Andrew Wei, MBBS, Ph.D. @MonashUni @US_FDA U.S. Food and Drug Administration Approves Onureg® (azacitidine tablets), a New Oral Therapy, as Continued Treatment for Adults in First Remiss...

Andrew Wei, MBBS, Ph.D. @MonashUni @US_FDA U.S. Food and Drug Administration Approves Onureg® (azacitidine tablets), a New Oral Therapy, as Continued Treatment for Adults in First Remiss...

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Andrew Wei, MBBS, Ph.D. Alfred Hospital and Monash University U.S. Food and Drug Administration Approves Onureg® (azacitidine tablets), a New Oral Therapy, as Continued Treatment for Adults in First Remission with Acute Myeloid Leukemia.

The approval is focused on the findings of the seminal phase 3 QUAZAR ® AML-001 trial, in which Onureg treatment resulted in a statistically significant and clinically significant overall survival (OS) improvement, the primary endpoint of the research, of almost 10 months compared to placebo. Median OS from randomization was greater than two years (24.7 months; 95 % confidence interval [CI]: 18.7 to 30.5) in patients receiving Onureg versus 14.8 months (95 % CI: 11.7 to 17.6) in patients receiving placebo (Hazard Ratio [HR]: 0.69; 95 % CI: 0.55 to 0.86; p=0.0009). Onureg remained unchanged until disease development or toxicity was intolerable. Onureg has alerts and precautions as to the risk of replacement with other azacitidine drugs, myelosuppression, increased early mortality and embryo-fetal toxicity in patients with myelodysplastic syndrome (MDS). Onureg should not be supplemented with intravenous or subcutaneous azacitidine due to significant variations in pharmacokinetic parameters, as this can result in a fatal adverse reaction. In 49 percent and 22 percent of the patients who received Onureg, new or deteriorating Grade 3 or 4 neutropenia and thrombocytopenia occurred. In 12 per cent of patients, febrile neutropenia occurred. Full blood counts should be controlled, dosing should be altered as prescribed, and if myelosuppression occurs, standard supportive treatment should be given. Enrollment in the AZA-MDS-003 trial was discontinued early due to a higher rate of early fatal and/or serious adverse reactions in the Onureg arm compared with the placebo arm. Beyond controlled trials, treatment of MDS with Onureg is not recommended. When administered to a pregnant woman, Onureg may cause fetal damage.

The FDA issued the New Drug Application priority review status, and the European Medicines Agency validated a marketing authorisation application (MAA) for this indication in May 2020.

Results of QUAZAR ® AML-001 Pivotal Study

Onureg's FDA approval is based on evidence from QUAZAR ® AML-001, an international, randomized, double-blind, Phase 3 trial.1 Qualifying patients were 55 years of age or older, had AML, were not candidates for hemophilia within four months of first CR or CRi after intensive induction chemotherapy with or without consolidation therapy (per investigator preference prior to study entry), and were not candidates for hemophilia 472 patients were enrolled in the study, randomized 1:1, to receive either Onureg 300 mg (n=238) or placebo (n=234) orally, once daily, for a 28-day period of 14 days, plus best supportive treatment.

Results showed significantly improved OS in patients with AML in remission compared to placebo with continued treatment with Onureg, identifying Onureg as a new continuing therapy choice for patients who are unable to complete intensive curative therapy, including HSCT. Median OS, the primary endpoint, was greater than two years from randomization (24.7 months; 95 percent CI: 18.7 to 30.5) in the Onureg arm compared to 14.8 months for placebo (HR: 0.69; 95 percent CI: 0.55 to 0.86; p=0.0009). A subgroup review demonstrated continuity in the value of OS to either CR or CRi patients. The median period of treatment for Onureg1 was 12 cycles (1 to 82), and placebo was 6 cycles (1 to 76).

In 15 per cent of patients who received Onureg, significant adverse reactions occurred. Severe adverse effects included pneumonia (8%) and febrile neutropenia (7%) in 2 % of patients receiving Onureg. One fatal side effect (sepsis) occurred in a patient receiving Onureg. Nausea (65 percent, 24 percent), vomiting (60 percent, 10 percent), diarrhea (50 percent, 21 percent), fatigue / asthenia (44 percent, 25 percent), constipation (39 percent, 24 percent), pneumonia (27 percent, 17 percent), abdominal pain (22 percent, 13 percent), arthralgia (14 percent, 10 percent), reduced appetite (14 percent, 10 percent) were the most common adverse reactions to Onureg versus placebo. Among patients who received Onureg, 8 percent of patients encountered permanent discontinuation due to an adverse reaction.

At the American Society of Hematology (ASH) Annual Meeting in December 2019, findings from the QUAZAR ® AML-001 trial were first discussed.


This year, almost 20,000 new cases of acute myeloid leukemia ( AML) will occur in the United States, accounting for 1.1% of all cancer cases, with an estimated 11,180 deaths from the disease. In 2017, there were an estimated 64,500 individuals living with AML in the United States.3 AML is one of the most common adult acute leukemias. AML is characterized by the excessive growth in the bone marrow of abnormal cells and thus interferes with the normal development and function of blood cells. Due to the decreased development of red blood cells , platelets and white blood cells, it may present with symptoms of anemia, bleeding and infections.4 AML is a heterogeneous disorder associated with a number of genetic mutations, and may worsen quickly and lead to death if not treated promptly.5 AML response to treatment can be short-lived, indicating the initial reaction of patients to chemotropy.

By Onureg ®

Onureg, the first and only continued AML therapy approved by FDA for patients in remission, is an oral hypomethylating agent that is integrated into DNA and RNA. Hypomethylation of DNA, as well as direct cytotoxicity to dysfunctional hematopoietic cells in the bone marrow, is thought to be the key mechanism of action. Hypomethylation can restore normal function to genes that are essential to the proliferation and differentiation of cells.


ONUREG is recommended for continued care of adult patients with acute myeloid leukemia who have either achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intense induction chemotherapy and are unable to complete intense curative therapy.
Relevant INFORMATION ON Protection


In patients with documented extreme hypersensitivity to azacitidine or its ingredients, ONUREG is contraindicated.

Risks of replacement with other azacitidine drugs: The prescribed dosage and schedule for ONUREG are different from those for intravenous or subcutaneous azacitidine drugs because of significant variations in the pharmacokinetic parameters. Treatment of patients with intravenous or subcutaneous azacitidine at the recommended ONUREG dose can lead to a fatal adverse reaction. Treatment with ONUREG may not be successful at dosages prescribed for intravenous or subcutaneous azacitidine. Do not supplement Intravenous or subcutaneous azacitidine with ONUREG.
Myelosuppression: 49 percent and 22 percent of patients who received ONUREG encountered new or deteriorating Grade 3 or 4 neutropenia and thrombocytopenia. In 12 percent, febrile neutropenia occurred. Due to neutropenia and thrombocytopenia a dose reduction was needed for 7 percent and 2 percent of patients. ONUREG was discontinued by less than 1 percent of patients due to either neutropenia or thrombocytopenia. Track full blood counts and, as prescribed, change the dose. Provide standard supportive treatment if myelosuppression occurs, including hematopoietic growth factors.
Increased early mortality in patients with myelodysplastic syndrome (MDS): In AZA-MDS-003, randomized to ONUREG or placebo 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to MDS. 107 obtained a median of 5 cycles of ONUREG 300 mg daily for a 28-day period lasting 21 days. Owing to a higher frequency of early fatal and/or extreme adverse reactions in the ONUREG arm compared with placebo, enrollment was discontinued early on. Sepsis was the most common fatal adverse reaction. The safety and efficacy of ONUREG for MDS has not been determined. Outside of controlled trials, treatment of MDS with ONUREG is not recommended.
Embryo-Fetal Toxicity: When given to a pregnant woman, ONUREG can cause fetal damage. In pregnant rats, azacitidine induced fetal death and defects at a single intraperitoneal dose lower than the maximum daily human dose of oral azacitidine on a mg / m2 basis. Advise pregnant women of the possible danger to a fetus. Advise females with reproductive ability to use appropriate contraceptives during ONUREG treatment and after the last dose for at least 6 months. Advise males with reproductive ability with female partners to use reliable contraceptives during ONUREG treatment and for at least 3 months after the last dose.

In 15 percent of patients who received ONUREG, severe adverse reactions occurred. In about 2 percent, severe adverse reactions included pneumonia (8 percent) and febrile neutropenia (7 percent). In a patient who received ONUREG, one fatal adverse reaction (sepsis) occurred.
The most common (almost 10%) adverse reactions with ONUREG versus placebo were nausea (65%; 24%), vomiting (60%; 10%), diarrhea (50%; 21%), fatigue / asthenia (44%; 25%), constipation (39%; 24%), pneumonia (27%; 17%), abdominal pain (22%; 13%), arthralgia (14%; 10%), decreased aphthalgia.
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