Bristol Myers Squibb Receives EC Approval for Onureg (Azacitidine Tablets) as First Oral Maintenance Therapy for AML Patients in First Remission
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European Commission
The European Commission, abbreviated as the EU Commission, is a supranational body under the European Union. Within the EU political system, the European Commission primarily undertakes executive tasks, thus being roughly equivalent to the government in a national system. However, the European Commission has other functions as well. In particular, except for the few circumstances specified in the treaties, the European Commission is the only institution with legislative power in the EU legislative process.
In first-line continuation therapy, compared with placebo, Onureg significantly prolonged overall survival and relapse-free survival!
AML (Image source: checkrare.com)
Bristol-Myers Squibb (BMS) recently announced that the European Commission (EC) has approved Onureg (azacitidine tablets) as a first-line oral maintenance therapy for the treatment of patients who have achieved complete remission (CR) or complete remission with incomplete platelet count recovery (CRi) following induction therapy (with or without consolidation therapy), and who are not eligible for or have chosen not to undergo hematopoieticStem cellsTransplantation (ASCT) for Acute MyeloidLeukemia(AML) adult patients. AML is one of the most common acute leukemias in adults.
Notably, Onureg is the first and only once-daily oral first-line maintenance therapy in Europe for patients with a broad range of AML subtypes in first remission. Following its launch, Onureg will address the urgent unmet medical need for new maintenance treatment options within the AML patient population. Data from the pivotal QUAZAR AML-001 study demonstrated that, among patients with AML in first remission, first-line maintenance therapy with Onureg showed significant benefits in overall survival (OS) and relapse-free survival (RFS) compared with placebo. Subgroup analysis indicated that the OS benefit was consistent in patients achieving CR or CRi.
In the United States, Onureg was approved by the FDA in September 2020 for the continuation treatment of adult patients with AML in first remission, specifically: for the continuation treatment of adult patients with AML who have achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy, and who are not candidates to complete curative therapy (such as ASCT). In the United States, Onureg isFDAThe first and only approved maintenance therapy for AML patients in remission.
Regarding dosing, Onureg may be continued until disease progression or unacceptable toxicity. Due to significant differences in pharmacokinetic parameters, Onureg should not be substituted for intravenous or subcutaneous azacitidine.
The active pharmaceutical ingredient of Onureg is CC-486 (azacitidine), an oral hypomethylating agent that incorporates into DNA and RNA, allowing for sustained epigeneticGeneticsRegulation. Currently, the drug is being developed as aEpigeneticsModifier, for use with various blood specimens`Tumor`treatment. The primary mechanism of action of this drug is believed to be DNA hypomethylation and direct cytotoxicity to abnormal hematopoietic cells in the bone marrow. Hypomethylation may restore the normal function of genes critical for differentiation and proliferation.
Onureg-Azacitidine Chemical Structural Formula
AML is the most common type of acute leukemia. AML originates in the bone marrow but quickly 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 normal hematopoiesis, leading to a decrease in healthy white blood cells, red blood cells, and platelets. AML is a complex and heterogeneous disease associated with various genetic mutations. If left untreated, it typically progresses rapidly.
NewDiagnosisAdult patients with AML can typically achieve complete remission following induction chemotherapy, but many will relapse and experience poor outcomes. Patients in remission urgently require a maintenance therapy regimen that can reduce the risk of relapse and prolong overall survival.
This approval is based on the efficacy and safety results from the pivotal Phase 3 QUAZAR AML-001 study. The study evaluated the efficacy and safety of Onureg as first-line maintenance therapy in patients with newly diagnosed AML who achieved a first complete remission (CR or CRi) following intensive induction chemotherapy and were ineligible for ASCT at screening. The results demonstrated that, as first-line maintenance therapy, Onureg significantly extended overall survival (OS, primary endpoint) by nearly 10 months compared with placebo (median OS: 24.7 months vs. 14.8 months, p=0.0009) and more than doubled relapse-free survival (RFS, key secondary endpoint) (median PFS: 10.2 months vs. 4.8 months, p=0.0001), representing statistically significant and clinically meaningful improvements.
Andrew Wei, Principal Investigator of the QUAZAR AML-001 study, stated: “In the EU, although many AML patients achieve remission through induction therapy, due to the potentially short duration of remission and the persistently high risk of relapse, particularly those who are ineligible`Stem cells`"For patients meeting transplantation criteria, the need for AML maintenance therapy regimens therefore remains unmet. The European Commission's approval of Onureg will deliver clinical benefits to AML patients and transform the AML treatment landscape, including across a range of patient subtypes."
QUAZAR AML-001 Clinical Data (Click image to enlarge)
QUAZAR AML-001 is an international, randomized, double-blind, placebo-controlled phase III study, enrolling patients aged ≥55 years with de novo or secondary acute myeloid leukemia (AML), with intermediate- or high-risk cytogeneticGeneticsology, achieved first complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) following intensive induction chemotherapy. At the investigator's discretion, patients received intensive induction chemotherapy, with or without consolidation chemotherapy, and were deemed not to be hematopoieticStem cellsCandidates for transplantation (HSCT).
Following intensive induction chemotherapy, 81% of patients achieved CR and 19% achieved CRi. 80% 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: Onureg 300 mg (n=238) or placebo (n=234), administered once daily for 14 days per 28-day cycle. In the study, patients continued treatment until unacceptable toxicity or disease progression.
With a median follow-up of 41.2 months, the Onureg treatment arm demonstrated a significant improvement in the primary endpoint of overall survival (OS) compared with the placebo arm. The median OS from randomization was 24.7 months in the Onureg arm versus 14.8 months in the placebo arm (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 Onureg arm compared with 4.8 months in the placebo arm (p=0.0001; HR=0.65 [95% CI: 0.52, 0.81]). Regardless of cellularGeneticsRegardless of risk category, prior consolidation status, or CR/CRi status at enrollment, both OS and RFS were improved in the Onureg treatment group compared with the placebo group. Compared with the placebo group, health-related quality of life (HRQoL) in the Onureg treatment group was maintained from baseline.
The median treatment duration for Onureg was 12 cycles (1–80), compared with 6 cycles (1–73) for placebo. The most common adverse events (AEs) of any grade for Onureg 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% and 25% of patients in the Onureg and placebo groups, respectively, primarily infections, which were reported in 17% and 8% of patients in the two groups, respectively. Treatment discontinuation due to AEs occurred in 13% and 4% of patients in the Onureg and placebo groups, respectively.