UPDATED February 11, 2016 // Defibrotide has shown promising efficacy in phase 2 studies for the treatment of hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), a rare but all too often fatal complication of hematopoietic stem cell transplantation (HSCT).
Now, phase 3 data uphold that promise.
The researchers are hoping that the results will be sufficient for approval by the United States Food and Drug Administration (FDA). A decision is expected by March 31.
The drug is already approved for the treatment of severe VOD in Europe, under the name Defitelio (Jazz Pharmaceuticals, Inc).
At present, defibrotide is available in the United States as an investigational new drug for the treatment of patients with hepatic VOD with multiorgan dysfunction, defined as renal or pulmonary dysfunction, following HSCT.
Novel Use of Historical Controls
The phase 3 trial made novel use of historical controls to assess the safety and efficacy of defibrotide and to show that the drug confers significant survival benefit in adult and pediatric HSCT patients who develop this serious complication as a result of their transplant.
The results were published online on January 29 in Blood.
"We used a novel methodology to generate rigorously selected historical controls, which is in itself a novel approach to the investigation of a life-threatening orphan disease," lead author Paul G. Richardson, MD, from the Dana-Farber Cancer Institute in Boston, told Medscape Medical News.
"This is a syndrome that in its severe form can result in 80% to 90% mortality. Defibrotide is a therapy shown to be effective for severe VOD/SOS in a number of phase 2 studies, so there was a lack of equipoise in randomizing patients to a treatment that could be lifesaving, versus just best supportive care. Conversely, the use of rigorous historical control methodology has hopefully met the requirement for an adequate comparator," Dr Richardson said.
Defibrotide a "Great Advance"
"Veno-occlusive disease has been a devastating complication of transplantation, with a very high risk of dying when patients develop it, and there hasn't been any good intervention," Linda J. Burns, MD, medical director at the Health Services Research Center for International Blood and Marrow Transplant Research in Minneapolis, told Medscape Medical News.
"What we typically do for patients is support them as best we can, and some of them will heal and survive, but that is a minority of patients," Dr Burns commented. She was not involved in the research but said that she has used defibrotide in her patients.
"It has been studied in previous clinical trials, so it is exciting to see these good results borne out in this phase 3 trial. It is a wonderfully done study, and I am very hopeful that it will meet with FDA approval," she said.
Dr Richardson, who was instrumental in the original discovery of this indication for defibrotide, presented results of the phase 3 trial at a meeting last year, as reported by Medscape Medical News.
The trial was conducted in 102 patients with established hepatic VOD/SOS and advanced multiorgan failure. The patients received defibrotide 25 mg/kg per day intravenously for 21 days.
The patients were compared with 32 carefully matched historical control persons who were identified from 6867 medical charts of HSCT patients by a blinded, independent medical review committee.
Survival rates 100 days post HSCT were 38.2% for the defibrotide group and 25.0% for the control group (estimated difference, 23.0%; 95.1% confidence interval [CI], 5.2% - 40.8%; P = .0109).
Complete response rates were 25.5% for the defibrotide patients and 12.5% for the control persons (19% difference; 95.1% CI, 3.5% - 34.6%; P = .0160).
"Defibrotide has lifesaving potential in my view, and this trial demonstrates this with a significant reduction in mortality," Dr Richardson said. "Given that over 80% of patients died without treatment and 40% survived with the use of defibrotide therapy as part of this trial, the results are particularly compelling. This is additionally significant, because these were patients with very advanced multiorgan failure in whom little or no survivorship would be expected.”
"The difference in complete response is also highly significant, and further supports a treatment effect," he added.
Data from other trials show that defibrotide is more effective when given early, or even prophylactically, Dr Richardson said, citing a study by Dr Selim Corbacioglu and colleagues, published in 2012 in the Lancet, in which defibrotide was given prophylactically in high-risk children undergoing transplant, and the incidence of VOD was reduced by 50%.
Defibrotide is a first-in-class oligonucleotide that was originally discovered as a byproduct of heparin. It is derived from porcine mucosa, Dr Richardson explained.
Remarkably, defibrotide appears to stabilize endothelium and has both profibrinolytic effects and antithrombotic properties without significant systemic bleeding risk. It also has anti-inflammatory properties.
The development of defibrotide was based on a hypothesis that Dr Richardson first proposed in 1995. The agent was initially developed by Pharma Research SRL, a spinoff from Crinos Industria Farmacobiologica SpA, an Italian company focused on developing compounds to correct coagulation and thrombotic disorders, he said.
In 2013, Jazz Pharmaceuticals acquired rights to the drug for distribution in Europe and, in 2014, in the United States.
Dr Richardson said that intellectual property rights regarding defibrotide for this indication were deferred to facilitate its development. "We just wanted to move the process as quickly as possible for this life-threatening complication of transplant, and the company, to its great credit, approached this as a true mission of mercy, despite the real risks of studying a new and unapproved agent in a high-risk setting."
Dr Richardson admitted he is very excited about the results from the study.
"Defibrotide is a potentially lifesaving drug, in my opinion, and to see it demonstrated to be effective in such sick patients with no other treatment options is very gratifying."
Dr Burns agrees that his excitement is warranted.
"I concur. Before, we did not have anything to offer these patients. I've been in the transplant field for almost 30 years. I've had many patients die from this syndrome because of the drugs I've had to give them that are vital to be used for transplant. My hope is that this will be very helpful, and also that this research will provide guidance to physicians on how to use the drug safely and effectively," she said.
The study was supported by Jazz Pharmaceuticals. Dr Richardson is a member of advisory committees for and has received research funding from Jazz Pharmaceuticals. Dr Burns has disclosed no relevant financial relationships.
Blood. Published online January 29, 2016. Abstract
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Cite this: Defibrotide's Promise in Rare but Fatal Syndrome Post HSCT - Medscape - Feb 08, 2016.