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MARSEILLE, France—Trophos SA, a clinical stage pharmaceutical company developing innovative therapeutics for indications with under-served needs in neurology and cardiology, announced recently the start of clinical development for TRO40303, a novel mitochondria pore modulator.

The company's leaders believe that TRO40303 could become the first treatment to reduce the cardiac reperfusion injury that contributes significantly to the morbidity and mortality seen post myocardial infarction (MI). The first-in-human study will enroll healthy volunteers and will compare the safety and tolerability of a single dose of TRO40303 to placebo. The initiation of this study follows what the company called "promising" preclinical results, "which suggest TRO40303 can significantly reduce infarct size following cardiac ischemia-reperfusion."
 
"The initiation of the clinical development of our second mitochondrial pore modulator, TRO40303, represents a major advance for Trophos," says Damian Marron, Trophos' CEO. "There are around 1.6 million cardiac reperfusion procedures performed in hospitals and specialist clinics each year in the major markets. This program fits perfectly with Trophos strategy of creating value by targeting niche, high medical need markets.

Marrons adds that Trophos is excellently positioned to deliver on its strategic goals with this program "and with our lead product, olesoxime, in a phase 3 study for the orphan neurological disease of amyotrophic lateral sclerosis as part of the EU-funded MitoTarget project."

The objective of this phase I study is to assess the safety, tolerability and pharmacokinetics of single escalating doses of TRO40303 as an intravenous infusion at different rates compared with placebo in 64 healthy volunteers. Results from the study are expected in Q1 2010 and will allow the compound to be moved rapidly into a phase II proof-of-concept study in acute MI patients with large myocardial infarct undergoing percutaneous transluminal coronary angioplasty (PTCA also known as coronary or balloon angioplasty) during percutaneous coronary intervention (PCI), where TRO40303 will be dosed as a single iv short infusion immediately prior to the emergency intervention.

"A treatment is urgently required to prevent cardiac reperfusion injury, which is a major problem in the care of MI patients despite the overall improvements in prognosis in recent years," says Dr. Jean-Louis Abitbol, chief medical officer at Trophos. "Cardiac reperfusion injury is a significant unmet medical need with no existing treatment that contributes to long-term morbidity, progression to heart failure and death following a MI. The role of mitochondrial permeability transition in cardiac reperfusion injury has recently been validated clinically making this is a tremendous opportunity for our novel mitochondrial pore modulator, TRO40303, discovered and developed in our laboratories, which targets this mechanism."

Use of thrombolytics and balloon angioplasty to rapidly reperfuse heart tissue with oxygen following a MI has greatly reduced morbidity and mortality. Paradoxically, about 50 percent of the damage to heart tissue following MI is due to re-oxygenation leading to a burst of reactive oxygen species as energy production by mitochondria is reactivated. The mechanism of action of TRO40303 involves prevention of stress-induced mitochondrial permeability transition, a target implicated in cardiac reperfusion injury.
 
In vitro, TRO40303 improved oxidative stress-induced cardiomyocyte survival that was correlated with a reduction in reactive oxygen species production, slowed triggering of mitochondrial permeability transition and reduced cytoplasmic and mitochondrial calcium overload while also reducing the release of apoptotic factors, key events in cardiac reperfusion injury. As proof of concept, in an animal model of MI, treatment with TRO40303 at the time of reperfusion was shown to significantly reduce infarct size. 

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