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 the successful completion of its phase 1 dose escalation study of TRO40303, a novel mitochondria pore modulator. 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).
“We are very pleased with the highly satisfactory results of this rigorous and extensive phase 1 study of TRO40303. This will allow us to initiate our important phase 2 proof-of concept trial of TRO40303 in the second half of this year with our consortium partners in the EU funded MitoCare project,” 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 is a tremendous opportunity for our 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 program 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, in a phase 3 study for the orphan neurological disease of amyotrophic lateral sclerosis as part of the EU funded MitoTarget project.”
The objective of the phase 1 study was 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 demonstrate that TRO40303 can be safely administered by the i.v. route in humans at doses expected to be pharmacologically active. Trophos plans to present the full results of this study at a major cardiology congress in the second half of 2011.
The phase 2 proof-of-concept study of TRO40303 is to be sponsored by Trophos and performed as part of the EU funded MitoCare project (see release of December 14, 2010) 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). TRO40303 will be administered as a single i.v. infusion prior to the reperfusion by angioplasty.
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 an animal model of MI, treatment with TRO40303 at the time of reperfusion was shown to significantly reduce infarct size.
This innovative program has been supported by a grant of nearly 1M Euros by the French Agence Nationale pour la Recherche (ANR) in a project named IRIstop.