2020-08-30| R&DTrials & Approvals

Bristol-Myers-Squibb Anticipates FDA Approval for CC-486 as a Treatment for Acute Myeloid Leukemia

by Pavel Ryzhov
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After registering positive results in Phase 3, QUAZAR AML-001 trial, the company would be expecting the oral hypomethylating agent to notch FDA authorization this week.

By Pavel Ryzhov, Ph.D.

In the world of cancer therapies, conventional chemotherapies have been around for many decades. However, with advances in patient care options and competition from new types of targeted therapies, more emphasis is being put on improving overall survival, relapse-free survival, and quality of life following treatment.

Despite the proven anti-cancer efficacy of the already approved chemotherapeutic agents, they have several adverse side effects that limit their administered dosage. Besides common off-target cytotoxicity that may lead to complications, increasingly important considerations are patient inconvenience and risk of injection site infections for drugs that must be intravenously administered. Therefore, investigating oral formulations of existing drugs would allow them to expand their medical use without sacrificing their clinical benefits [1].


Acute Myeloid Leukemia

There are several aggressive malignant blood disorders. Among them are myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), various lymphomas, and other types of leukemias. MDS is characterized by reduced production of regular blood cells in the bone marrow. In certain instances, depending on the patient, MDS may progress to AML [2].

Acute myeloid leukemia (AML) is a type of blood cancer and occurs in 3-5 people per 100,000 cases in the US, with the incident rate increasing with age. It is characterized by bone marrow failure and immature myeloid cell proliferation. Such rapid buildup of cells interferes with the production of normal blood cells, including erythrocytes and leukocytes and platelets. The standard treatment options include the “7+3” chemotherapy regimen, with seven days of cytarabine and three days of anthracycline [3].

If the patient enters complete remission (CR), consolidation therapy, consisting of additional chemotherapy and allogeneic hematopoietic stem cell transplant (allo-HSCT), is prescribed to improve overall survival (OS) chances depending on the patient. However, due to the complex genetics of AML progression and its aggressiveness, the majority of the patients relapse after induction treatment and die. This is an area of unmet clinical need, and several pharmaceutical companies are looking at improving maintenance treatment options.



Vidaza, an intravenous injection of epigenetic modifier azacitidine, is FDA-approved chemotherapy for the treatment of several myelodysplastic syndrome (MDS) subtypes and chronic myelomonocytic leukemia (CMML) [4]. It has also been studied in acute myeloid leukemia patients showing favorable outcomes compared to conventional care regimens [5].

It is produced by Celgene, now a subsidiary of Bristol-Myers-Squibb. Azacitidine is a pyrimidine ring analog of cytidine nucleoside, where 5-carbon is replaced with nitrogen to prevent methylation. Instead, replacement leads to covalent binding with DNA methyltransferases, enzymes responsible for methylation of DNA [6]. Methylation is a crucial epigenetic regulatory mechanism by which gene expression is regulated in cells [7].

The proposed mechanism of action for azacitidine is thought to be via DNA hypomethylation and direct cytotoxicity as a result of incorporation into DNA or RNA, and subsequent inhibition of protein synthesis and DNA damage. Hypomethylation of DNA may restore normal function for genes involved in differentiation and proliferation [4].



The oral formulation of azacitidine (CC-486) has been undergoing clinical testing for a few years. This route of administration would avoid injection-site reactions while improving patient convenience. Importantly, it allows for flexibility in testing alternative doses and treatment schedules. Extending the schedule and lowering the dose for the existing formulation of azacitidine has already shown increased efficacy in clinical trials [6]. This is significant because DNA demethylation requires longer drug exposure, and with a short plasma half-life for injectable, oral administration would prolong drug exposure to the cancer cells.

Early studies established the maximum tolerated dose (MTD) of orally administered azacitidine to be 480 mg once daily for 7 days and maximum concentration at 1.0 hour (range: 0.3–3.6 hours) after dosing, with a mean half-life of 0.6 hours [8]. No new adverse effects (AE) were identified as compared to the standard route of administration. More importantly, in patients with MDS, CMML, and AML, oral azacitidine at 300 mg once daily for 21 days demonstrated the greatest level of hypomethylation as compared to other regimens, including injectable versions of the drug [9].


USFDA Review

On May 1st, BMS announced FDA’s acceptance of its New Drug Application (NDA) for oral azacitidine as the maintenance treatment of adult AML patients who, after induction therapy are in complete remission or with incomplete blood count recovery and do not subject to hematopoietic stem cell transplantation [10]. The NDA is the latest step in the regulatory approval journey of CC-486.

The application has received a Priority Review and scheduled a Prescription Drug User Fee Act goal date to September 3rd, 2020. Also, in May 2020, European Medicines Agency received a Marketing Authorization Application for CC-486 for the same indication [11]. If approved, this drug would become a new standard of care for AML patients after induction therapy, especially considering that other competitors, like AbbVie’s Venclexta, are currently undergoing clinical trials with results due in 2021 [12].


QUAZAR AML-001 Trial

Prior to the FDA application, BMS announced positive results from its Phase 3 international, randomized, double-blind, placebo-controlled clinical trial (QUAZAR AML-001), evaluating the benefits of CC-486 as the maintenance therapy for AML [13]. With 472 enrolled patients, who were randomized 1:1, 300 mg oral azacitidine or placebo were administered for 14 days of a 28-day cycle along with the best supportive care. Most importantly, the primary endpoint of median OS from randomization was 24.7 months in CC-486 arm as compared to 14.8 months in a placebo arm. The secondary endpoint of median Relapse-free survival (RFS) was 10.2 months for CC-486 versus 4.8 months for placebo.

Both endpoints provided conclusive evidence of efficacy, and according to one of the investigators in the study, the results “show (the) potential to establish maintenance therapy as a new treatment paradigm” for patients with AML. These results served as a backbone for both FDA and EMA applications. In addition to AML, BMS is pursuing other disease indications for CC-486. There are several clinical trials underway, including both blood cancers (T-cell lymphoma [14], B-cell lymphoma [15], MDS [16, 17]), and solid tumors like melanoma [18] and metastatic non-small cell lung cancer [19].

The encouraging results highlight the potential benefits of investing in CC-486’s reformulation and additional testing of classic chemotherapeutic agents. Improvements in patient survival outcomes, convenience in drug administration, and better quality of life are critical metrics in our battle against cancer and must be pursued just as equally as novel treatment options.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: Novartis’ Asciminib Shines in Chronic Myeloid Leukemia Trial


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