Buoyed by the European Medicines Agency's recent reversal of its earlier negative decision on Defitelio (defibrotide), Gentium SpA unveiled its best ever quarter for the product and set out its stall on growing the market, albeit within a narrower indication.

The Como, Italy-based company recorded €7.8 million (US$10.4 million) in second-quarter sales for defibrotide, which it has sold on a named-patient basis in Europe for preventing or treating hepatic veno-occlusive disease (VOD) in patients undergoing hematopoietic stem cell transplant (HSCT). VOD is a rare but usually fatal complication of both autologous and allogeneic HSCT.

For the first six months of the year, the drug attained sales of €14.6 million, a gain of 26 percent on the same period in 2012. Total revenues for the company during the same period reached €18.3 million, and it recorded net income of €2.6 million. Cash at the end of the quarter stood at €16.2 million.

The company originally filed a European marketing authorization application in May 2011, but the EMA's Committee for Medicinal Products for Human Use (CHMP) formally issued a negative opinion last March, having earlier indicated its stance in advance feedback to the company. (See BioWorld Today, Feb. 25, 2013.)

The CHMP reversed that decision in late July, however, following a request for a re-examination from Gentium, which altered its positioning of the product. "We opted to no longer position the drug for prevention," CEO Khalid Islam told BioWorld Today. There is no other drug approved for the condition in either Europe or the US, where defibrotide has orphan drug designation. The appeal was the only one of six so far this year that has been successful, he said.

It remains to be seen whether physicians will continue to use the drug off-label in the preventive setting, particularly in high-risk patients, such as those with familial macrophage activation syndrome (FMAS) and osteopetrosis (also known as marble syndrome), where the risk of VOD can be 60 percent or more.

Prophylaxis or early therapy is "highly recommended" in consensus guidelines for managing the risk of VOD in osteopetrosis patients undergoing bone marrow transplant, issued by the European Society for Immunodeficiencies and the European Group of Blood and Marrow Transplantation.

The drug, a complex mixture of the salts of single-stranded oligo deoxyribonucleotides isolated from porcine mucosa, is thought to act by protecting patients from endothelial cell damage caused by irradiation or by chemotherapy, which can otherwise lead to increased levels of thrombosis and to vein occlusion. In the treatment setting, it is thought to act by upregulating plasmin activation, leading to a breakdown of blood clots.

Treatment of VOD currently accounts for a majority of sales. "The management estimates that it's 65 percent for treatment, 35 percent for prophylaxis," Islam said. Formal European Commission approval of the drug, which is expected shortly, could increase uptake further. "It makes it a hell of a lot easier for physicians to obtain the drug," he said.

A price increase may accompany a commercial launch later this year, although the company is not yet disclosing its plans. "We've obviously evaluated what price we want to have at launch," he said. The product, which is dosed according to patients' body weight, currently costs an average of $20,000 to $25,000 per patient. In the U.S., where defibrotide is available under a treatment IND, the price is capped at $40,000 per patient.

In certain countries, however, the company is unable to recoup any cost and is required to supply the drug for free. "Irony has it Italy is one of them," Islam said. However, he said reimbursement will likely follow formal approval within 100 days, following the introduction of a new rule in Italy.

The drug is currently undergoing a Phase III trial in the U.S. "We're looking to file by the end of 2013 – we might be slightly late," Islam said. Its stands to receive a $7 million milestone from its partners, Sigma-Tau Pharmaceuticals Inc., of Gaithersburg, Md. It would also receive 38 percent royalty rate on net sales, while Sigma-Tau will cover commercialization costs.

In Japan, defibrotide could become part of the medical response to the expected emergence of radiation-related illnesses following the Fukushima nuclear disaster in 2011. An investigator-initiated Phase I trial at Fukushima Medical University on its use in the prevention of HSCT-associated VOD will report data shortly. "They have been pushing us to conduct a Phase II/III study in prevention of VOD," Islam said. The Japanese government would likely provide the bulk of the funding.

Elsewhere, Gentium is also considering other indications for the drug. "We're looking at acute graft-vs.-host disease (GvHD), on which we already have important data," Islam said. Here the presumed mechanism also focuses on minimizing the consequences of damage to endothelial cells, as GvHD arises from the cytokine cascade triggered by endothelial injury. A Phase III trial in this indication has been penciled in for 2014.