Defibrotide Approved for Hepatic VOD After Stem Cell Transplant

March 30, 2016
Silas Inman

The FDA has approved a new agent for the treatment of severe hepatic veno-occlusive disease, a rare but often fatal complication in patients who receive chemotherapy and hematopoietic stem cell transplantation.

The FDA has approved a new agent for the treatment of severe hepatic veno-occlusive disease (VOD), a rare but often fatal complication in patients who receive chemotherapy and hematopoietic stem cell transplantation (HSCT).

Defibrotide sodium (Defitelio) garnered FDA approval based on data from three trials which collectively showed that with the agent, 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.

The FDA approval is for the treatment of adult and pediatric patients who experience VOD (also known as sinusoidal obstructive syndrome [SOS]) with renal or pulmonary dysfunction following HSCT. Severe hepatic VOD occurs in approximately 2% of patients treated with HSCT and has an 84% mortality rate.

"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 the journal Blood.

"Although HSCT has improved substantially over the last decade, hepatic VOD/SOS with multi-organ failure (MOF) remains a very real and life-threatening complication post-HSCT, and for which there are no currently approved therapies."

The three 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 involving 102 adult and pediatric patients with hepatic VOD and advanced MOF, daily defibrotide was administered at 25 mg/kg, and outcomes for patients in the defibrotide arm were compared with historical data from 32 control patients with similar baseline characteristics. In this trial, 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%. The complete response rates after 100 days were 25.5% with defibrotide versus 12.5% in the control arm—a 19%.

In the second study, which enrolled 75 patients, the 100-day survival was 44%. In the final study, which was an expanded access program that contained 351 patients, the 100-day survival rate was 45% with defibrotide.

The most common adverse events (AEs) associated with defibrotide were hypotension, diarrhea, vomiting, nausea, and epistaxis, which were typically manageable. 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%).

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.

Richardson PG, Riches ML, Kernan NA, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure [published online ahead of print January 29, 2016]. Blood.