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.
Mitochondrial injury and dysfunction are implicated in ischemia-reperfusion injury, the tissue damage that occurs when blood flow and associated oxygen delivery are re-established after a period when they have been denied. Reperfusion of the heart after myocardial infarction triggers a surge of reactive oxygen species (ROS) and acute calcium overload in mitochondria, which can trigger the opening of the mitochondrial permeability transition pore (MPTP). This opening causes the mitochondria to swell and release cytochrome c, which leads the cell into programmed cell death. In atherosclerotic renal artery stenosis, blood flow to the kidney is impaired, leading to hypoxia and death of proximal tubular cells. This suggests a possible role for elamipretide in myocardial infarction (heart attack), both to reduce ROS and to retain cytochrome c in association with the mitochondrial membrane.
In May 2010, Stealth announced that FDA had granted its application for an Investigational New Drug (IND) for elamipretide (then known as Bendavia), with its lead clinical program focused on ischemia-reperfusion injury, and specifically acute myocardial infarction (AMI).
In September 2010, Stealth Peptides announced the results of the first–in–human elamipretide clinical trial. The Phase I double–blind, placebo–controlled, randomized, multiple-ascending-dose trial was conducted in healthy volunteers of both sexes across what the company says was a broad age range. Participants received one of five ascending doses of elamipretide or placebo via four-hour intravenous infusion.
The drug exhibited dose-proportional plasma pharmacokinetics up to the then-anticipated clinical dose and beyond it by several-fold (the highest dose was 0.250 mg/kg/hr). Within that range, it appeared safe and well-tolerated, with no serious adverse events reported. This trial appears to be NCT01115920, which is listed as completed, but no results are posted, and no publications appear to have been issued.
In November 2011, Stealth announced that cardiologist Dr. Robert Kloner had presented data from three independent labs during the annual meeting of the American Heart Association (AHA). These studies showed that elamipretide ameliorated ischemia-reperfusion injury in cultured cells and in occlusion-based sheep and rabbit models.
In April 2012, Stealth announced the results of three Phase I trials that assessed the risk of interactions between elamipretide and several drugs that are routinely administered to people undergoing surgical procedures in hospital settings. Intravenous infusion of elamipretide did not appear to affect the pharmacodynamics of standard doses of heparin, aspirin, or clopidogrel.
In June 2012, Stealth announced that it had enrolled the first patient in the Phase II EMBRACE-STEMI trial (NCT01572909), which was intended to test elamipretide in acute coronary syndrome (ACS) patients with acute ST-segment elevation myocardial infarction (STEMI).
Researchers presented several additional studies relevant to myocardial infarction and other ACS at AHA scientific meetings in 2012 and 2013, reporting elamipretide’s beneficial effects on post-ischemic heart mitochondrial membrane fluidity, cardiolipin content, and infarct size (though not hemodynamics) (and again here) in in vivo sheep and ex vivo guinea pig models. Further preclinical work was published in 2016.
In April 2013, international investigators published the rationale and design of EMBRACE-STEMI.
At AHA conferences in August and November 2013, scientists at East Carolina University reported that elamipretide was protective in various preclinical models of cardiac injury, including ischemia-reperfusion.
In March 2015, Stealth announced the results of EMBRACE-STEMI. The trial’s primary endpoint was the integrated serum levels of creatine kinase MB (CK-MB), an enzyme used at the time to assess post-MI myocardial damage (today, CK-MB has been replaced by troponin assays, which are both more specific and more sensitive to cardiac injury). The area under the curve of CK-MB in patients administered elamipretide was nonsignificantly lower than in those administered placebo (5570 ± 486 vs. 5785 ± 426 ng*h/mL, with peak levels of 217 vs. 267 ng/mL, respectively). There were also no significant differences in safety outcomes or patient tolerability.
The press release noted that there were fewer subjects wth preexisting hypertension in the elamipretide group than the placebo group in the primary analysis population (38% versus 60%). Stealth or affiliated scientists therefore conducted a post hoc analysis in patients with hypertension only. In this subgroup, elamipretide-treated subjects experienced significantly lower infarct volumes (35.8 vs. 52.6 mL, p=0.03) and improved ST-segment resolution at 24 hours post-MI (p=0.05) than did placebo-treated subjects, consistent with reduced cardiac damage in elamipretide-treated subjects. In an additional post hoc analysis, there was a trend toward reduced risk of new-onset heart failure in elamipretide- vs. placebo-treated subjects (14% [8/58] vs. 25% [15/60] p=0.16).
The results were presented at the American College of Cardiology 64th Annual Scientific Session and were published in April 2016. The primary analysis was confirmed; the post hoc stratified analysis by hypertensive status was not presented. Additionally, the published report indicated that elamipretide-treated subjects did not have more favorable outcomes than placebo in prespecified MRI, angiographic, electrocardiographic, or clinical outcomes, and the area under the curve of their serum troponin I was nonsignificantly higher than in the placebo group.
