FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia

Abstract

On August 3, 2017, the FDA granted regular approval to Vyxeos (also known as CPX-351; Jazz Pharmaceuticals), a liposomal formulation of daunorubicin and cytarabine in a fixed combination, for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or acute myeloid leukemia (AML) with myelodysplasiarelated changes (AML-MRC). Approval was based on data from Study CLTR0310-301, a randomized, multicenter, open-label, active-controlled trial comparing Vyxeos with a standard combination of daunorubicin and cytarabine ("7þ3") in 309 patients 60-75 years of age with newly diagnosed t-AML or AML-MRC. Because of elemental copper concerns with the Vyxeos formulation, patients with Wilson disease were excluded from the study. Vyxeos demonstrated an improvement in overall survival (HR 0.69; 95% confidence interval, 0.52-0.90; P ¼ 0.005) with an estimated median overall survival of 9.6 months compared with 5.9 months for the "7þ3" control arm. The toxicity profile of Vyxeos was similar to that seen with standard "7þ3" with the exception of more prolonged neutropenia and thrombocytopenia on the Vyxeos arm. Because the pharmacology of Vyxeos differs from that of other formulations of daunorubicin and cytarabine, labeling includes a warning against interchanging formulations during treatment. This is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC.

Nanoparticles in the clinic: An update

“…4 In the pivotal efficacy study (NCT01696084), VYXEOS provided a significant (p value = .005) improvement in overall survival of 9.6 months as compared to 5.9 months in the free drug control. 2,5 Importantly, this trial also showed that VYXEOS provided improved efficacy at a lower cumulative daunorubicin and cytarabine dose as compared to free drug counterparts. 6 Since 2016, the number of clinical trials of VYXEOS has increased from 7 to 21 with the most recent trials investigating the use of VYXEOS in additional patient populations (e.g., children; NCT03826992) and leukemias (e.g., lymphoblastic leukemias; NCT03575325).…”

“…Since our previous article, three nanomedicines have been approved: Patisiran/ONPATTRO, VYXEOS, and NBTXR3/Hensify. VYXEOS is a combination chemotherapy nanoparticle, developed and marketed by Jazz Pharmaceuticals that, encapsulates a synergistic molar ratio of cytarabine to daunorubicin of 5:1 and received FDA approval for the treatment of acute myeloid leukemia in August of 2017 . VYXEOS are 100 nm bilamellar liposomes where the lipid membrane consists of desaturated phosphatidylcholine:distearylphosphatidylglycerol:cholesterol (7:2:1M ratio) .…”

“…VYXEOS are 100 nm bilamellar liposomes where the lipid membrane consists of desaturated phosphatidylcholine:distearylphosphatidylglycerol:cholesterol (7:2:1M ratio) . In the pivotal efficacy study (NCT01696084), VYXEOS provided a significant ( p value = .005) improvement in overall survival of 9.6 months as compared to 5.9 months in the free drug control . Importantly, this trial also showed that VYXEOS provided improved efficacy at a lower cumulative daunorubicin and cytarabine dose as compared to free drug counterparts .…”

“…VYXEOS is a combination chemotherapy nanoparticle, developed and marketed by Jazz Pharmaceuticals that, encapsulates a synergistic molar ratio of cytarabine to daunorubicin of 5:1 and received FDA approval for the treatment of acute myeloid leukemia in August of 2017. 2,3 VYXEOS are 100 nm bilamellar liposomes where the lipid membrane consists of desaturated phosphatidylcholine:distearylphosphatidylglycerol:cholesterol (7:2:1M ratio). 4 In the pivotal efficacy study (NCT01696084), VYXEOS provided a significant (p value = .005) improvement in overall survival of 9.6 months as compared to 5.9 months in the free drug control.…”

Sequentially Site‐Specific Delivery of Apoptotic Protein and Tumor‐Suppressor Gene for Combination Cancer Therapy

“…To address this issue, nanocarrier‐based systems for codelivery of multiple drugs have increasingly been empoldered to offer a spatio‐temporal unification of separate pharmacokinetics of different drug payloads, which are evidenced to be more effective in preclinical and clinical studies . For instance, Vyxeos, a liposomal preparation coloaded with cytarabine and daunorubicin (5:1 molar ratio), has been approved by the U.S. Food and Drug Administration for acute myeloid leukemia treatment . Vyxeos can maintain a constant 5:1 drug ratio in the plasma of patients for up to 24 h after intravenous administration, which shows significantly enhanced anticancer efficacy with prolonged survival period compared with the conventional cocktail of cytarabine and daunorubicin (7:3 molar ratio) …”