Bristol Myers Squibb Announces EMA Validation of Marketing Authorization Application for Oral Azacitidine (CC-486) as First-Line Maintenance Therapy in Adults with AML in Remission

May 23, 2020 /BioonBIOON/ -- Bristol-Myers Squibb (BMS) recently announced that the European Medicines Agency (EMA) has accepted the Marketing Authorization Application (MAA) for CC-486 (oral azacitidine), an oral hypomethylating agent indicated for acute myeloid leukemia in patients who are in remission following intensive induction chemotherapy.Leukemia(AML) Maintenance therapy for adult patients, specifically: for use in achieving first complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) after intensive induction chemotherapy (with or without consolidation chemotherapy), who are not suitable for or choose not to undergo hematopoieticStem CellsMaintenance Therapy for Adult Patients with AML Undergoing Hematopoietic Stem Cell Transplantation (HSCT).

The EMA has confirmed the completeness of the MAA and has initiated the centralized review procedure. Currently, the New Drug Application (NDA) for CC-486 for the same indication is also under review in the United StatesFDAPriority review; the Prescription Drug User Fee Act (PDUFA) target date is September 3, 2020.

CC-486 (oral azacitidine) is an oral hypomethylating agent that incorporates into DNA and RNA, allowing for sustained epigeneticHeredityregulation. Currently, CC-486 is being developed as aEpigeneticsModifiers, for use in various blood productsTumorof treatment. The primary mechanisms of action of this drug are considered to be DNA hypomethylation and direct cytotoxicity against abnormal hematopoietic cells in the bone marrow. Hypomethylation may restore the normal function of genes critical for differentiation and proliferation.

Acute Myeloid Leukemia (AML) is the most common type of acute leukemia. AML originates in the bone marrow but rapidly enters the bloodstream. Unlike normal blood cell development, in AML, the rapid accumulation of abnormal white blood cells in the bone marrow can interfere with the production of normal blood cells, leading to reduced levels of healthy white blood cells, red blood cells, and platelets. AML is a complex and heterogeneous disease associated with various genetic mutations, and if left untreated, the condition typically deteriorates rapidly.

NewDiagnosisAdult patients with AML typically achieve complete remission through induction chemotherapy; however, many experience relapse and poor outcomes. There is an urgent need for a treatment regimen that can reduce the risk of relapse and prolong overall survival in patients who are in remission. CC-486 has the potential to address the critical unmet medical need for novel maintenance therapies in the AML patient population.

This MAA is based on the efficacy and safety results from the pivotal Phase III QUAZAR AML-001 study, which enrolled patients with newly diagnosed acute myeloid leukemia who achieved remission after intensive induction chemotherapy.Diagnosisconducted in AML patients, evaluating the efficacy and safety of CC-486 (oral azacitidine) as first-line maintenance therapy. The results showed that, compared with the placebo group, the CC-486 treatment group demonstrated statistically significant and clinically meaningful improvements in overall survival (median OS: 24.7 months vs. 14.8 months, p=0.0009) and progression-free survival (median PFS: 10.2 months vs. 4.8 months, p=0.0001) during first-line maintenance therapy.

Noah Berkowitz, M.D., Senior Vice President of Global Hematology Development at Bristol-Myers Squibb, stated, “For patients with AML, maintaining remission remains an extremely important factor in disease treatment. The acceptance of this MAA represents a significant step toward providing CC-486 to eligible patients in the European Union, a therapy with the potential to reduce the risk of disease recurrence and prolong overall survival.”

QUAZAR AML-001 is an international, randomized, double-blind, placebo-controlled Phase III study enrolling patients aged ≥55 years with newly diagnosed (de novo) or secondary acute myeloid leukemia (AML) at intermediate or high cytogenetic risk.Heredityachieved first complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) after intensive induction chemotherapy. According to the investigator’s choice, patients received intensive induction chemotherapy, with or without consolidation chemotherapy, and were considered not to be hematopoieticStem CellsCandidates for Hematopoietic Stem Cell Transplantation (HSCT).

Following intensive induction chemotherapy, 81% of patients achieved complete remission (CR), and 19% achieved complete remission with incomplete hematologic recovery (CRi). Eighty percent of patients had received at least one cycle of consolidation therapy prior to study enrollment. Subsequently, 472 patients were randomized in a 1:1 ratio to receive either CC-486 300 mg (n=238) or placebo (n=234), administered once daily for 14 days per 28-day cycle. Patients continued treatment until unacceptable toxicity or disease progression occurred.

With a median follow-up of 41.2 months, the CC-486 treatment group demonstrated significant improvement in the primary endpoint of overall survival (OS) compared with the placebo group. The median OS from randomization was 24.7 months in the CC-486 group versus 14.8 months in the placebo group (p=0.0009; HR=0.69 [95% CI: 0.55, 0.86]). For the key secondary endpoint of relapse-free survival (RFS), the median RFS was 10.2 months in the CC-486 group compared with 4.8 months in the placebo group (p=0.0001; HR=0.65 [95% CI: 0.52, 0.81]). Regardless of cellHeredityRegardless of risk category, prior consolidation status, or CR/CRi status at enrollment, the CC-486 treatment group demonstrated improvements in both OS and RFS compared with the placebo group. Compared with the placebo group, health-related quality of life (HRQoL) in the CC-486 treatment group remained unchanged from baseline.

The median duration of treatment with CC-486 was 12 cycles (range, 1–80), compared with 6 cycles (range, 1–73) for placebo. The most common adverse events (AEs) of any grade for CC-486 and placebo were nausea (65% vs. 24%), vomiting (60% vs. 10%), and diarrhea (50% vs. 22%). The most common grade 3–4 adverse events for CC-486 and placebo were neutropenia (41% vs. 24%), thrombocytopenia (23% vs. 22%), andAnemia(14% vs 13%). Serious adverse events occurred in 34% of patients in the CC-486 treatment group and 25% of patients in the placebo group, primarily infections, which were reported in 17% and 8% of patients in the two groups, respectively. Treatment was discontinued due to adverse events (AEs) in 13% of patients in the CC-486 treatment group and 4% of patients in the placebo group. (Bioon.com)

Original Source: European Medicines Agency Validates Bristol-Myers Squibb’sapplications for Idecabtagene Vicleucel (Ide-cel, bb2121) and CC-486