Stealth BioTherapeutics‘ lead investigational product candidate, elamipretide (approved and marketed as FORZINITY™ for Barth syndrome), is an antioxidant peptide compound that readily penetrates cell membranes and targets the inner mitochondrial membrane, where it binds reversibly to the key mitochondrial lipid cardiolipin. Cardiolipin is a phospholipid synthesized within the mitochondrial matrix that confers the distinctive folded shape to the inner mitochondrial membrane, helps organize the supercomplexes of the electron transport chain, and is crucial to its function. When a mitochondrion is damaged, cardiolipin moves to the outer mitochondrial membrane, where it triggers the selective destruction of the damaged organelle (mitophagy). Conversely, if the mitochondrion is damaged beyond repair, it will eject cariolipin and the key inner membrane protein cytochrome c outside itself, triggering “cellular suicide” (apoptosis).
Elamipretide stabilizes mitochondrial structure and sustains mitochondrial respiration, thereby improving electron transport chain function and ATP production in several animal models of age-related diseases, most notably renal disease, mitochondrial disorders, and heart failure. It achieves this in part by protecting cardiolipin from oxidative damage and maintaining its normal interactions with cytochrome c, thus preventing it from being ejected and triggering apoptosis.
Because of their high energy demands, Cardiac muscle cellls (cardiomyocytes) have some of the highest mitochondrial densities of any cell in the body, and the mitochondria in human heart failure (HF) patients and animal models of the disease exhibit multiple structural abnormalities, including abnormally high total numbers, reduced size, fragmentation, and disruption of the inner and outer mitochondrial membranes, including oxidative damage to the key mitochondrial phospholipid cardiolipin. These structural abnormalities are associated with abnormal function, including impaired respiration. Theses features suggest the potential of elamipretide in HF.
Starting in 2014, Stealth launched a series of trials and reported several preclinical studies using elamipretide in HF. Two of these trials have been reported in the scientific literature with mixed results; other trials appear to have been completed but never reported in the scientific literature or the results announced via press release. As of October 2025, Stealth’s pipeline page has no entries for elamipretide in heart failure.
In July 2014, Stealth launched a Phase I single-center, randomized, double-blind, placebo-controlled trial of four doses of elamipretide in subjects with stable mild to moderate heart failure due to left ventricular (LV) systolic dysfunction (NCT02388464). The main endpoints were pharmacokinetic and safety parameters, but the investigators also collected LV end-systolic volume (LVESV) as a preliminary efficacy endpoint. (In May 2015, Stealth launched a similar-sounding trial (NCT02388529), but they withdrew it prior to enrollment).
In May 2015, Stealth announced the results of the dose-ascending trial, which it dubbed PREVIEW, as they were presented at the European Society of Cardiology (ESC) Heart Failure Congress. They were ultimately published in 2017. Plasma elamipretide concentrations peaked at the end of the four-hour infusion and fell rapidly, becoming undetectable by 24 hours after the initiation of treatment. The investigators reported a significant reduction in LV end-diastolic volume (−18 mL; P=0.009) and end-systolic volume (−14 mL; P=0.005) upon completion of the infusion in the highest-dose group. However, there were no changes in NT-proBNP (a biomarker of cardiac muscle damage) or high-sensitivity C-reactive protein (hsCRP). No serious adverse events were observed.
In February 2016, researchers funded by Stealth reported preclinical work with elamipretide in a microembolization-induced canine heart failure model. Six weeks after their last microembolization, fourteen dogs with LV ejection fraction (EF) ≈30% were randomized to 3 months of subcutaneous elamipretide or saline control. In controls, LVEF remained stable or declined after treatment, while it increased in elamipretid-treated dogs (36±2% versus 30±2%; P<0.05). Elamipretide also normalized plasma tumor necrosis factor-α and C-reactive protein and restored several measures of mitochondrial function. It also lowered the overall burden of reactive oxygen species in these animals.
In June 2016, Stealth announced that it had launched two randomized, double-blind, placebo-controlled Phase II trials of four weeks of elamipretide in heart failure. PROGRESS-HF (NCT02788747) was to test the effects of elamipretide in subjects with stable heart failure with reduced ejection fraction (HFrEF), with the primary endpoint being change from baseline in LV end-systolic volume as assessed on MRI. RESTORE-HF (NCT02814097) was to test the drug in persons with HF with preserved ejection fraction (HFpEF), with the primary endpoint being changes in diastolic heart function at rest and during a submaximal stress test. At the time, Stealth anticipated topline data in the second half of 2017.
Also in June 2016, Stealth issued a press release about an ex vivo study using cardiac tissue from patients undergoing heart transplant for terminal HF with reduced systolic function or healthy donor controls, treated or not treated with elamipretide. Mitochondrial function was impaired in tissue from HF patients relative to controls, and elamipretide treatment reversed or ameliorated most of these deficits. This study was published in 2019.
PROGRESS-HF was published in May 2020. Neither the change from baseline in LESV nor in LVEF was different from placebo at either tested dose of elamipretide. Secondary and exploratory endpoints in NT-proBNP and 6MWT were also not significantly different from placebo, and there was only a nonsignificant trend toward improvement in the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary scores.
The Clinicaltrials.gov entry for RESTORE-HF indicates that it was completed in June 2017, but as of October 2025, a diligent search has turned up no announcement on its results or a scientific report. A 2017 editorial indicated that the trial was complete, although the results had not been reported, while a 2019 commentary and a 2020 review paper assert that it was ongoing at the time of their writing (though the former of these also indicates that PROGRESS-HF was ongoing, when in fact it had been completed two years earlier and reported out the following year).
In October 2016, Stealth announced the launch of the Phase II clinical IDDEA-HF trial (NCT02914665) to assess elamipretide in patients who had been hospitalized with congestive heart failure. Within 72 hours of presentation, subjects were to be randomized to receive either elamipretide or placebo intravenously daily for up to a week. The primary endpoint was change in NT-proBNP, with change in clinical status and safety and tolerability as secondary endpoints. Similar to the situation with RESTORE-HF, however, the Clinicaltrials.gov entry for this trial indicates it was completed in November 2017, but as of October 2025, no record is at hand of a press release or scientific publication. (Again, the 2019 commentary asserts that it was ongoing at the time of its writing).
