Trophos Publishes The Identification And Characterization Of The Novel Cardioprotective Compound, TRO40303
Published: Jul 28, 2010
“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.” said Rebecca Pruss, CSO 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. TRO40303 is the second product coming from our 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 (ALS, or Lou Gehrig’s Disease) and a Phase 2 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 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 2nd 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.
Damian Marron, Trophos’ CEO added “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. 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”
About Trophos: http://www.trophos.com
Trophos is a clinical stage pharmaceutical company developing innovative therapeutics for indications with under-served needs in neurology and cardiology. The Company has a novel and proprietary cholesterol oxime based chemistry platform generating a pipeline of drug candidates, with the lead product, olesoxime (TRO19622), in phase 3 development and a second product, TRO40303, planned to enter the clinic in 2010. Trophos' mitochondrial pore modulator compounds enhance the function and survival of stressed cells via modulation of dysfunctional mitochondria through interactions at the permeability transition pore (mPTP). Recently published clinical studies support the therapeutic rationale for mitochondria targeted drugs, which Trophos is uniquely placed to exploit.
Trophos was founded in 1999, is based in Marseille, France and currently has 25 employees.
 Author list: Schaller, S , Paradis, S , Ngoh, GA , Assaly, R , Buisson, B, Drouot, C , Ostuni, MA , Lacapere, J-J , Bassissi, F , Bordet, T , Berdeaux, A , Jones, SP , Morin, D  and Pruss, RM .  Trophos, Marseille, France ;  INSERM U955/03, Paris, France ;  University of Louisville, Louisville, KY, USA,  INSERM U773/CRB3, Paris, France
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