Staff Writer

Despite its moniker, privately held Stealth Peptides Inc. is poised to make a name for itself in the development of mitochondrial-targeted therapies, potentially addressing cardiovascular, renal, ophthalmologic, neurologic and metabolic indications.

Stealth, located in Boston, was founded five years ago by lead investor Morningside Ventures, which in-licensed early stage technologies from a group of undisclosed collaborating academic institutions.

For the first two to three years, the company literally operated in stealth mode as the team studied the mitochondrial-directed actions of its class of short peptides – 500 to 700 Daltons each – as well as their biological activity, explained Travis Wilson, a Morningside member and CEO of Stealth.

In fact, the company's name was selected because the peptides that form the basis of its platform protect mitochondria nonselectively, in a "stealth"-like approach.

Two years ago, Stealth scientists identified lead compound, Bendavia, and moved the new chemical entity into multiple Phase I trials to examine safety, tolerability and pharmacokinetics. The initial clinical indication is ischemia reperfusion and microvascular injury, a common complication of interventional procedures for acute myocardial infarction and coronary bypass surgery.

In September 2010, the company reported that Bendavia was well tolerated in a study of healthy male and female volunteers who received a single dose of the compound as an intravenous infusion over an extended period.

In August, Stealth presented data from animal studies at the American Heart Association's Cardiovascular Scientific Sessions in New Orleans, reporting that animal models for interventional procedures demonstrated beneficial biologic effects and confirmed the significance of Bendavia's mechanism of action, which preserves mitochondrial function under pathological conditions, for ischemia reperfusion and microvascular injuries.

The company plans to present additional data at the AHA Scientific Sessions and the American Society of Nephrology's Kidney Week 2011, both in November, Wilson told BioWorld Today.

A Phase II study of Bendavia in 300 patients in the U.S. and Europe is "imminent," Wilson added. The trial will focus on ischemia reperfusion injury in patients experiencing acute ST-segment elevation myocardial infarction (STEMI).

The prospective, multicenter, randomized, double-blind, placebo-controlled dose-ranging EMBRACE-STEMI (Evaluation of the Myocardial effects of Bendavia for reducing Reperfusion injury in patients with Acute Coronary Events – ST-wave Elevation Myocardial Infarction) trial will assess the safety, tolerability and efficacy of intravenously administered Bendavia against standard-of-care therapy.

Stealth, which has only 15 employed and contracted members in its "extended team," is working with a multinational contract research organization for EMBRACE-STEMI, which is designed primarily to evaluate the impact of Bendavia on limiting the size of infarcted myocardium and preventing reflow in patients who have undergone successful reperfusion using primary percutaneous coronary intervention and stenting. The company expects to report data in 18 to 24 months, according to Wilson.

Unlike other start-ups, which often work with a single investigator and lab and frequently encounter problems trying to replicate early results or translate those to patients when they move into blinded studies, Stealth has worked with numerous investigators and independent labs on Bendavia from the start.

"The clinical trial is based upon solid animal work, using a variety of species and conducted in a variety of academic and commercial laboratories," explained Richard Straube, the company's chief medical officer. "We feel very confident that our data, which are very consistent across labs and species, support the potential of this compound as a drug in STEMI."

Although STEMI/myocardial infarction is the initial indication, the compound's basic mechanism appears to stabilize mitochondria from typical insults, including oxidative stress and elevated glucose, that occur in a variety of injuries.

In most diseases, lethal symptoms result from cascading cell death that occurs from necrosis or apoptosis or from a disruption of cells that causes secondary problems – for example, the prevention of endothelial blood flow, Straube explained. By stabilizing the mitochondria, Bendavia appears to prevent abnormalities both in vitro and in vivo that result from cell disruption in chronic and acute events.

"This drug has rather phenomenal activity across a wide variety of diseases in animal models – not only ischemia reperfusion and microvascular dysfunction such as you see in heart attacks, but also in stroke, transplantation, diabetic complications, ophthalmologic diseases, renal problems and neurodegenerative diseases," Straube said.

Beyond Bendavia, which is a platform in and of itself, Stealth is developing other compounds in its family of peptides for use in different types of diseases.

"We're trying to tease out which compound might be optimal for each disease state," Straube said.

Stealth could move Bendavia to a new drug application (NDA) in certain indications – a process that likely would take three to five years – but also has weighed partnering opportunities.

Wilson declined to specify how much money Stealth has raised to date, noting, "It's fair to say that we've been very strongly supported by Morningside and we've got the opportunity to move forward with the current trial as well as additional indications over the next three to five years."

The timing and indication for an NDA filing will be driven by study findings, Wilson added.

The reperfusion injury associated with myocardial infarction represents a field "littered with failed drugs," Straube acknowledged, but Bendavia is different, he said. The compound is taken up selectively by local mitochondria and – unlike other mitochondrial drugs – appears to penetrate both healthy and injured mitochondria.

"We've achieved independent uptake under mitochondrial stress, which makes us fairly unique and novel in the mitochondria drug arena," Straube pointed out.

In addition, Stealth's technology maintains the efficient flow of electrons through the electron chain transport system, in turn preventing many downstream mitochondrial pathophysiologic changes and enabling mitochondria to maintain normal respiration and adenosine triphosphate levels and to prevent the release of cytochrome C.

"Instead of mopping up reactive oxygen species (ROS), which is the final pathway to cell death, we actually prevent the development of that process through mitochondrial stabilization," Straube said. "We can act as an antioxidant but, more importantly, we turn off the production of ROS before it starts. That's a critical difference compared to other mitochondrial drugs."

Biotech start-ups Radical Therapeutix, of La Jolla, Calif., and Cambridge, Mass.-based DecImmune Therapeutics Inc. are among the players seeking to limit the tissue damage that occurs following myocardial infarction. (See BioWorld Today, Aug. 26, 2010, and March 9, 2011.)

The potential market is huge, with heart attacks killing an estimated 1.2 million each year in the U.S. alone. Although beta blockers and ACE inhibitors are used to treat the condition, those drugs don't address the damage caused by reperfusion.

Developing a me-too antioxidant that simply chases reactive oxygen "is almost a no-win game," Wilson said. "You really have to prevent ROS from forming, and our mitochondrial-directed actions do just that."