Jazz Pharmaceuticals plc did what Gentium SpA was unable to accomplish by bringing the long U.S. saga of Defitelio (defibrotide) to a successful finish.

Early Wednesday, the FDA approved the drug to treat adults and children who develop hepatic veno-occlusive disease (VOD) with additional kidney or lung abnormalities after they receive hematopoietic stem cell transplantation (HSCT).

Defibrotide is the sodium salt of a complex mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA. The therapy is the first approved by the FDA to treat severe hepatic VOD.

“Hepatic veno-occlusive disease is a very rare and often deadly complication of hematopoietic stem cell transplantation, so this is a very sick population,” Karen Smith, global head of R&D and chief medical officer of Jazz, told BioWorld Today. “Defitelio offers a single course of treatment that’s curative, so this approval is incredibly important for these patients.”

Hepatic VOD can occur in patients who receive chemotherapy and HSCT when veins in the liver become blocked, causing swelling and a decrease in blood flow in the liver, potentially leading to liver damage. In the most severe form of hepatic VOD, the patient may also develop kidney and lung failure. Although fewer than 2 percent of patients develop severe hepatic VOD after HSCT, approximately 80 percent of patients who develop the condition do not survive.

The efficacy of Defitelio was evaluated in 528 patients with hepatic VOD and renal or pulmonary dysfunction following HSCT who were enrolled across three studies: a prospective phase II and phase III study and an expanded access study. Patients treated with defibrotide at 6.25 mg/kg every six hours across the three studies had survival rates of 38 percent to 45 percent at day 100 post-HSCT.

The most common adverse events (AE) related to defibrotide during clinical trials were hypotension, diarrhea, vomiting, nausea and nose bleeds. The most common serious AEs were hypotension (11 percent) and pulmonary alveolar hemorrhage (7 percent).

In 2011, Gentium, which was based in Villa Guardia, Italy, pulled its new drug application (NDA) for defibrotide – then its lead candidate – just 36 hours after receiving a letter from the FDA citing numerous refuse-to-file issues regarding the NDA. (See BioWorld Today, Aug. 19, 2011.)

With no agents approved and no others in the pipeline for the indication, Gentium had been running its U.S. clinical program under an investigational new drug application since 2007. In its initial review of the NDA, the FDA raised concerns regarding the completeness of the defibrotide datasets, both for treatment and prevention studies, and asked the company to conduct additional quality reviews of the original datasets and databases. The FDA also requested additional details regarding the conduct and monitoring of the trials by the independent review committee.

The refuse-to-file issues were unrelated to potential review issues raised in 2008, when the data safety monitoring board (DSMB) in the phase III study of defibrotide in VOD required the enrollment of more patients for statistical powering. Although no safety issues were involved, the DSMB required the study’s sample size to be increased to 160 patients in the treatment arms and to 80 patients in the historical control arm to meet the statistical requirement under the company’s special protocol assessment. (See BioWorld Today, Nov. 21, 2008.)


Despite its early stumbles in the U.S., the drug was subsequently approved in Europe, although only after some jostling with the EMA. Gentium filed a European marketing authorization application in May 2011, and a year later the EMA’s Committee for Medicinal Products for Human Use (CHMP) formally issued a negative opinion. The CHMP reversed its decision following a request for re-examination by the company, which opted out of a suggested use to prevent VOD. With no other drug approved to treat hepatic VOD in Europe or the U.S., that move swayed the CHMP. (See BioWorld Today, Aug. 14, 2013.)

Jazz, of Dublin, stepped in later that year and picked up Gentium for $57 per share, valuing the company at $1 billion. (See BioWorld Today, Dec. 23, 2013.)

Jazz moved the drug to market in Europe in 2014, although sales of the drug by Gentium on a named-patient basis had begun earlier. Defitelio recorded sales of about $70.7 million in 2015, according to Cortellis Competitive Intelligence.

But Jazz still had to navigate another bend in the road. Sigma-Tau Pharmaceuticals Inc., of Gaithersburg, Md., a subsidiary of Pomezia, Italy-based Sigma Tau Group, held rights to defibrotide in the Americas through a pre-existing agreement with Gentium.

Jazz completed that maneuver in July 2014, acquiring the rights to defibrotide in the U.S. and the rest of the Americas in return for $75 million up front to Sigma-Tau, which also was eligible for milestone payments of $25 million upon acceptance of the NDA filing in VOD and up to another $150 million based on timing of the FDA approval.

In December 2014, Jazz initiated the rolling NDA for defibrotide in severe hepatic VOD. The FDA accepted the NDA in September 2015, granting priority review and setting a PDUFA date of March 31. The agency had previously granted orphan drug designation to defibrotide.

Jazz plans to begin shipping Defitelio within a week. The company said the drug will be priced at a wholesale acquisition cost of $825 for a 200 mg/2.5 ml single patient use vial. The product is dosed by patient size and weight, but the company estimated that treatment will call for approximately three vials per day for children and nine vials per day for adult patients.

Jazz said it will offer several patient support programs to provide access to Defitelio, including a reimbursement assistance program and a patient assistance program for qualified patients.

Analysts voiced little surprise at the approval but agreed the FDA win increased the upside potential for Jazz.

“Although in line with our expectations, the approval is a clear positive, particularly in light of increasing concerns in the market in recent weeks,” J.P. Morgan analyst Jessica Fye wrote in a company alert. “Bigger picture, Defitelio represents another potentially high-value product that will ultimately help diversify JAZZ’s revenues/earnings.”

Fye projected a peak sales opportunity of more than $350 million annually, based on an assumed net U.S. price of $90,000 per adult and $35,000 per child for a recommended treatment period of at least 21 days.

Physician awareness is another plus for Defitelio, according to Fye. She noted that a poll of physicians in attendance at the recent combined annual meetings of Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation revealed that about 72 percent viewed defibrotide as the preferred strategy for treating VOD and 85 percent understand the importance of treating early to improve outcomes.

As part of its launch plans, Jazz will continue to offer education to physicians about how to recognize and treat VOD, Smith said.

Leerink Partners LLC analyst Jason Gerberry indicated the label was expected for the ultra-rare condition, which affects approximately 1,700 U.S. patients annually. He forecast an estimated $150 million in U.S. sales in 2021, assuming no approval for a broader prophylactic indication.

Smith agreed the label was “reflective” of the hepatic VOD patient population. Although the company’s first priority is a successful U.S. launch, she said Jazz will continue to seek guidance from the FDA on a path forward for Defitelio to prevent VOD in high-risk patients and, potentially, to treat other conditions.

“This is an excellent drug and excellent molecule,” Smith said. “We’ve been very happy working with the FDA, and we’ll continue to explore the use of Defitelio in other potential indications.”

On Wednesday, shares of Jazz (NASDAQ:JAZZ) closed at $124.03 for a gain of $3.08.