Trophos has announced the final patient completion of a phase II study of TR040303 in patients treated for acute myocardial infarction. Outcome data of this study is expected to be available towards the end of 2013.
The phase II proof-of-concept study has been designed to evaluate the efficacy and safety of Trophos TRO40303, a novel mitochondria pore modulator with broad cytoprotective properties, to treat cardiac ischemia reperfusion injury in acute myocardial infarction patients.
The clinical study is part of the FP7 collaborative MitoCare project, granted €6 million by the European Commission. The project is led by Trophos and operated by a consortium of 16 European institutions specialising in clinical and basic research, biomarkers, imaging and informatics.
165 patients were enrolled in ten centres in four European countries, (France, Norway, Denmark and Sweden) in a double-blind, randomised, placebo-controlled study. Patients received an intravenous bolus of TRO40303 or matching placebo immediately preceding percutaneous coronary intervention (primary PCI) to treat a first acute STEMI.
The primary endpoint of the study is the reduction of myocardial tissue damage. The level of damage is assessed by measuring cardiac proteins, Troponin I and CK that are released into the circulation. An additional major endpoint is the measurement of infarct size as a percentage of the at-risk myocardium, expressed by myocardial salvage index. This is assessed by cardiac magnetic resonance imaging (CMR) performed between three and five days after intervention.
“Preventing mitochondrial permeability transition and subsequent tissue damage resulting from reperfusion is a promising approach to the treatment of ischaemia reperfusion injury that should significantly reduce infarct size in STEMI patients,” said Dan Atar, professor of cardiology, University of Oslo, Norway, and principal investigator for the study. “We look forward to sharing the clinical experience of this innovative compound and comparing CMR with plasma biomarkers as predictors of outcome in STEMI patients as soon as the results become available.”
“Trophos is very pleased to report completion of the clinical part of the MitoCare study,” said Wilfried Hauke, chief medical officer at Trophos. “TRO40303 offers a therapeutic option for the treatment of acute myocardial infarction. Further reducing the tissue damage due to reperfusion injury is expected to improve the long-term outcome in these patients.”
About TRO40303 and cardiac reperfusion injury
Use of fibrinolytics and balloon angioplasty to rapidly reperfuse heart tissue with oxygen following myocardial infarction has greatly reduced morbidity and mortality. Although restoring blood flow to the heart is critical to the survival of heart tissue, paradoxically, this process may cause additional damage known as reperfusion injury, due to a burst of reactive oxygen species from mitochondria as energy production is reactivated.
TRO40303 was shown to reduce stress induced mitochondrial permeability transition, a target implicated in cardiac reperfusion injury (Schaller et al, www.ncbi.nlm.nih.gov/pubmed/20215409). The compound is taken up rapidly by cardiac tissue and interacts with the cholesterol uptake site of TSPO, a mitochondrial outer membrane protein that is highly expressed in heart.
In vitro studies using isolated cardiomyocytes showed that TRO40303 improved oxidative stress-induced cardiomyocyte survival. This was correlated with a reduction in reactive oxygen species production, reduced mitochondrial calcium overload and slowed triggering of mitochondrial permeability transition, reducing the release of apoptotic factors, all key events in cardiac reperfusion injury. The discovery and development of TRO40303 through phase I was supported in part by a grant of nearly €1 million from the French Agence Nationale pour la Recherche in a project named IRIstop.
