Bendavia and Beneficial Biologic Activity
Bendavia™, Stealth Peptides’ lead compound, is a new chemical entity that targets mitochondria to treat ischemia reperfusion injury, which commonly occurs with many cardiovascular, renal and neurologic insults. Stealth Peptides’ lead clinical program is for acute myocardial infarction (AMI), an indication with clear clinical metrics for FDA marketing approvals and demonstrating the beneficial biologic activity of Bendavia.
Preventing mitochondrial abnormalities
Due to Bendavia’s ability to penetrate epithelial monolayer cultures with tight junctions, it appears that there is transcellular transport of the molecule. In vitro studies of Bendavia have shown that the compound concentrates in the mitochondria at levels between 1,000 and 5,000-fold that measured in the extra-mitochondrial space. This compound appears to have minimal effects on cell cultures in which it has been tested. However, it prevents a variety of mitochondrial abnormalities when the cells are disrupted by a variety of oxidative agents including hydrogen peroxide, peroxynitrite, tert-butyl hydroperoxide and 1-methyl-4-phenyl-1,2,3,6-tetrahydrapyridine. Following tissue damage and insults with these agents, Bendavia has been shown to profoundly ameliorate:
- Uncoupling of the electron transport chain
- Loss of the electrochemical potential (ΔΨm) across the mitochondrial membrane
- Loss of ATP
- Swelling of the mitochondria
- Release of cytochrome c into the cytoplasm
- Increase in intracellular reactive oxygen species (ROS)
- Increase in lipid peroxidation
- Increase in upregulation of heme-oxygenase-1
- Increase in apoptosis as determined by caspase-3 increase and Terminal dUTP nick end labeling (TUNEL) positive cells
- Increase in necrotic cells
- Overall decreased cell survival
Reducing damage central to many diseases
As detailed in the Ischemia Reperfusion Injury section, these abnormalities appear to be central to the development of reperfusion injury. Increasing animal data (see Bendavia and AMI) support that Bendavia can reduce the degree of damage following re-establishment of coronary blood flow to the heart at extremely low doses and systemic concentrations. Although acute myocardial infarction is the initial targeted indication for Bendavia, the compound has beneficial effects in a wide range of models as might be expected, since mitochondrial dysfunction is a critical component of most pathophysiologic processes.
Benefit has also been shown in animal models of stroke, acute renal injury due to ischemia, pancreatic islet cell transplantation, neurodegenerative diseases (Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Parkinson’s disease), radiation exposure, drug-induced tissue injury (radio-contrast agents, cisplatin, aminoglycosides and acetaminophen), diabetic renal and peripheral nerve complications, diabetic retinopathy, macular degeneration, and cataract formation.
Bendavia and Acute Myocardial Infarction
Bendavia™ appears to have strong mitochondrial protective effects in in vitro studies. Since most recent data suggest that mitochondrial dysfunction is a central pathway in reperfusion injury, it is not unexpected that Bendavia has been shown to significantly decrease left ventricular infarct area in multiple species and models of acute myocardial ischemia reperfusion. In a large animal (30-40 kg) study with 1 hour of ischemia, and administration of Bendavia by IV prior to reperfusion, the compound demonstrated reductions in infarct size that were greater than 45 percent relative to placebo.
Comparison with Cyclosporine A: Proof of Concept
While multiple interventions with other therapies have shown promising results in animal models but have failed in human trials, Stealth Peptides believes that the chances of success with Bendavia in the transition between animals and humans is substantially increased based on recent data with Cyclosporine A (CsA), a drug that similarly prevents the opening of the mitochondrial permeability transition pore. This drug has recently been shown to reduce infarct size in small animal models of coronary artery ischemia reperfusion. Piot et al. showed that this preclinical benefit could be reproduced in patients given the drug at the time of reperfusion during primary percutaneous coronary intervention (PCI) for acute, ST-segment elevation myocardial infarctions (STEMI). Follow-up of these patients by Mewton et al. showed that this initial benefit was maintained for at least 6 months.
In addition, using serial cardiac magnetic resonance imaging (cMRI), it was shown that CsA decreased the magnitude of pathologic cardiac remodeling compared to control patients. Although CsA is unlikely to ever be approved for this indication, these data validate that animal models of coronary ischemia reperfusion can be predictive of human responses for mitochondrial protective compounds. As demonstrated in multiple animal models and species, Bendavia has proven to be at least as good and in most cases better than CsA in standard AMI models with compounds that have strong mitochondrial protective effects. Thus, the results with Bendavia in animal models of ischemia reperfusion injury are expected to translate to patients in a manner similar to that seen with CsA.
Bendavia and AMI models
In an acute myocardial ischemia reperfusion model, rabbits were subjected to 30 minutes of ischemia followed by 180 minutes of reperfusion. Infusion of Bendavia or vehicle was started 20 minutes prior to reperfusion and continued through the reperfusion period.
In this model, Bendavia and CsA each demonstrated a statistically significant infarct size reduction relative to placebo. When hearts with similar sized ischemia areas-at-risk were compared (area at risk 40-60 percent of the total area of the left ventricle) the following results were seen:
Bendavia reduced the infarct area and this reduction exceeded that seen with CsA. No difference in myocardial salvage was observed with Bendavia administered prior to reperfusion and continued for either 1 or 3 hours after restoration of blood flow.