Data Supports Potential Mechanism for Gentium's Defibrotide in Cancer, Diabetic Nephropathy and Veno-Occlusive DiseaseNEW YORK--(BUSINESS WIRE)--Jul 16, 2007 - Gentium S.p.A. (Nasdaq: GENT) announced the presentation of six of preclinical abstracts and posters supporting key mechanism for of Defibrotide in the regulation, inhibition and protection of key regulatory proteins effecting human cancers, diabetic nephropathy and endothelial damage. The data was presented at the International Society on Thrombosis and Haemostasis in Geneva, Switzerland being held from July 6 - 12, 2007.
"Results presented at this meeting are very important in the further elucidation of the mechanistic behavior of Defibrotide in these diseases," commented Laura Ferro, M.D., President and CEO of Gentium. "They further support the results that we have seen in prior clinical trials of Defibrotide to treat veno-occlusive disease and multiple myeloma."
In the first poster, entitled: DEFIBROTIDE DIRECTLY ENHANCES THE ACTIVITY OF PLASMIN investigators reported data that supported the ability of Defibrotide to enhance the activity of Plasmin, a potent and non-specific serine protease that employs a pivotal function in fibrinolysis by virtue of its ability to effectively degrade fibrin clots. The fibrinolytic activity in humans should be depressed in many diseases and conditions, including hepatic veno-occlusive disease. The stimulation of plasmin by Defibrotide was concentration-dependent. Investigators believe that these findings can, in part, explain the fibrinolytic activity of Defibrotide.
In the second poster, entitled: DEFIBROTIDE MODULATES HEPARANASE EXPRESSION IN ENDOTHELIAL AND TUMOR CELLS: A POTENTIAL MECHANISM OF ACTION, investigators presented data supporting the ability of Defibrotide to reverse the heparanase gene expression induced by glucose. A significant downregulation of heparanase gene expression was also observed in multiple myeloma cells. Studies revealed that Defibrotide is able to downregulate heparanase expression in a dose dependent manner. heparanase is a critical factor in maintaining the integrity of glomerular basement membrane seen in such conditions as diabetic nephropathy, contributes to tumor cell invasion and angiogenesis.
In the third poster, entitled: DEFIBROTIDE PROTECTS ENDOTHELIAL CELLS AGAINST STRESS-INDUCED CELL DEATH VIA INHIBITION OF THE EXTRINSIC APOPTOSIS PATHWAY, investigators, whom had previously shown that Defobrotide can save endothelial cells from chemotherapy induced apoptosis, presented data addressing the question whether Defibrotide can also protect against other forms of cell stress and which signal transduction mechanisms underlie this protection. Results demonstrated that Defibrotide protects endothelial cells against chemotherapy- and starvation-induced cell death, whereupon the mechanism is rather the blockade of the extrinsic apoptosis pathway instead of an active proliferation induction, suggesting no interference with the intrinsic apoptotic pathway.
In a fourth poster entitled: THE PHARMACOKINETICS OF DEFIBROTIDE IN NON-HUMAN PRIMATES IS DOSE DEPENDENT investigators presented data that further supporting linear dose dependant and pharmacokinetic activity of Defibrotide in animals. These data confirm direct methods of measuring pharmacokinetics of Defibrotide with a colorimetric method.
In a fifth poster, entitled: DEFIBROTIDE MEDIATED INHIBITION OF HEPARINASE I. POTENTIAL CLINICAL IMPLICATIONS investigators concluded that the potentiation of the anticoagulant effect of heparin in patients treated simultaneously with Defibrotide may be due in part to the inhibition of endogenous heparin degrading enzymes. Defibrotide has been shown to release antithrombotic mediators such as tissue factor pathway inhibitor (TFPI). In this study, co-administration of Defibrotide with heparin produced an augmentation of the effect of heparin and an increase in the biologic half-life. Defibrotide produced an almost complete inhibition of heparinase digestion. Subsequent studies in animals have revealed that the anticoagulant effects of both unfractionated heparin and low molecular mass heparins are potentiated by Defibrotide.
In a sixth poster, entitled: DEFIBROTIDE AND ITS MOLECULAR FRACTIONS DO NOT CROSS-REACT WITH HIT ANTIBODIES. IMPLICATIONS IN THE MANAGEMENT OF HIT, investigators presented important preclinical data that support that Defibrotide does not cross-react with heparin-induced antibodies. Heparin induced thrombocytopenia (HIT) is an immune disease related to heparin exposure, in which patients are at risk of developing life- and limb-threatening thrombosis caused by the formation of certain antibodies. Serum for 141 patients was evaluated in the presence of Defibrotide. Results of these studies demonstrated that HIT antibodies are not generated with defibrotide treatment.
Gentium, S.p.A., located in Como, Italy, is a biopharmaceutical company focused on the research, development and manufacture of drugs to treat and prevent a variety of vascular diseases and conditions related to cancer and cancer treatments. Defibrotide, the Company's lead product candidate, is an investigational drug that has been granted a Fast Track Designation by the U.S. FDA to treat Severe VOD in recipients of stem cell transplants, Orphan Drug status by the U.S. FDA to treat and prevent VOD and Orphan Medicinal Product Designation by the European Commission to treat and prevent VOD.
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Gary Gemignani, 212-332-1666
Chief Financial Officer
Posted: July 2007