Trophos SA has announced today that the first patient has been treated in a phase II proof-of-concept study to investigate the efficacy and safety of Trophos’ TRO40303, a novel mitochondria pore modulator, to treat cardiac ischemia-reperfusion injury (IRI) in acute myocardial infarction (MI) patients.
TRO40303 could become the first treatment to reduce the cardiac reperfusion injury that contributes significantly to the morbidity and mortality seen after a heart attack (myocardial infarction - MI). The study is supported by the EU FP7 MitoCare project (see below). Results are expected before the end of 2012.
Commented Dr Jean-Louis Abitbol, chief medical officer at Trophos: “A treatment is urgently required globally to prevent cardiac reperfusion injury. This is a major problem in the care of MI patients despite the overall improvements in prognosis in recent years. There is no existing treatment for this problem 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 a tremendous opportunity for Trophos’ novel mitochondrial pore modulator, TRO40303, discovered and developed in our laboratories to target this mechanism.”
“There are around 1.6 million cardiac reperfusion procedures performed in hospitals and specialist clinics each year in the western world alone,” added Damian Marron, Trophos’ CEO. “This programme fits perfectly with Trophos strategy of creating value by targeting niche, high unmet medical need markets. Trophos is excellently positioned to deliver both on its goals with TRO40303 and with our lead product, olesoxime, with results due around year end of a phase III study for the orphan neurological disease of amyotrophic lateral sclerosis (ALS) as part of the EU funded MitoTarget project.”
The phase II proof-of-concept study of TRO40303 is sponsored and led by Trophos and performed as part of the EU funded MitoCare project (see release of December 14, 2010). The study is in collaboration with 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 is Professor Dan Atar from Oslo University Hospital, Norway. The study is a placebo-controlled, 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). TRO40303 is administered as a single iv infusion prior to the reperfusion by angioplasty.
TRO40303 previously successfully completed a phase I study to assess the safety, tolerability and pharmacokinetics of single escalating doses of TRO40303 as an intravenous infusion at different rates compared with placebo in 72 healthy volunteers. The results demonstrated that TRO40303 can be safely administered by the iv route in humans at doses expected to be pharmacologically active. Full results of this study were recently presented at the European Society of Cardiology 2011 held in Paris from 27th-31st August (Schaller et al, ESC 2011 Paris, N88427, Phase I clinical trial of TRO40303, a new mPTP inhibitor for reducing reperfusion injury).
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 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. 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 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 a model of MI, treatment with TRO40303 at the time of reperfusion was shown to significantly reduce infarct size. This innovative program was supported by a grant of nearly EUR one million by the French Agence Nationale pour la Recherche (ANR) in a project named IRIstop, (see release of February 28 2008).
This clinical study is part of a collaborative project named MitoCare (grant agreement number: Health-2010-261034). The European Commission has awarded a grant of EUR six million to MitoCare, a 2.5 year international, translational medicine project led by Trophos. MitoCare forms part of the seventh framework programme of the European Community for Research, Technological Development and Demonstration Activities (FP7). MitoCare, which began in January 2011, is being conducted by 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. As well as the clinical study MitoCare is undertaking translational research to identify biomarkers and confounding/predictive factors in cardiac IRI and research in order to improve understanding and use of pre-clinical models of cardiac IRI (see release of December 14 2010).
For more information, visit www.trophos.com
TRO40303 could become the first treatment to reduce the cardiac reperfusion injury that contributes significantly to the morbidity and mortality seen after a heart attack (myocardial infarction - MI). The study is supported by the EU FP7 MitoCare project (see below). Results are expected before the end of 2012.
Commented Dr Jean-Louis Abitbol, chief medical officer at Trophos: “A treatment is urgently required globally to prevent cardiac reperfusion injury. This is a major problem in the care of MI patients despite the overall improvements in prognosis in recent years. There is no existing treatment for this problem 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 a tremendous opportunity for Trophos’ novel mitochondrial pore modulator, TRO40303, discovered and developed in our laboratories to target this mechanism.”
“There are around 1.6 million cardiac reperfusion procedures performed in hospitals and specialist clinics each year in the western world alone,” added Damian Marron, Trophos’ CEO. “This programme fits perfectly with Trophos strategy of creating value by targeting niche, high unmet medical need markets. Trophos is excellently positioned to deliver both on its goals with TRO40303 and with our lead product, olesoxime, with results due around year end of a phase III study for the orphan neurological disease of amyotrophic lateral sclerosis (ALS) as part of the EU funded MitoTarget project.”
The phase II proof-of-concept study of TRO40303 is sponsored and led by Trophos and performed as part of the EU funded MitoCare project (see release of December 14, 2010). The study is in collaboration with 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 is Professor Dan Atar from Oslo University Hospital, Norway. The study is a placebo-controlled, 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). TRO40303 is administered as a single iv infusion prior to the reperfusion by angioplasty.
TRO40303 previously successfully completed a phase I study to assess the safety, tolerability and pharmacokinetics of single escalating doses of TRO40303 as an intravenous infusion at different rates compared with placebo in 72 healthy volunteers. The results demonstrated that TRO40303 can be safely administered by the iv route in humans at doses expected to be pharmacologically active. Full results of this study were recently presented at the European Society of Cardiology 2011 held in Paris from 27th-31st August (Schaller et al, ESC 2011 Paris, N88427, Phase I clinical trial of TRO40303, a new mPTP inhibitor for reducing reperfusion injury).
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 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. 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 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 a model of MI, treatment with TRO40303 at the time of reperfusion was shown to significantly reduce infarct size. This innovative program was supported by a grant of nearly EUR one million by the French Agence Nationale pour la Recherche (ANR) in a project named IRIstop, (see release of February 28 2008).
This clinical study is part of a collaborative project named MitoCare (grant agreement number: Health-2010-261034). The European Commission has awarded a grant of EUR six million to MitoCare, a 2.5 year international, translational medicine project led by Trophos. MitoCare forms part of the seventh framework programme of the European Community for Research, Technological Development and Demonstration Activities (FP7). MitoCare, which began in January 2011, is being conducted by 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. As well as the clinical study MitoCare is undertaking translational research to identify biomarkers and confounding/predictive factors in cardiac IRI and research in order to improve understanding and use of pre-clinical models of cardiac IRI (see release of December 14 2010).
For more information, visit www.trophos.com
