Products

Date: 2018-08-23

Type of information: Granting of a Market Authorisation in the EU

Product name: Vyxeos™

Compound: cytarabine and daunorubicin liposome injection

Therapeutic area: Cancer - Oncology

Action mechanism:

• antimetabolite/antimitotic agent/cytotoxic agent. Vyxeos® is an advanced liposomal formulation that delivers a fixed-ratio (1:5) of daunorubicin and cytarabine.
• Daunorubicin has antimitotic and cytotoxic activity. It forms complexes with DNA by intercalation between base pairs. It inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. Vyxeos™ (cytarabine and daunorubicin liposome injection), or CPX-351, is a combination of cytarabine and daunorubicin encapsulated within a nano-scale liposome at a 5:1 molar ratio. Vyxeos was granted orphan drug status by the FDA and the European Commission for the treatment of acute myeloid leukemia. Vyxeos™ was granted Breakthrough Therapy Designation for the treatment of adults with therapy-related AML or AML with myelodysplasia-related changes and was also granted Fast Track designation by the FDA for the treatment of older patients with secondary AML.

About VyxeosTM Vyxeos 44 mg/100 mg powder for concentrate for solution for infusion is an advanced liposomal formulation that delivers a fixed-ratio (1:5) of daunorubicin and cytarabine to the bone marrow that has been shown to have synergistic effects at killing leukaemia cells in vitro and in animal models. Vyxeos is the first product developed with the company's proprietary CombiPlex® platform, which enables the design and rapid evaluation of various combinations of therapies. Vyxeos received Orphan Drug Designation by the European Commission in January 2012 and by the U.S. Food and Drug Administration ( FDA ) in September 2008 for the treatment of AML. Vyxeos received Promising Innovative Medicine (PIM) designation from the Medicines and Healthcare Products Regulatory Agency in the United Kingdom . Vyxeos received U.S. FDA approval and orphan drug exclusivity on August 3, 2017 for the treatment of adults with newly-diagnosed t-AML or AML-MRC

Company: Jazz Pharmaceuticals (Ireland)

Disease: acute myeloid leukemia

Latest news:

• • On August 23, 2018, the European Commission approved Vyxeos® 44 mg/100 mg powder for concentrate for solution for infusion for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukaemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).
• The Marketing Authorisation Application (MAA) for Vyxeos® included clinical data from five studies, including the pivotal Phase 3 study. Data from the Phase 3 study was published in the Journal of Clinical Oncology in July 2018 . The study evaluated the efficacy and safety of Vyxeos compared to 7+3 chemotherapy in 309 patients 60 to 75 years of age with newly diagnosed t-AML or AML-MRC, a rapidly progressing and life-threatening blood cancer. The study met its primary endpoint as Vyxeos demonstrated a superior improvement in overall survival compared to the 7+3 treatment regimen. The median overall survival for the Vyxeos treatment group was 9.6 months compared with 5.9 months for the 7+3 treatment group (2-sided p-value = 0.005; HR [95% confidence interval] = 0.69 [0.52, 0.90]). Vyxeos was also associated with a significantly higher remission rate than 7+3 with a complete response rate of 37% versus 26%; p=0.036. In addition, the overall rate of hematopoietic stem cell transplant (HSCT) was 34% in the Vyxeos arm and 25% in the 7+3 arm. The reported adverse reactions with Vyxeos were generally consistent with the known safety profile of cytarabine and daunorubicin therapy.
• The incidences of non-haematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with Vyxeos. Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients in the Vyxeos arm and 0.7% of patients in the control arm. Six percent of patients in both the Vyxeos and control arm had a fatal adverse reaction on treatment or within 30 days of therapy that was not in the setting of progressive disease. The most common adverse reactions (incidence = 25%) were bleeding events, fever, rash, swelling, nausea, sores in the mouth or throat, diarrhea, constipation, muscle pain, tiredness, stomach pain, difficulty breathing, headache, cough, decreased appetite, irregular heartbeat, pneumonia, blood infection, chills, sleep disorders and vomiting.
• • On June 29, 2018, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending marketing authorisation of Vyxeos® 44 mg/100 mg powder for concentrate for solution for infusion for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukaemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).
• • On August 3, 2017, the FDA approved Vyxeos® for the treatment of adults with two types of acute myeloid leukemia (AML): newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC).
• The safety and efficacy of Vyxeos® were studied in 309 patients with newly diagnosed t-AML or AML-MRC who were randomized to receive Vyxeos® or separately administered treatments of daunorubicin and cytarabine. The trial measured how long patients lived from the date they started the trial (overall survival). Patients who received Vyxeos® lived longer than patients who received separate treatments of daunorubicin and cytarabine (median overall survival 9.56 months vs. 5.95 months).
• Common side effects of Vyxeos® include bleeding events (hemorrhage), fever with low white blood cell count (febrile neutropenia), rash, swelling of the tissues (edema), nausea, inflammation of the mucous membranes (mucositis), diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, shortness of breath (dyspnea), headache, cough, decreased appetite, abnormal heart rhythm (arrhythmia), lung infection (pneumonia), blood infection (bacteremia), chills, sleep disorders and vomiting.
• Patients who have a history of serious hypersensitivity to daunorubicin, cytarabine or any component of the formulation should not use Vyxeos®. Patients taking Vyxeos ®should be monitored for hypersensitivity reactions and decreased cardiac function. Vyxeos® has been associated with serious or fatal bleeding events. Daunorubicin has been associated with severe damage (necrosis) where the drug leaks into the skin and subcutaneous tissue from the intravenous infusion (extravasation). Women who are pregnant or breastfeeding should not take Vyxeos®, because it may cause harm to a developing fetus or a newborn baby.
• The prescribing information for Vyxeos® includes a boxed warning not to interchange Vyxeos® with other daunorubicin- and/or cytarabine-containing products.
• The FDA granted this application Priority Review and Breakthrough Therapy designations.

 

• • On October 3, 2016, Jazz Pharmaceuticals announced the initiation of a rolling submission of a New Drug Application (NDA) to the FDA on September 30, 2016 , seeking marketing approval of Vyxeos™ (cytarabine and daunorubicin liposome injection), an investigational agent for the treatment of acute myeloid leukemia (AML). The company expects to complete the submission of the NDA by early 2017, and will request a priority review. Vyxeos was granted Breakthrough Therapy Designation in May 2016 for the treatment of adults with therapy-related AML or AML with myelodysplasia-related changes.  Celator Pharmaceuticals completed and announced the results of its Phase 3 trial evaluating Vyxeos in patients with high-risk AML in March 2016 . Jazz Pharmaceuticals completed the acquisition of Celator Pharmaceuticals in July 2016 .

Patents:

Submission of marketing authorization application USA :

Submission of marketing authorization application UE: 2017-11

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2017-08-03

UE authorization: 2018-08-23

Favourable opinion UE: 2018-06-28

Favourable opinion USA:

Orphan status USA: 2008-08-22

Orphan status UE: 2012-01-11

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes