Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease: An Analysis of Clinical Benefit As Determined By Number Needed to Treat (NNT) to Achieve Complete Response and to Improve Survival

Introduction: Hepatic veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplantation (HSCT) and, in severe cases, is associated with multi-organ failure and mortality rates exceeding 80% (Coppell et al. Biol Blood Marrow Transplant, 2010, p157-168). In the US there are currently no FDA-approved treatments for severe VOD. Defibrotide, an oligonucleotide with a mechanism of action that encompasses both restoration of the thrombo-fibrinolytic balance and endothelial cell protection, has recently been approved for the treatment of severe VOD following HSCT in the EU. The data presented are based on the primary and secondary endpoint analyses provided to the European Medicines Agency (EMA) that formed the basis of the defibrotide approval in the EU.

Methods: A pivotal phase 3 study examined the efficacy and safety of defibrotide 25 mg/kg/day in patients with severe VOD (n=102) compared to historical controls (n=32) (Defibrotide Summary of Product Characteristics. Villa Guardia, Italy: Gentium SpA; 2013). The study’s primary endpoint was complete response (CR) (in terms of improvements in total bilirubin and resolution of multi-organ failure measured by renal and/or pulmonary dysfunction) by 100 days post-HSCT; secondary endpoints included survival 100 days and 180 days post-HSCT. We calculated the number needed to treat (NNT) with defibrotide to achieve one complete response and the NNT to prevent one death 100 days post-HSCT in patients with severe VOD compared to historical controls who did not receive defibrotide in order to evaluate how defibrotide compared to other novel and efficacious agents used for rare conditions in hemato-oncology. NNT is calculated as the reciprocal of the absolute risk reduction (1/ARR), where ARR is equal to the control minus experimental event rates (Laupacis et al, New Engl J Med, 1988, p1728-1733).

Results: In the defibrotide trial, complete response by day 100 was achieved in 23.5% of the defibrotide-treated patients and 9.4% of the historical controls (P=0.013), which equated to an NNT of 7 (1/(0.235-0.094)) to achieve one complete response 100 days post-HSCT. Day 100 survival was 38.2% in the defibrotide group and 25.0% in the historical control group (P=0.034) (Defibrotide Summary of Product Characteristics. Villa Guardia, Italy: Gentium SpA; 2013). Therefore, the NNT to prevent one death in this study was 8 (1/(0.382-0.25)). To compare the NNTs in this analysis with those in other studies, a literature search was conducted, identifying a selected number of pediatric oncology clinical trials published within the previous 10 years each of which reported 5-year EFS rates (Sorrell et al, Cancer, 2012, p4806-4814; La et al, Int J Radiat Oncol Biol Phys, 2011, p1151-1157; Chou et al, Cancer, 2009, p5339-5348; Lange et al, Blood, 2008, p1044-1053; MacDonald et al, Cancer, 2005, p2862-2871). NNTs calculated from that review ranged from 5 to 50.

Conclusion: The results of this pivotal Phase 3 trial showed improved complete response and survival in defibrotide-treated patients compared to historical controls who did not receive defibrotide for the treatment of severe VOD. The number needed to treat to achieve this benefit proved either comparable or lower than the NNT obtained for other widely-accepted and approved therapeutic medical interventions in hemato-oncology.

Support: Jazz Pharmaceuticals

Off-Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease in the United States.