The FDA has approved defibrotide sodium (Defitelio) as a treatment for severe hepatic veno-occlusive disease (VOD) with associated kidney or lung abnormalities following hematopoietic stem cell transplantation (HSCT), based on data from the collection of 3 studies.
Across the single-arm trials, two of which were prospective and one that was an expanded access study, 38% to 45% of patients were alive at 100 days following HSCT. The current 100-day survival rates with best supportive care following HSCT for patients with severe hepatic VOD are 21% to 31%, according to the FDA.
Severe hepatic VOD occurs in approximately 2% of patients treated with HSCT and has an 84% mortality rate. The approval for defibrotide followed a priority review by the FDA that was granted after a rolling submission that was allowed under a fast track designation. The PDUFA deadline was March 31, 2016.
“The approval of Defitelio fills a significant need in the transplantation community to treat this rare but frequently fatal complication in patients who receive chemotherapy and HSCT,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement.
The 3 studies that were instrumental in the approval of defibrotide included 528 patients with hepatic VOD and multi-organ dysfunction after HSCT. The FDA recommended dose of intravenous defibrotide based on these studies is 6.25 mg/kg every 6 hours until resolution of VOD.
In the first study, which was a phase III trial with 102 patients, the 100-day post-HSCT survival rate was 38.2%. In the second study, which enrolled 75 patients, the 100-day survival was 44% (95% CI, 33-55). In the final study, which was an expanded access program that contained 351 patients, the 100-day survival rate was 45% with defibrotide (95% CI, 40-51).
Specifically in the phase III study, which was published inBlood, defibrotide was explored in 102 adult and pediatric patients with hepatic VOD and advanced multi-organ failure. Daily defibrotide was administered at 25 mg/kg. Outcomes for patients in the defibrotide arm were compared with historical data from 32 control patients with similar baseline characteristics.
The 100-day post-HSCT survival rate was 38.2% in the defibrotide arm compared with 25.0% in the control group, representing an estimated difference of 23.0% (95.1% CI, 5.2%-40.8%;P= .0109). The complete response rates after 100 days were 25.5% with defibrotide versus 12.5% in the control arm, which was a 19% difference (95.1% CI, 3.5-34.6; P= .0160).
The most common adverse events (AEs) associated with defibrotide were hypotension, diarrhea, vomiting, nausea, and epistaxis, which were typically manageable. Defibrotide is contraindicated for patients on concurrent anticoagulants or fibrinolytic therapies.
Hypotension, which was the most common AE, occurred in 39.2% of patients treated with defibrotide versus 50% in the control arm. There were no differences in other common hemorrhagic AEs between defibrotide and the control, respectively, including pulmonary alveolar (11.8% and 15.6%) and gastrointestinal (7.8% and 9.4%).
"Based on the results of this pivotal phase III study, we believe defibrotide provides a promising treatment option for patients with this urgent unmet need," lead author and principal investigator Paul G. Richardson, MD, Dana-Farber Cancer Institute, said in a statement when the data were published in Blood. "Although HSCT has improved substantially over the last decade, hepatic VOD with multi-organ failure remains a very real and life-threatening complication post-HSCT, and for which there are no currently approved therapies."
Prior to the FDA approval, defibrotide received an orphan drug designation to prevent VOD in May 2003. Additionally, in October 2013, defibrotide was approved by the European Medicines Agency under exceptional circumstances for severe hepatic VOD.