidative stress, and enhancement/improvement of ATP production or mitochondrial bioenergetics. (PMIDs: 39940712, 32680996) Additional cell-based research using live-cell imaging reported that elamipretide moderated the kinetics of BAX recruitment in a staurosporine apoptosis model without significantly delaying the onset or final total amount of BAX recruitment, and it did not significantly impair/slow cytochrome c release or mitochondrial fragmentation in that setting. (PMID: 34022923)

Key findings (each cites a source)

• A review reported that elamipretide has a structure described as enabling uptake across cell types with highly selective mitochondrial targeting, and that it selectively binds cardiolipin in the inner mitochondrial membrane to stabilize mitochondrial cristae structure, reduce oxidative stress, and enhance ATP production. [PMID 39940712]
• A randomized clinical trial (MMPOWER-3) reported that in a genetically confirmed primary mitochondrial myopathy population, elamipretide did not meet primary endpoints related to change from baseline at week 24 for the 6-minute walk test and total fatigue score versus placebo, while it was described as well-tolerated with most adverse events mild to moderate. [PMID 37268435]
• A post hoc analysis of the MMPOWER-3 trial reported that a subgroup with disease-causing nuclear DNA pathogenic variants showed an improvement in the 6-minute walk test compared with placebo, while the mtDNA pathogenic variant cohort showed no difference versus placebo; it also reported trends/corroborating results within mtDNA-replisome related subsets and motivated a follow-up phase 3 trial design. [PMID 39574155]
• In an animal model study, LPS-induced mitochondrial dysfunction/oxidative stress/inflammation and hippocampus-dependent learning and memory impairment in mice were reported, and elamipretide treatment was reported to ameliorate learning and memory impairment in behavioral tests alongside protective effects on mitochondrial dysfunction and oxidative stress and changes described in BDNF signaling and synaptic-related proteins/structures. [PMID 31747905]
• A rat cardiac ischemia-reperfusion study reported that elamipretide mitigated impairments in mitochondrial structure-function after ischemia-reperfusion, including alleviation of decreases in activity of complexes I, II, and IV, improvement of cristae network fragmentation, and improved biophysical properties of biomimetic membranes by aggregating cardiolipin; it also reported that elamipretide did not prevent reduction of cardiolipin concentration after ischemia-reperfusion. [PMID 32680996]
• A mouse aging study reported that elamipretide mitigated frailty accumulation and showed partial reversal of age-related declines in functional measures of cardiac strain and skeletal muscle fatigue resistance, while reporting that no statistically significant changes in gene expression or DNA methylation profiles indicative of molecular reorganization or reduced biological age were detected in most groups; pathway analyses were reported to show shifts including upregulation of genes involved in fatty acid metabolism, mitochondrial translation, and oxidative phosphorylation, and downregulation of inflammation. [PMID 40080911]