Defibrotide Mechanism of Action Data to Be Presented at Mechanisms Linking Cancer and Inflammation Symposium.

Defibrotide Shown to Modulate Immune Functions of the Endothelium 

VILLA GUARDIA (Como), Italy -- Gentium S.p.A. (NASDAQ:GENT) today announced that mechanism of action data on Defibrotide will be presented in a poster entitled "Defibrotide, A DNA-Based Drug, Modulates Immune Functions Of The Endothelium: Impact For Cancer Therapy And Transplantation," authored by G. Eissner, Ph.D., Vice President, Chief of Biology Research for Gentium; M. Iacobelli, M.D., Vice President, Scientific Director for Gentium; G. Koehl; E. Geissler; R. Andreesen; and E. Holler. The poster will be presented at the Keystone Symposium "Mechanisms Linking Inflammation and Cancer," held in Santa Fe, N.M., February 10-15, 2007. The poster will be presented in the first Poster Session of the Symposium on Sunday, February 11, from 7:30 p.m. to 10:00 p.m. Mountain time.

Defibrotide, the Company's lead product candidate in the U.S., is an investigational drug that has been granted Orphan Drug status by the U.S. Food and Drug Administration to prevent and to treat severe veno-occlusive disease (VOD) and Fast Track designation for the treatment of severe VOD in recipients of stem cell transplants. Defibrotide is currently in a U.S. Phase III trial to treat severe VOD and a European Phase II/III trial to prevent VOD in pediatric patients.

The authors of the paper concluded, "Our data suggest that while Defibrotide is known for its anti-inflammatory and endothelium-protecting function, it also inhibits (tumor) blood vessel formation, and thus should be considered for further testing as an anticancer agent. A combination of Defibrotide with (suboptimal) concentration with other angiogenesis inhibitors could reduce treatment related toxicities that have been observed in the past."

In the preclinical study to be presented by Dr. Eissner, the anti-angiogeneic potential of Defibrotide was tested in vitro using human microvascular endothelial cells forming vessel structures across a layer of dermal fibroblasts. The results demonstrated that Defibrotide at concentrations corresponding to pharmacologic Defibrotide blood levels reduces vessel formation significantly when applied on a daily basis. This result could be confirmed by alternative in vitro angiogenesis assays.

In vivo, the murine dorsal skin-fold chamber model was used and is based on inoculating human gastric cancer (TMK-1) cells. Tumor angiogenesis was significantly attenuated by Defibrotide, as assessed by the computer-guided Image J analysis of the microvascular density in micrographs.

Regarding the signal transduction mechanism of Defibrotide, Western blotting results show that Defibrotide reduces phosphorylation-activation of p70S6 kinase, which is a key target in the PI3K/Akt/mTOR signaling pathway linked to angiogenesis. In addition, proliferation assays suggest that Defibrotide selectively blocks migration and tube formation of endothelial cells and does not influence endothelial proliferation.

Commenting on these data, Laura Ferro, M.D., president and chief executive officer of Gentium, said, "These preclinical results further define Defibrotide's mechanism of action and provide us with greater insight into its potential as an anticancer agent. Further, these data corroborate the clinical benefit Defibrotide has demonstrated in a variety of human clinical settings, including VOD, multiple myeloma and deep vein thrombosis, to name a few."

About VOD

Veno-occlusive disease (VOD) is a potentially life-threatening condition. Certain high-dose chemotherapy and radiation therapies and stem cell transplantation (SCT) can damage cells of the blood vessels and result in VOD, a blockage of the small veins of the liver that can lead to liver failure and the failure of other organs (severe VOD). SCT is a frequently used treatment following high-dose chemotherapy and radiation therapy. The International Bone Marrow Transplant Registry estimated that in 2002 approximately 45,000 people received blood and bone marrow transplants, which are types of SCT. Based on the Company's review of more than 200 published papers, it believes that approximately 20% of patients who undergo SCT develop VOD, approximately one-third of those who develop VOD progress to severe VOD and approximately 80% of severe VOD patients die within 100 days of the SCT. The Company believes that there are no approved therapies to treat or prevent VOD in the U.S. or the EU.

About Gentium

Gentium S.p.A. is a biopharmaceutical company focused on the research, discovery and development of drugs derived from DNA extracted from natural sources, and drugs that are synthetic derivatives, to treat and prevent a variety of vascular diseases and conditions related to cancer and cancer treatments. Defibrotide, the Company's lead product candidate in the U.S., is an investigational drug that has been granted Orphan Drug status by the U.S. Food and Drug Administration to prevent and to treat VOD and Fast Track designation for the treatment of severe VOD in recipients of stem cell transplants.

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