Shares in Gentium SpA fell 20 percent last week on news that the lengthy approval process for defibrotide, a drug for the treatment and prevention of hepatic veno-occlusive disease (VOD) in patients undergoing hematopoietic stem cell transplant, had just become longer.

Preliminary feedback, following an oral presentation to the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP), indicated the CHMP is likely to adopt a negative stance when it comes to a formal vote on the application next month.

Villa Guardia, Italy-based Gentium said it does not expect a shift in that position in the interim. It can lodge an appeal against a negative decision, but it is still waiting to receive formal notification from the CHMP.

"We need to wait and see what the EMA is going to say," Salvatore Calabrese, Gentium's chief financial officer, told BioWorld Today.

Although an undoubted setback for a company of its size, it is better insulated than most to absorb the shock. "The company is selling the drug on a named-patient basis, and we are profitable," Calabrese said.

Defibrotide racked up sales of €17.1 million (US$22.5 million) for the first nine months of last year. "We are 40 percent up in 2012 vs. 2011," Calabrese said. The company reported total revenue of €21.6 million for the period and (non-GAAP-adjusted) earnings before interest, depreciation and taxes (EBIDTA) of €3 million. It held €11 million in cash as of Sept. 30, 2012.

Hepatic VOD, a blockage of blood vessels in the liver, is an invariably fatal complication of hematopoietic stem cell transplant, for which there is no approved therapy. Defibrotide, which comprises a complex mixture of the salts of single-stranded oligodeoxyribonucleotides obtained from the mucosa of pigs, has multiple anti-thrombotic, anti-inflammatory and anti-ischemic effects. "The drug was approved in Italy back in 1986," Calabrese said. That approval was for deep vein thrombosis. Gentium is developing the drug for VOD under orphan drug rules.

It originally filed a European Marketing Authorization Application in May 2011, based on data from two Phase III trials, a pediatric prevention trial and a treatment trial in adults. The pediatric trial data were published in the April 7, 2012, issue of The Lancet in a paper titled, "Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial."

In the intent-to-treat population (n = 356), 22 (12 percent) out of 180 patients in the drug treatment group developed VOD by 30 days, as compared with 35 (20 percent) of 176 patients in the placebo arm.

The result was statistically significant (p = 0.048.). The drug also reduced the incidence and severity of graft-vs.-host disease, a major complication in allogeneic hematopoietic stem cell transplants.

Its Phase III treatment trial was an open-label study, in which subjects were compared with matched historic controls, a tactic that is rarely popular with drug regulators, but one which Gentium found difficult to avoid in this particular setting, given the lack of alternative treatments.

Defibrotide previously hit a roadblock in the U.S., where the drug has been available under the FDA's expanded access to investigational drugs for treatment use rule. It originally filed a new drug application in July 2011, but withdrew it a month later because of data quality issues. The company plans to resubmit this year.

"It's taken some time to fix the database," Calabrese said.

The stock (NASDAQ:GENT) plunged more than 40 percent to a low of $6.96 after the news broke last Thursday, but it clawed back some of those losses to end the day at $9.61, a gain of 14 cents.