Tuesday, 14 December 2010

POC study of novel cardioprotective compound, TRO40303

Trophos SA, a clinical stage pharmaceutical company developing innovative therapeutics from discovery to clinical validation for indications with under-served needs in neurology and cardiology, announces today a European Union award of EUR 6 million to support MitoCare, a 2.5 year international, translational medicine project.

MitoCare, which will begin in January 2011, will be conducted by a 16 partner consortium and led by Trophos. MitoCare forms part of the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (FP7). MitoCare will investigate the efficacy and safety of TRO40303 in a phase 2 proof-of-concept study to treat cardiac ischemia-reperfusion injury (IRI) in acute myocardial infarction (MI) patients and develop knowledge of biomarkers and models of cardiac ischemia-reperfusion injury.
“We are proud the European Union, after extensive expert evaluation, has chosen to support the MitoCare project and Trophos is very pleased to be collaborating with a distinguished panel of clinical, academic and SME partners,” said Damian Marron, Trophos’ CEO. “There are around 1.6 million cardiac reperfusion procedures performed in hospitals and specialist clinics each year in the western world alone. This program fits perfectly with Trophos’ strategy of creating value by targeting niche, high medical need markets. 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.”

“Trophos is excellently positioned to deliver on its goals with this program as well as with our lead product, olesoxime, in a phase 3 study for the orphan neurological disease of amyotrophic lateral sclerosis as part of another EU funded project, MitoTarget,” added Damian Marron.

Trophos is leading a consortium of nine clinical centers, three basic research centers and four SME’s (including Trophos), for a total of 16 teams around Europe specializing in clinical and basic research, biomarkers, imaging and informatics (see note). MitoCare’s main aims are to 1) demonstrate the therapeutic efficacy and safety of TRO40303, a novel mitochondrial pore modulator, in the treatment of ischemia-reperfusion injury in a phase 2 POC study in acute MI patients, 2) translational research to gain a greater understanding of the biomarkers and confounding/predictive factors in cardiac IRI and 3) research to improve understanding and use of pre-clinical models of cardiac IRI.

The TRO40303 clinical study will be sponsored by Trophos and performed by a consortium of prominent European clinical investigators, all of whom have extensive prior experience conducting and collaborating in large multi-centre clinical trials in cardiac IRI. The principal investigator will be Professor Dan Atar from Oslo University Hospital, Norway. The study will be a placebo-controlled, phase 2 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 administered as a single IV infusion prior to the reperfusion by angioplasty.

The translational research will focus on exploration of predictive and confounding factors of response in humans, analysis of new markers for necrosis and heart failure, analysis of variability in pre-clinical models and comparison of human and pre-clinical data to identify the most predictable pre-clinical models.

TRO40303, the second of Trophos’ proprietary cholesterol oxime mitochondrial pore modulators, is currently undergoing a phase 1 study (see release of 28 September 2010) in healthy volunteers. Results from this study are expected in Q1 2011.

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. Studies reported by Trophos and colleagues recently in JPET (Schaller et al, http://www.ncbi.nlm.nih.gov/pubmed/20215409) show that TRO40303 binds directly to the cholesterol site of the mitochondrial outer membrane protein, TSPO, which is associated to the mitochondrial permeability transition pore and is highly expressed in heart, 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 a pre-clinical model of MI, treatment with TRO40303 at the time of reperfusion was shown to significantly reduce infarct size.

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 per cent of the damage to heart tissue following MI treated by reperfusion is due to re-oxygenation leading to a burst of reactive oxygen species and an increase in mitochondrial calcium levels as energy production by mitochondria is reactivated. Together this leads to mitochondrial permeability transition, which is a transition from the normal physiological role of the mitochondria into pro-apoptotic machinery that releases factors into the cytoplasm that induce apoptosis. The role of mitochondrial permeability transition in cardiac reperfusion injury is well documented and has recently been clinically validated with a prototype mitochondrial pore blocker.

The MitoCare consortium partners are:

* Trophos.
* AP-HP, Hôpital Henri Mondor.
* AP-HP, Hôpital Européen Georges Pompidou.
* AP-HP, Hôpital Lariboisière.
* Inserm, Institut Mondor de Recherche Biomédicale (IMRB).
* Universitetet i Bergen, Haukeland University Hospital.
* Region Nordjylland, Aalborg University Hospital.
* Lunds Universitet, Lund University Hospital.
* Region Hovedstaden, Gentofte Hospital.
* Karolinska Institutet, Karolinska University Hospital
* University of Bristol, School of Biochemistry.
* Firalis S.A.S.
* Goeteborgs Universitet, Sahlgrenska University Hospital
* Imacor A.B.
* Mobile Health S.A.S.
* Oslo Universitetssykehus HF, Ullevål University Hospital.