Products

severe veno-occlusive disease (VOD) in patients undergoing haematopoietic (blood) stem-cell transplantation

* On March 30, 2016, the FDA approved Defitelio® (defibrotide sodium) to treat adults and children who develop hepatic veno-occlusive disease (VOD) with additional kidney or lung abnormalities after they receive a stem cell transplant from blood or bone marrow called hematopoietic stem cell transplantation (HSCT). This is the first FDA-approved therapy for treatment of severe hepatic VOD. HSCT is a procedure performed in some patients to treat certain blood or bone marrow cancers. Immediately before an HSCT procedure, a patient receives chemotherapy. Hepatic VOD can occur in patients who receive chemotherapy and HSCT. Hepatic VOD is a condition in which some of the veins in the liver become blocked, causing swelling and a decrease in blood flow inside the liver, which may lead to liver damage. In the most severe form of hepatic VOD, the patient may also develop failure of the kidneys and lungs. Fewer than 2 percent of patients develop severe hepatic VOD after HSCT, but as many as 80 percent of patients who develop severe hepatic VOD do not survive.
The efficacy of Defitelio® was investigated in 528 patients treated in three studies: two prospective clinical trials and an expanded access study. The patients enrolled in all three studies had a diagnosis of hepatic VOD with liver or kidney abnormalities after HSCT. The studies measured the percentage of patients who were still alive 100 days after HSCT (overall survival). In the three studies, 38 to 45 percent of patients treated with Defitelio® were alive 100 days after HSCT. Based on published reports and analyses of patient-level data, the expected survival rates 100 days after HSCT would be 21 to 31 percent for patients with severe hepatic VOD who received only supportive care or interventions other than Defitelio®.
The most common side effects of Defitelio® include abnormally low blood pressure (hypotension), diarrhea, vomiting, nausea and nosebleeds (epistaxis). Serious potential side effects of Defitelio that were identified include bleeding (hemorrhage) and allergic reactions. Defitelio should not be used in patients who are having bleeding complications or who are taking blood thinners or other medicines that reduce the body’s ability to form clots.
The FDA granted the Defitelio® application priority review status, which facilitates and expedites the development and review of certain drugs in light of their potential to benefit patients with serious or life-threatening conditions. Defitelio® also received orphan drug designation. Shipments of Defitelio to distribution channels will commence within a week.  Jazz Pharmaceuticals will offer patient support through its JumpStart program to help provide access to Defitelio. This program includes a reimbursement assistance program for providing information on benefit or reimbursement questions. Additionally, a patient assistance program (PAP) will be available to help qualified patients gain access to Defitelio.

* On September 30, 2015, Jazz Pharmaceuticals announced that the FDA has accepted for filing with Priority Review its recently submitted New Drug Application (NDA) for defibrotide. Priority Review status is designated for drugs that may offer major advances in treatment or provide a treatment where no adequate therapy exists. Based on timelines established by the Prescription Drug User Fee Act (PDUFA), FDA review of the NDA is expected to be completed by March 31, 2016. The NDA includes safety and efficacy data from three clinical studies of defibrotide for the treatment of hepatic VOD with MOD following HSCT, as well as a retrospective review of registry data from the Center for International Blood and Marrow Transplant Research. The safety database includes over 900 patients exposed to defibrotide in the clinical development program for the treatment of hepatic VOD.
* On December 11, 2014, Jazz Pharmaceuticals announced the initiation of a rolling submission of a New Drug Application (NDA) to the FDA for defibrotide for the treatment of severe hepatic veno-occlusive disease (VOD) in patients undergoing hematopoietic stem-cell transplantation (HSCT) therapy. Defibrotide has been granted Fast Track Designation to treat severe VOD by the FDA.
Jazz Pharmaceuticals expects to complete the submission of the NDA in the first half of 2015, at which time the company will be requesting a Priority Review of the application. Earlier this year, Jazz Pharmaceuticals acquired the rights to defibrotide in the U.S. and other markets in North America, South America and Central America. Jazz Pharmaceuticals markets defibrotide in Europe under the name Defitelio®.

* On March 31, 2014,  Jazz Pharmaceuticals and Gentium have announced the commencement of the European commercial launch of Defitelio® (defibrotide), the first licensed product for the treatment of severe hepatic veno-occlusive disease (severe VOD or sVOD) in patients over one month of age undergoing haematopoietic stem cell transplantation (HSCT) therapy.  The companies have launched Defitelio in Germany and Austria and expect to continue the launch in 27 additional European countries on a rolling basis during 2014 and 2015.

* On November 14, 2013, Gentium and Link Healthcare have announced that defibrotide has been designated as an orphan drug for the treatment of hepatic veno-occlusive disease (VOD). The sponsor of defibrotide is Link Healthcare, Gentium’s exclusive distribution partner in Australia. The main characteristics of the orphan drug policy in Australia are: It is intended for drugs which aim to treat diseases with a prevalence of 2,000 patients/subjects or less in the Australian population (23 million). It allows for a waiver of application and evaluation and no annual registration fees. It provides five-year period of exclusivity (under consideration by the Australian jurisdiction). Gentium will now work with Link to commence the Marketing Application process in Australia.

* On October 22, 2013, Gentium has announced that the European Commission has granted a Marketing Authorization for Defitelio® (defibrotide) for the treatment of severe hepatic veno-occlusive disease in adults and children undergoing hematopoietic stem cell transplantation therapy. Defitelio® is the first approved treatment in the European Union for this life-threatening condition. This authorization is the formal endorsement of the positive opinion received from the European Medicine Agency’s CHMP on July 26, 2013. The Company intends to begin commercialization of Defitelio® in the European Union in December 2013.

* On 25 July 2013, the Committee for Medicinal Products for Human Use (CHMP) has recommended the granting of the marketing authorisation for Defitelio®, intended for the treatment of severe hepatic veno-occlusive disease (VOD) in patients undergoing haematopoietic (blood) stemcell transplantation. On 21 March 2013, the CHMP had originally adopted a negative opinion for both treatment and prevention of VOD in blood stem-cell transplantation therapy. At the request of the applicant, the CHMP started a re-examination of its opinion and following the re-examination, the CHMP adopted a final positive opinion recommending that the medicine be granted authorisation but only for the treatment of severe VOD in patients undergoing blood stem-cell transplantation.

* On June 4, 2013, Gentium has announced  that, the Company has filed the documentation requesting a Re-examination of the negative opinion given by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP), regarding the Marketing Authorisation (MAA) for defibrotide to treat and prevent hepatic veno-occlusive disease (VOD) in adults and children undergoing hematopoietic stem cell transplantation therapy. In accordance with European regulations, the CHMP has 60 days to consider a revision of the initial opinion and consequently a final recommendation may be made by the end of July.

* On April 16, 2013, Gentium has announced that it has requested a re-examination of the negative opinion adopted, by the  CHMP, on March 22nd, regarding the Marketing Authorisation submitted for Defibrotide to treat and prevent hepatic veno-occlusive disease in adults and children undergoing hematopoietic stem cell transplantation therapy. The appeal involves a reexamination of the original MAA and must be based on the data already submitted.

* On 21 March 2013, the Committee for Medicinal Products for Human Use (CHMP) has adopted a negative opinion, recommending the refusal of the marketing authorisation for the medicinal product Defitelio®, intended for the treatment and prevention of hepatic veno-occlusive disease in blood stem cell transplantation therapy. The CHMP concluded that results from the prevention study did not provide sufficiently convincing evidence of the medicine’s benefit and there were problems with the way the study was conducted, including problems with documentation and the reporting of data. In the treatment study, the number of patients in the historical control group was considered to be too low and the Committee was concerned about the fact that some patients who were originally chosen to be in the historical control group were excluded from the study. It was therefore not possible to conclude on the medicine’s benefit as a treatment. In addition, there was a lack of data on the way the medicine is eliminated by the kidneys in children and patients with reduced kidney function. This concerned the Committee since a safety concern was identified in children who received high doses of Defitelio®. Therefore the CHMP concluded that the benefits of Defitelio did not outweigh its risks and recommended that it be refused marketing authorisation.

* On February 21, 2013, Gentium has announced that, the Company had presented an oral explanation at the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) as part of its Marketing Authorization Application (MAA) for defibrotide to treat and prevent hepatic veno-occlusive disease (VOD) in adults and children undergoing hematopoietic stem cell transplantation therapy. Following the oral explanation, based on preliminary feedback from the CHMP, Gentium expects an opinion recommending against approval of the Marketing Authorization Application for Defibrotide to treat and prevent hepatic veno-occlusive disease in adults and children undergoing hematopoietic stem cell transplantation therapy. While not a final decision, the Company considers it unlikely that this position will change before the formal vote is undertaken next month. If a formal negative recommendation is issued, and depending upon the nature of the objections, the Company may appeal such negative decision.

* On January 17, 2013, Gentium has announced that it has been informed that its marketing authorization application for defibrotide to treat and prevent hepatic veno-occlusive disease (VOD) in adults and children undergoing haematopoietic stem cell transplantation therapy will be on the agenda for discussion at the CHMP meetings scheduled to be held on February 18-21, 2013. The Company submitted its MAA for Defibrotide to the EMA onMay 10, 2011 and submitted responses to the second List of Outstanding Issues (“LoOIs”) on December 18, 2012.

* On December 18, 2012, Gentium has announced that it has submitted responses to the second List of Outstanding Issues (“LoOIs”) to the CHMP in connection with the company’s Marketing Authorization Application for defibrotide to treat and prevent hepatic veno-occlusive disease  in adults and children undergoing haematopoietic stem cell transplantation therapy. Gentium expects to receive an opinion from the CHMP regarding the approval of defibrotide during the first quarter of 2013, based on the EMA review process timeline.

* On October 10, 2012, Gentium has announced that it has received a second List of Outstanding Issues (“LoOIs”) from the CHMP in connection with its MAA for defibrotide to treat and prevent hepatic veno-occlusive disease  in adults and children undergoing haematopoietic stem cell transplantation therapy. The second LoOIs has reset the EMA’s approval timetable back to Day 180. The Company plans to submit its response to the LoOls within 60 days, in line with the new regulatory timetable. 

* On September 26, 2012, Gentium has announced that, following the Company’s presentation of Oral Explanations to the CHMP on September 19, 2012, the CHMP has decided to adopt a second List of Outstanding Issues (“LoOI”) relating to the MAA for defibrotide to treat and prevent hepatic veno-occlusive disease in adults and children undergoing haematopoietic stem cell transplantation therapy. 

*On September 11, 2012, Gentium has announced that it has been asked to present oral explanations on September 19, 2012 to the CHMP as part of the review process of the Company’s Marketing Authorization Application for defibrotide to treat and prevent hepatic veno-occlusive disease in adults and children undergoing haematopoietic stem cell transplantation therapy. Following this meeting, Gentium expects a final CHMP opinion in Q4 2012.

* On June 21, 2012, Gentium has announced that it has submitted its responses to the Day 180 List of Outstanding Issues (the “LoOIs”) received from the European CHMP with respect to the Company’s Marketing Authorization Application (MAA) for Defibrotide to treat and prevent hepatic veno-occlusive disease (VOD) in adults and children undergoing haematopoietic stem cell transplantation therapy. Gentium expects to receive an opinion from the CHMP regarding the approval of defibrotide during the third quarter of 2012

* On February 21, 2012, Gentium announced that it has submitted its response to the Day 120 List of Questions (the “LoQs”) issued by the European CHMP with respect to the Company’s Marketing Authorization Application for Defibrotide to treat and prevent hepatic veno-occlusive disease in adults and children undergoing haematopoietic stem cell transplantation therapy.

Following the submission of the Day 120 LoQs responses, the CHMP will continue its review of the MAA and will either issue an opinion on the MAA or submit a List of Outstanding Issues (LoOIs) requiring further clarification, the latter of which will stop the review clock to permit the Company time to respond. The CHMP is expected to reach its final opinion no later than day 210 calculated based on the EMA review process timeline.

* On December 29, 2011, Gentium provided an update on the European Marketing Authorization Application for defibrotide. Following a clarification meeting recently held with the Company’s Rapporteurs, Gentium anticipates submitting a response to the Day 120 List of Questions (LoQs) from the CHMP in the first quarter of 2012.

* On October 20, 2011, Gentium provided an update on the European Marketing Authorization Application for Defibrotide to treat and prevent hepatic veno-occlusive disease (VOD) in adults and children undergoing haematopoietic stem-cell transplantation therapy. The Company has received and reviewed the Day 120 List of Questions (LoQs) from the European Medicines Agency’s (the “EMA”) Committee for Medical Products for Human Use (the “CHMP”) and anticipates that it will submit its responses by the end of December.

* On August 17, 2011, Gentium announced that it has voluntarily withdrawn the New Drug Application (NDA) for defibrotide following recent correspondence from the FDA identifying numerous “Refuse to File” issues regarding the Company’s NDA submission. In their initial review, the FDA raised concerns regarding the completeness of the datasets for both the treatment and prevention studies. The FDA requested that the Company 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.