Results from Phase 3 Trial of Defibrotide for the Treatment of Severe Veno-Occlusive Disease and Multi-Organ Failure Published Online in BLOOD
"Based on the results of this pivotal phase 3 study, we believe defibrotide provides a promising treatment option for patients with this urgent unmet need," said lead author and principal investigator,
Defibrotide is an investigational agent in
About the Study
The phase 3 study investigated the safety and efficacy of defibrotide in adult and pediatric patients with established hepatic VOD/SOS with MOF. Patients (n=102) given 25 mg/kg/day defibrotide were compared with 32 historical controls identified from review of medical charts of HSCT patients by an independent medical review committee, blinded to outcome. Baseline characteristics between groups were well balanced. The historical-control methodology offers a novel approach for phase 3 evaluation of orphan diseases associated with high mortality, where a placebo control would be unethical.
Defibrotide was associated with a statistically significant improvement in Day +100 post-HSCT survival, the primary endpoint, compared to the historical controls. The estimated between-group difference in Day +100 survival was 23.0% (95.1% confidence interval (CI): 5.2%-40.8%; P=.0109), using a propensity-adjusted analysis. The difference of complete response (CR) rates by Day +100 post-HSCT, a secondary endpoint, resulted in an estimated between-group difference adjusted for propensity score of 19.0% (95.1% CI: 3.5 – 34.6; P=.0160). Median duration of treatment with defibrotide was 21.5 days.
Hypotension was the most common adverse event in both groups (39.2% with defibrotide and 50.0% for historical controls). Related adverse events included hemorrhage and hypotension. There was no difference in the incidence of common hemorrhagic events between defibrotide and the historical controls.
HSCT is a potentially curative procedure to treat patients with malignant and non-cancerous hematologic disorders such as leukemia, lymphoma and aplastic anemia, congenital immunodeficiency and autoimmune disorders.2 Hepatic VOD, also known as SOS, is a rare, early and life-threatening complication of HSCT.
In the U.S., defibrotide is an investigational drug for the treatment of patients with hepatic VOD with multi-organ dysfunction (MOD), defined as renal or pulmonary dysfunction, following HSCT. Defibrotide was granted Orphan Drug Designation by the
Defibrotide is being made available as an investigational new drug (IND) free of charge through an expanded access Treatment Protocol. The ongoing expanded access Treatment Protocol is currently enrolling patients diagnosed with VOD in the U.S. Expanded access programs are part of an effort by the
1. Coppell JA et al. Biol Blood Marrow Transplant. 2010; 16 (2): 157-168.
2. Ikehara S. New strategies for BMT and organ transplantation. Int J Hematol. 2002;76(Suppl 1):161-4.
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