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FDA has approved Onureg, a new oral therapy based on Azacitidine, as continued treatment for adults in first remission with acute myeloid leukemia


The FDA ( U.S. Food and Drug Administration ) has approved Onureg ( Azacitidine 300 mg tablets, CC-486 ) for the continued treatment of adult patients with acute myeloid leukemia ( AML ) who achieved first complete remission ( CR ) or complete remission with incomplete blood count recovery ( CRi ) following intensive induction chemotherapy and who are not able to complete intensive curative therapy.

Onureg, the first and only FDA-approved continued AML therapy for patients in remission, is an oral hypomethylating agent that incorporates into DNA and RNA. The main mechanism of action is thought to be hypomethylation of DNA, as well as direct cytotoxicity to abnormal hematopoietic cells in the bone marrow. Hypomethylation may restore normal function to genes that are critical for cell differentiation and proliferation.

The approval is based on results from the pivotal phase 3 QUAZAR AML-001 study in which treatment with Onureg resulted in a statistically significant and clinically meaningful improvement in overall survival ( OS ), the study’s primary endpoint, of nearly 10 months compared to placebo.
Median overall survival from time of randomization was greater than two years ( 24.7 months; 95% confidence interval [ CI ]: 18.7 to 30.5 ) among patients who received Onureg compared to 14.8 months ( 95% CI: 11.7 to 17.6 ) among patients receiving placebo ( hazard ratio [ HR ]: 0.69, 95% CI: 0.55 to 0.86; p=0.0009 ).
Onureg was continued until disease progression or unacceptable toxicity.

Onureg has warnings and precautions for risks of substitution with other Azacitidine products, myelosuppression, increased early mortality in patients with myelodysplastic syndromes ( MDS ) and embryo-fetal toxicity.

Due to substantial differences in the pharmacokinetic parameters, Onureg should not be substituted for intravenous or subcutaneous Azacitidine as it may result in a fatal adverse reaction.

New or worsening grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received Onureg, respectively.
Febrile neutropenia occurred in 12% of patients.
Complete blood counts should be monitored, dosing should be modified as recommended and standard supportive care should be provided if myelosuppression occurs.

Enrollment was discontinued early in the study AZA-MDS-003 due to a higher incidence of early fatal and/or serious adverse reactions in the Onureg arm compared with the placebo arm.
Treatment of MDS with Onureg is not recommended outside of controlled trials.

Onureg can cause fetal harm when administered to a pregnant woman.

QUAZAR AML-001 Trial

QUAZAR AML-001 is a phase 3, international, randomized, double-blind study. Eligible patients were ages 55 years or older, had acute myeloid leukemia, were within four months of achieving first CR or CRi following intensive induction chemotherapy with or without consolidation treatment ( per investigator preference prior to study entry ), and were not candidates for hematopoietic stem cell transplant ( HSCT ) at the time of screening.
The study enrolled 472 patients, randomized 1:1 to receive either Onureg 300 mg ( n=238 ) or placebo ( n=234 ) orally, once daily, for 14 days of a 28-day cycle, plus best supportive care.

Results have shown continued treatment with Onureg has significantly improved overall survival in patients with acute myeloid leukemia in remission compared to placebo, establishing Onureg as a new continued therapy option for patients who are not able to complete intensive curative therapy, including HSCT.
Median overall survival, the primary endpoint, from time of randomization was greater than two years ( 24.7 months; 95% CI: 18.7 to 30.5 ) in the Onureg arm compared to 14.8 months for placebo ( HR: 0.69, 95% CI: 0.55 to 0.86; p=0.0009 ).
A subgroup analysis showed consistency in the overall survival benefit for patients in either CR or CRi.
The median duration of treatment was 12 cycles ( 1 to 82 ) for Onureg and 6 cycles with placebo ( 1 to 76 ).

Serious adverse reactions occurred in 15% of patients who received Onureg. Serious adverse reactions in 2% or more of patients who received Onureg included pneumonia ( 8% ) and febrile neutropenia ( 7% ).
One fatal adverse reaction ( sepsis ) occurred in a patient who received Onureg.
The most common 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 appetite ( 13%, 6% ), febrile neutropenia ( 12%, 8% ), dizziness ( 11%, 9% ) and pain in extremity ( 11%, 5% ).
Of patients who received Onureg, permanent discontinuation due to an adverse reaction occurred in 8% of patients.

Acute myeloid leukemia

There will be nearly 20,000 new cases of acute myeloid leukemia in the United States this year, accounting for 1.1% of all cancer cases, with an estimated 11,180 deaths resulting from the disease.
There were an estimated 64,500 people living with acute myeloid leukemia in the United States in 2017.
Acute myeloid leukemia is one of the most common acute leukemias in adults. AML is characterized by the rapid growth of abnormal cells in the bone marrow and as such interferes with normal blood cell production and function. Because of the impaired production of red blood cells, platelets and white blood cells, it can present with signs of anemia, bleeding and infections.
Acute myeloid leukemia is a heterogeneous disease associated with diverse genetic mutations, and can rapidly progress and lead to death if not promptly treated.
Acute myeloid leukemia response to treatment may be of short duration, meaning following patients' initial response to chemotherapy, there is still a very high risk of relapse, thus representing a significant unmet need for continued therapy options that prolong overall survival. ( Xagena )

Source: BMS, 2020

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