Gentium completes Defibrotide clinical studies, plans to file for regulatory approval

Gentium S.p.A. today announced that ongoing preclinical and clinical studies on Defibrotide have been completed and confirmed its plan to file for regulatory approval of Defibrotide with the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) by the end of the second quarter of 2011.

In the preclinical studies conducted, Defibrotide showed no inhibitory effects in human liver microsomes, indicating that Defibrotide is expected to have a low potential for drug-drug interaction.

In a reproductive toxicity study in rats and rabbits, Defibrotide given by 2-hour infusion showed maternal toxicity with effects on pregnancy and intrauterine development of the progeny, while effects on embryofetal development could not be determined. Defibrotide is being developed for the prevention and treatment of Veno-Occlusive Disease (VOD) in stem cell transplant recipients. Given the disease status and pre-transplant and chemo-inductive therapy regimens, pregnant females are unlikely to be included in the Defibrotide population.

A hERG tail current study with Defibrotide showed no inhibition of the hERG channel at any of the doses tested.

In line with these findings, a thorough ECG study demonstrated that Defibrotide did not prolong QT/QTc interval in healthy human volunteers at either the therapeutic dose (6.25 mg/kg) or at the supra-therapeutic dose (15 mg/kg), and showed no effects on other ECG parameters. The expected effect on the QT/QTc interval was observed with moxifloxacin as a positive control.

Also in line with previous studies, plasma pharmacokinetics in these healthy volunteers typically showed that Defibrotide had short half-life dose-dependent increase in Cmax and AUC and dose-independent clearance.

"No serious adverse events were reported in any of the 52 healthy subjects enrolled in our studies," said Dr. Massimo Iacobelli, Scientific Director of Gentium S.p.A. "A total of 30 mild adverse events were reported in 13 subjects: 5 in the Defibrotide therapeutic dose arm, 3 in the Defibrotide supra-therapeutic dose arm, 9 in the placebo arm, and 13 in the moxifloxacin arm. These results indicate that both the therapeutic dose and supra-therapeutic dose of Defibrotide were well tolerated in healthy volunteers."