University of Milan spin-off founded in 2004 and now fully owned by Genextra S.p.A.
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1 Mitochondrial Platform Targeting the Permebility Transition Pore
2 Company Overview University of Milan spin-off founded in 2004 and now fully owned by Genextra SpA Focused on identifying and advancing novel chemical classes of small molecules designed to modulate the activity of the mitochondrial permeability transition pore (mptp), a validated mitochondrial target involved in cellular ageing, senescence and apoptosis Proprietary medicinal chemistry: pipeline of rationally designed NCEs Has assembled technologies and unique knowledge of mitochondrial stressinduced damage and its effects on cellular ageing Highly talented team and committed world-class mitochondria experts advisors R&D facilities based within the IFOM-IEO Campus facilities in Milan 2
3 Background 100% 100% 53% 79% DRUG DISCOVERY DRUG DISCOVERY NANOTECHNOLOGY MITOCHONDRIAL MPTP ONCOLOGY TARGETED DIAGNOSTICS NANOTECH PLATFORM THERAPIES PLATFORM T P DRUG DISCOVERY BILE ACIDS THERAPEUTICS University of Milan Spinoff Created by Genextra University of Milan Spinoff acquired by Genextra 3
4 Novel Drug Discovery Platform Today Focus Achieved Compounds in development for clinical use in AMI Foundation Founded on break-through discoveries on p66/mptp pathway Key Insight Identifying the mptp as downstream key molecular target involved in mitochondrial stress induced cellular ageing Developed innovative HTS/Screened 270,000 compounds and identified novel mptp inhibitors POC validation in animal models Evaluating potential in other diseases Unique knowledge on PTP biology mptp inhibitor chemistry Nature 1999 Cell, Vol Nature :309-13; Cell, Vol 122, , July 29, 2005 Broad therapeutic potential 4
5 mptp Mechanism of Action The mitochondrion in a healthy cell CYTOSOL INTERMEMBRANE SPACE II I Q III C IV MATRIX 5
6 mptp opening and cell death CYTOSOL (release of apoptotic factors) Outer membrane rupture The mitochondrion in a diseased cell C C C C C Solutes Ca 2+ overload Oxidative stress I II Q III IV MATRIX (swelling) Cessation of respiration (loss of Ψ m ) Reversal of ATP synthase Energy depletion Matrix swelling and OMM rupture Release of apoptotic factors Necrosis/Apoptosis Ca 2+, ATP, Ψ, p66sch, ROS mptp OPENING free diffusion of solutes across the membranes APOPTOSIS/ NECROSIS DISEASE 6
7 The mptp and Disease Assesment of infarct size by biomarker measurment Serum creatine kinase measurment every 4 hours on day 1 and every 6 hours on day 2 and 3 after coronary reperfusion CsA administration results in a reduction in infarct size Neuroprotective effects of systemic NIM811 (CypA analogue) on ischemia-induced brain of approximately 40% as measured by creatine kinase release damage SHR rats were subjected to 2hrs of focal ischemia by CCA-MCA occlusion followed by treatment with either vehicle or NIM811 at 1hr after commencement of reperfusion and mean infarct volumes measured at 24hrs There is no difference between DMSO-treated and untreated animals Tissue damage was reduced by ~40% in animals treated with NIM811 compared to treatment with vehicle Ppif -/- mice (cyd null) Effect of CypD deficiency on spatial learning and memory Mice were tested in 6-arm radial water maze Transgenic AD-type mice overexpressing mutant amyloid precursor protein and Ab (mapp) made more errors in locating the hidden platform than other groups of mice mapp/ppif-/- mice demonstrated Survival times following diagnosis of better performance than mapp late-stage ALS in mice caryying the SOD1-G93A mutant gene At diagnosis intracerebroventricular infusions of CsA or its vehicle were started Endpoint was paralysis of both hindlimbs Group mean Studies using CsA and Ppif -/- mice (cypd null - a molecular component of the mptp) have highlighted a potential role for the mptp in the values are represented by horizontal bars progression of several diseases Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy are inherited muscle disorders caused by mutations of genes encoding the extracellular matrix protein collagen VI Histological analysis of skeletal muscles from wild-type, knockout (Col6a1-/-) and double knockout (Col6a1-/-, Ppif-/-) mice show a different quantification of damagedfibers from diaphragms Changes in mitochondrial absorbance after 10 min of incubation with PEG The greater the change in absorbance, the greater the mitochondrial shrinkage CypD inhibitor, Debio-025, reduces mitochondrial swelling and necrotic disease manifestation in mdx mice, a model of Duchenne muscular dystrophy 7
8 mptp Inhibitors for the Treatment of Lethal Reperfusion Injury in the Setting of Acute Myocardial Infarction
9 Congeania s mptp Inhibitors for the Treatment of Ischemia Reperfusion Injury in Acute Myocardial Infarction Congenia has identified mptp inhibitors for the treatment of ischemia reperfusion injury in the setting of acute myocardial infraction Selection of IND candidate 3Q 2010 Treatment administered to patients iv 5 mins before Balloon angioplasty (single iv bolus or continuous infusion are clinical possibilities) Equal or better clinical efficacy than Cyclosporin A Heart ischemia leads to infarct size of up to 70% Reperfusion of tissue can reduce infarct size, but paradoxically reperfusion also leads to tissue death and contributes to final infarct size (LRI) Methods to reduce LRI have shown clinical benefit 9
10 PoC in Rabbit In Vivo Myocardial Infarction Model When given 5 mins before reperfusion CG-PTPi_2 is cardioprotective in an in vivo Rabbit model of acute myocardial infarction Cardioprotection at this dose in this Rabbit model was similar to CsA Necrotic Area (g) vehicle A-B CG-PTPI_2 CsA Rabbits were subjected to Left Anterior Descending (LAD) coronary artery occlusion for 30 mins followed by 4 hrs of reperfusion CG-PTPi_2 (15 mg/kg) and CsA (10 mg/kg) were administered by iv bolus 5 mins prior to reperfusion Note, as with CsA in the clinical proof of concept trial, there is greater protection when the area at risk is larger (In collaboration with Prof Ovize, Ospice di Lyon) Area at Risk (g) Infarcted area / area at risk Control * CsA 10 mg/kg * p = 005 * CG-PTPi_2 15 mg/kg 10
11 Summary Created and performed an innovative HTS to screen for compounds that inhibit the mitochondrial permeability transition pore (mptp) Identified several chemical classes of mptp inhibitors Identified compounds that are more potent than CsA and act via a different molecular component of mptp Human PoC in acute myocardial infarction has been obtained with cyclosporine A a known Cyp D (mptp) inhibitor However, due to numerous limitations of CsA, there is still a great need for a selective and potent mptp inhibitor Pre-IND development for AMI is ongoing 11
12 Congenia srl Via G De Grassi, Milan, Italy congeniainfo@congeniait
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