Trophos publishes the identification and characterization of novel cardioprotective compound
MARSEILLE, France—Trophos SA, a clinical-stage pharmaceutical company developing therapeutics from discovery to clinical validation for indications with under-served needs in neurology and cardiology, announced this week that it had published important data on TRO40303, which will enter clinical development shortly with the ultimate aim to reduce mortality and morbidity in myocardial infarction (MI) patients, and which the is reportedly “the second most advanced cholesterol oxime to be discovered by Trophos.”
The article, titled “TRO40303 (3,5-seco-4-nor-cholestan-5-one oxime-3-ol), a new cardioprotective compound, inhibits mitochondrial permeability transition” was published in the June issue of the Journal of Pharmacology And Experimental Therapeutics. The studies reported in the paper by Schaller et al. demonstrate the potential for this compound to protect heart tissue from ischemia-reperfusion injury induced when treating MI.
“We are very pleased to publish this important work, which was conducted in collaboration with a distinguished international scientific network, in such a prestigious publication as JPET,” says Rebecca Pruss, chief scientific officer at Trophos. “Cardiac reperfusion injury is a significant unmet medical need that contributes to long-term morbidity and progression to heart failure due to a MI. The role of mitochondrial permeability transition in cardiac reperfusion injury has recently been validated clinically. It is a tremendous clinical opportunity for the novel cholesterol oxime compounds discovered by Trophos that target this mechanism.”
In addition to being “second most important,” TRO40303 is the second product coming from Trophos’ discovery strategy screening for compounds promoting survival of pathophysiologically stressed cells.
“Olesoxime (TRO19622), our first compound to enter clinical development, is now in a pivotal clinical trial to establish efficacy in patients with amyotrophic lateral sclerosis,” Pruss says, “and a Phase II study in patients with spinal muscular atrophy will soon begin enrolling patients indicating that this class of compounds is safe and well tolerated both in animals and humans. We believe additional compounds in this family may be useful to treat other serious unmet medical needs.”
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 as well as neurodegenerative diseases and other pathologies.
The studies reported by Trophos and colleagues show that TRO40303 binds directly to the cholesterol site of the mitochondrial outer membrane protein, TSPO, which is highly expressed in heart and is associated to the mitochondrial permeability transition pore, allowing rapid uptake of TRO40303 into cardiac tissue. In vitro, TRO40303 reportedly 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.
TRO40303 has completed preclinical safety and toxicology studies required for entry into Phase I. The first clinical studies of TRO40303 in healthy volunteers are planned to start in the second half of 2010 using a clinical formulation developed to allowing intravenous administration of TRO40303 immediately prior to emergency balloon angioplasty in patients suffering an acute MI.
“We are particularly excited that there is increasing evidence that the mechanism of action of our cholesterol oxime family of mitochondrial pore modulator compounds will have tremendous commercial potential for chronic neurological and neurodegenerative disorders as well as non-neurologic conditions such as cardiac ischemia-reperfusion injury,” says Damian Marron, Trophos’ CEO. “There are around 1.6 million cardiac reperfusion procedures performed each year in the major markets and currently no available treatments to prevent ischemia-reperfusion injury. This fits perfectly with Trophos strategy of creating value by of targeting niche, high medical need markets”