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Transcript

((Voice Over))
Acute myeloid leukemia, or AML, is a complex heterogeneous disease. Due to advanced age at the time of diagnosis and the need for aggressive treatment to achieve remission, AML is often associated with poor survival outcomes. Adults with t-AML and AML-MRC have a particularly poor prognosis.

The development of new treatment options and achieving meaningful improvements in treating these patients has been challenging. The 7+3 chemotherapy regimen has remained the foundation and has been the standard of care for AML induction for over 40 years.

As a pioneer in liposomal nanotechnology research, Dr. Lawrence Mayer has led the development of multiple liposomal products in the pharmaceutical industry. With VYXEOS, he saw an opportunity to answer the high unmet need for adult patients \with newly-diagnosed t-AML or AML-MRC.

((Dr. Mayer))
VYXEOS is the first FDA-approved dual-drug liposomal technology that encapsulates daunorubicin and cytarabine, the foundation drugs of the 7+3 regimen. VYXEOS was designed for simultaneous delivery of the 2 individual medications in 1 liposome at a fixed 1:5 molar ratio that is sustained in the bone marrow for a prolonged period of time.

How is VYXEOS different from the traditional 7+3 regimen? When administering daunorubicin and cytarabine individually, as with the 7+3 regimen, each drug has its own unique pharmacokinetics and distribution within the body. VYXEOS was developed to control the relative daunorubicin and cytarabine levels that reach leukemia cells.

((Voice Over))
Designed with dual-drug liposomal technology, VYXEOS is a nanoscale liposome of daunorubicin and cytarabine. Through extensive preclinical research, a molar ratio of one to five of daunorubicin to cytarabine was carefully selected, allowing for a synergistic effect at killing leukemia cells.

Pharmacokinetic studies have demonstrated that following a 90-minute intravenous infusion, VYXEOS exhibits a prolonged half-life with greater than 99% of daunorubicin and cytarabine in the plasma, remaining encapsulated within the liposomes.

Due to the pharmacokinetics and simultaneous delivery, with in vitro and in vivo studies, VYXEOS has been shown to deliver daunorubicin and cytarabine in a fixed one-to-five molar ratio to leukemia cells.

Based on animal models, the mechanism of action for VYXEOS is thought to occur in 3 main steps:

  1. VYXEOS liposomes enter and persist in the bone marrow.
  2. The liposomes are taken up by leukemia cells to a greater extent than by normal bone marrow cells in a murine model.
  3. VYXEOS liposomes undergo degradation, releasing daunorubicin and cytarabine within the intracellular environment.

 

Once released within the intracellular environment, daunorubicin and cytarabine exert their antineoplastic activity. The 1:5 molar ratio of daunorubicin to cytarabine has been shown to have synergistic effects at killing leukemia cells in vitro and in animal models.

Dr. Arthur Louie is a board-certified clinical oncologist with over 30 years of experience in pharmaceutical research. He led the development of the clinical program for VYXEOS. He will now review some key efficacy and safety data for VYXEOS.

((Dr. Louie))
Based on experience throughout the clinical development program, we designed the pivotal phase 3 trial to look at VYXEOS in a population of adults with newly-diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

The pivotal phase 3 trial was a multicenter, open-label, active-controlled, superiority trial. In this trial, VYXEOS was studied in a head-to-head comparison versus the standard 7+3 (cytarabine and daunorubicin) regimen. The trial randomized 309 patients with newly-diagnosed t-AML or AML-MRC. This trial included patients with de novo AML with MDS-related cytogenetic abnormalities, AML with a history of myelodysplasia or chronic myelomonocytic leukemia, and t-AML.

The study established that VYXEOS is the first chemotherapy to demonstrate superior overall survival of 9.6 months vs 5.9 months for the control arm in adults with newly-diagnosed t-AML or AML-MRC.

((Voice Over))
Next, let’s review some safety data from the phase 3 trials. As shown in this table, reported adverse reactions were generally consistent with the known safety profile of daunorubicin and cytarabine therapy. Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients in the VYXEOS arm and 0.7% percent of patients in the control arm. VYXEOS was also associated with lower 30- and 60-day mortality rates compared to 7+3.

With its demonstrated improvement in overall survival compared to 7+3 in adult patients with newly-diagnosed therapy-related AML or AML with myelodysplasia-related changes, VYXEOS represents a significant therapeutic advance for these AML patients.

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INDICATION

VYXEOS is indicated for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t‑AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older.

IMPORTANT SAFETY INFORMATION

WARNING: DO NOT INTERCHANGE WITH OTHER DAUNORUBICIN AND/OR CYTARABINE-CONTAINING PRODUCTS

VYXEOS has different dosage recommendations than daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. Verify drug name and dose prior to preparation and administration to avoid dosing errors.

Contraindications

VYXEOS is contraindicated in patients with a history of serious hypersensitivity reactions to cytarabine, daunorubicin, or any component of the formulation.

Warnings and Precautions

Hemorrhage

Serious or fatal hemorrhage events, including fatal CNS hemorrhages, associated with prolonged thrombocytopenia, have occurred with VYXEOS. The overall incidence (grade 1-5) of hemorrhagic events was 74% in the VYXEOS arm and 56% in the control arm. The most frequently reported hemorrhagic event was epistaxis (36% in VYXEOS arm and 18% in control arm). Grade 3 or greater events occurred in 12% of VYXEOS-treated patients and in 8% of patients in the control arm. Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients in the VYXEOS arm and in 0.7% of patients in the control arm. Monitor blood counts regularly and administer platelet transfusion support as required.

Cardiotoxicity

VYXEOS contains daunorubicin, which has a known risk of cardiotoxicity. This risk may be increased in patients with prior anthracycline therapy, preexisting cardiac disease, previous radiotherapy to the mediastinum, or concomitant use of cardiotoxic drugs. Assess cardiac function prior to VYXEOS treatment and repeat prior to consolidation and as clinically required. Discontinue VYXEOS in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk. VYXEOS is not recommended in patients with cardiac function that is less than normal.

Total cumulative doses of non-liposomal daunorubicin greater than 550 mg/m2 have been associated with an increased incidence of drug-induced congestive heart failure. The tolerable limit appears lower (400 mg/m2) in patients who received radiation therapy to the mediastinum. Calculate the lifetime cumulative anthracycline exposure prior to each cycle of VYXEOS. VYXEOS is not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit.

Hypersensitivity Reactions

Serious or fatal hypersensitivity reactions, including anaphylactic reactions, have been reported with daunorubicin and cytarabine. Monitor patients for hypersensitivity reactions. If a mild or moderate hypersensitivity reaction occurs, interrupt or slow the rate of infusion with VYXEOS and manage symptoms. If a severe or life-threatening hypersensitivity reaction occurs, discontinue VYXEOS permanently, treat the symptoms, and monitor until symptoms resolve.

Copper Overload

VYXEOS contains copper. Consult with a hepatologist and nephrologist with expertise in managing acute copper toxicity in patients with Wilson’s disease treated with VYXEOS. Monitor total serum copper, serum non-ceruloplasmin-bound copper, 24-hour urine copper levels, and serial neuropsychological examinations during VYXEOS treatment in patients with Wilson’s disease or other copper-related metabolic disorders. Use only if the benefits outweigh the risks. Discontinue in patients with signs or symptoms of acute copper toxicity.

Tissue Necrosis

Daunorubicin has been associated with severe local tissue necrosis at the site of drug extravasation. Administer VYXEOS by the intravenous route only. Confirm patency of intravenous access before administration. Do not administer by intramuscular or subcutaneous route.

Embryo-Fetal Toxicity

VYXEOS can cause embryo-fetal harm when administered to a pregnant woman. Patients should avoid becoming pregnant while taking VYXEOS. If VYXEOS is used during pregnancy or if the patient becomes pregnant while taking VYXEOS, apprise the patient of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of VYXEOS.

MOST COMMON ADVERSE REACTIONS

The most common adverse reactions (incidence ≥25%) are hemorrhagic events (74%), febrile neutropenia (70%), rash (56%), edema (55%), nausea (49%), mucositis (48%), diarrhea (48%), constipation (42%), musculoskeletal pain (43%), fatigue (39%), abdominal pain (36%), dyspnea (36%), headache (35%), cough (35%), decreased appetite (33%), arrhythmia (31%), pneumonia (31%), bacteremia (29%), chills (27%), sleep disorders (26%), and vomiting (25%).

Please see full Prescribing Information, including BOXED Warning.

INDICATION

VYXEOS is indicated for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t‑AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older.

Important Safety Information

WARNING: DO NOT INTERCHANGE WITH OTHER DAUNORUBICIN AND/OR CYTARABINE-CONTAINING PRODUCTS

VYXEOS has different dosage recommendations than daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. Verify drug name and dose prior to preparation and administration to avoid dosing errors.