First-in-Class Defibrotide for VOD Launched in Europe

Becky McCall

April 03, 2014

The first-in-class drug defibrotide (Defitelio, Gentium S.p.A., acquired by Jazz Pharmaceuticals in early 2014) was launched in Europe this week for use in the treatment of severe veno-occlusive disease (VOD), a life-threatening complication that can occur after hematopoietic stem cell transplantation (HSCT).

The drug was approved by the European Medicines Agency (EMA) in October 2013 for the treatment of severe VOD. It was recommended for approval in July 2013 after a resubmission and re-evaluation of the data.

In March 2013, an application for defibrotide for both the prevention and treatment of VOD was not recommended for approval. The company then removed the prevention part of the application, leaving the narrow indication of severe VOD, which is considered to be an unaddressed medical need.

In the United States, a registration file is in the process of being submitted to the US Food and Drug Administration (FDA).

Defibrotide, an oligonucleotide that acts as a polydeoxyribonucleotide adenosine receptor, has demonstrated antithrombotic, anti-inflammatory, and anti-ischemic properties.

The phase 3 registration data that formed the basis of the EMA approval showed a significant improvement in survival in patients with severe VOD, compared with historical control subjects. Those data, which will likely be submitted for publication in the near future, were originally discussed at the 2013 annual meeting of the European Society for Blood and Marrow Transplant (EBMT).

Phase 3 Registration Trial Results

The multicenter international registration trial was based at the Dana-Farber Cancer Institute in Boston, with participating sites across North America and in Israel, and was sponsored by Gentium S.p.A.

In the study, 102 patients with severe VOD were treated with defibrotide 25 mg/kg per day for a median of 22 days. Four doses were administered intravenously every 6 hours.

Those patients were compared with 32 patients who made up the historic control group.

"The risk characteristics of patients participating in this trial included advanced multiorgan failure. The patients were, by design, the severest in all of the trials that we have done with defibrotide to date," explained principal investigator Paul Richardson, MD, professor of medicine at Harvard Medical School in Cambridge, Massachusetts. "They were very sick patients with an otherwise dismal prognosis, including a mortality expected to be in excess of 80%," he told Medscape Medical News in an interview.

Survival 100 days after HSCT was 52% better in the defibrotide group than in the control group (38% vs 25%; P < .05). Specifically, more patients in the defibrotide group achieved a complete response 100 days after HSCT (24% vs 9%).

Hemorrhagic adverse events were similar in the defibrotide and control groups (65% vs 69%). In the defibrotide group, 18% of patients experienced a drug-related toxicity that led to discontinuation; otherwise, defibrotide was generally well tolerated.

"There was a significant difference in response rate and a significant difference in survival in favor of the defibrotide-treated patients," Dr. Richardson reported. "Importantly, the novel historic control methodology used was validated by other independent registry data showing that the historic controls were consistently reflective of what happens if severe VOD is left untreated, in both the published literature and from at least 2 major databases."

"Based on the validation of the historic controls, we feel comfortable that these data are reflective of clinical benefit," said Dr. Richardson.

He added that the data are further supported by a landmark EBMT prospective randomized prevention trial, which showed the clinical benefit of defibrotide in more than 400 high-risk pediatric patients (Lancet. 2012;379:1301-1309), as previously reported by Medscape Medical News.

Interim data from the Treatment of an Investigational New Drug Study — the largest prospective evaluation of defibrotide to date — were also discussed at the EBMT meeting.

Of the 470 patients with severe VOD, 425 had undergone HSCT. They received defibrotide 25 mg/kg per day for a minimum of 21 days.

Interim results show that survival 100 days after HSCT is 48%, and complete response is in excess of 30%. Both findings are highly consistent with previous studies, and much better than expected, Dr. Richardson noted

Modest Beginnings by a Lake in Northern Italy

The story of defibrotide began in 1995 in Como, Italy. In fact, as it has in some of medicine's greatest discoveries, serendipity played a hand in the discovery of defibrotide. "It dropped out of the production process of heparin, and the scientists at Crinos [as Gentium S.p.A. was then known] decided to take a closer look," Dr. Richardson explained.

Its development was based on a hypothesis first proposed by Dr. Richardson, and then embraced by the company. That led to the first data showing the clinical benefit of defibrotide in 19 patients with severe VOD treated on a compassionate basis (Blood. 1998;92:737-744).

Dr. Richardson's conviction in the product as a novel therapy for VOD was borne out of the frustration of seeing the adverse effects of the clot-busting therapies — heparin and tissue plasminogen activator (tPA) — used at the time.

The first and very compelling use of defibrotide was in a 28-year-old patient of Dr. Richardson with relapsed Hodgkin's disease who was undergoing stem cell transplantation with curative intent. After HSCT, she developed the life-threatening complication of VOD related to the conditioning treatment that affects the microvessels of the liver, damaging the endothelial lining, leading to vascular occlusion and, ultimately, liver failure, and she experienced both kidney and pulmonary failure as well.

She was initially treated with heparin and tPA, which both failed and also caused bleeding. "We then abandoned those treatments and started defibrotide with an FDA authorization for compassionate use," reported Dr. Richardson. "What was so remarkable was that she tolerated the drug really well, had a dramatic reduction in her bilirubin level after 12 days of treatment, and had an improvement in her syndrome overall."

At the 12-day point — the standard cutoff for heparin and tPA — Dr. Richardson held treatment; she stabilized for 2 days but then significantly worsened. Treatment was restarted and she completed 4 weeks of therapy with defibrotide, achieving a complete response.

"Her bilirubin was initially 55 mg/dL and nobody expected her to survive," he explained, but she went on to do very well, with long-term survival.

This patient was 1 of the 19 reported in the first data. After that publication, larger clinical trials were conducted, including the phase 3 trial that was submitted for registration.

"It's taken a long time to get to where we are now," Dr. Richardson said. "It was a unique partnership with a small Italian pharmaceutical company that was willing to test this agent in such a difficult and challenging setting. Together, we [at Dana-Farber] built a foundation with various research grants for the project, and the company provided free drug, as well as supporting our determination to see this drug fulfill its potential for this life-threatening condition."

Reversal of the Physician–Company Relationship

The story of defibrotide turns the conventional concept of the pharmaceutical company–physician partnership on its head. Rather than having the pharmaceutical company vigorously promote a drug to the clinic, the doctors led the way. "We moved forward slowly because initially Gentium had only limited experience in developing new drugs and the field was incredibly complex, with no previous approvals in this setting, making this very much a learning experience for all of us," Dr. Richardson explained.

Defibrotide is a significant example of a progressive physician–pharma relationship, said Mohamad Mohty, MD, professor of hematology at Saint-Antoine Hospital and University Pierre & Marie Curie in Paris, and president-elect of the EBMT.

"This is a really a true model of how society can work hand in hand with pharmaceutical companies to develop effective products," said Dr. Mohty. "It's a crossfertilization, in that it allows us to let the company know what we need from a drug, and the company to let us know their needs from physicians. It can serve as a model to many other developments."

Dr. Richardson agrees that partnerships with pharma are a key way forward. "In reality, when we started the project years ago, it is reasonable to suggest that no mainstream pharmaceutical company would have so enthusiastically engaged in this type of problem, with such sick patients and in which attributable toxicities are very difficult to dissect," he said.

In fact, many leaders in the field have expressed their surprise at the development of defibrotide for severe VOD, acknowledging that this really is a place where even angels fear to tread, but applauded the achievement reflected by this unique approval.

"However, I truly believe that if you put the patient first and go from there, you usually won't go wrong," said Dr. Richardson, echoing a sentiment expressed by other clinicians at the meeting.

Defibrotide "has significantly improved patient outcomes in allogeneic and autologous transplants, and reduced the incidence of VOD," said Elaine Smyth, RGN, RSCN, nurse specialist in transplant at Our Lady's Children's Hospital in Crumlin, Dublin, who has used defibrotide under trial conditions for about 6 years. "Prior to this, children just received symptom management and still suffered terribly. Now we have reduced admissions to the ICU and hospital stays, with much better results overall."

For the continuing phase 3 study, Jazz Pharmaceuticals is collaborating with the EBMT to compile a registry of patients expected to undergo HSCT in the next 2 to 3 years.

An important part of the development of defibrotide is the support of the orphan products division of the FDA. A New Drug Application is currently being compiled, which the company hopes to have submitted and reviewed within the next year. In the absence of any approved treatments for VOD in the United States, defibrotide has been made available as an Investigational New Drug, through an expanded access treatment program, for patients with VOD.

Dr. Richardson reports serving on advisory committees for Gentium. Dr. Mohty reports receiving research support and honoraria from Gentium. Ms. Smyth has disclosed no relevant financial relationships.


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