A Comprehensive Monograph on Defibrotide (DB04932)

Executive Summary

Defibrotide represents a unique therapeutic agent in modern medicine, distinguished by its singular role as the only approved treatment for a rare, fulminant, and often fatal complication of hematopoietic stem-cell transplantation (HSCT). Marketed under the brand name Defitelio®, Defibrotide is a complex biologic drug, comprising a purified mixture of single-stranded polydeoxyribonucleotides derived from porcine intestinal mucosa.[1] Its sole indication is for the treatment of severe hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), accompanied by renal or pulmonary dysfunction.[3] This condition, which arises from endothelial damage caused by high-dose conditioning chemotherapy, carries a mortality rate exceeding 80% when left untreated.[1]

The mechanism of action of Defibrotide, while not fully elucidated, is understood to be pleiotropic, centered on the protection of vascular endothelial cells and the restoration of local thrombo-fibrinolytic balance in the hepatic microvasculature.[1] It exerts profibrinolytic, antithrombotic, and anti-inflammatory effects, primarily by modulating key regulatory proteins on the endothelial surface without inducing significant systemic anticoagulation.[2] The clinical efficacy of Defibrotide was established through a series of studies, including a pivotal Phase 3 trial that demonstrated a statistically significant improvement in Day +100 survival rates compared to meticulously selected historical controls.[6] This evidence base, while unconventional, was deemed sufficient for regulatory approval given the extreme lethality of the disease and the ethical impossibility of conducting a placebo-controlled trial.