2020-09-06| Trials & Approvals

Bristol Myers Squibb Notches Key Regulatory Win for Oral Formulation of Epigenetic Modifier

by Pavel Ryzhov
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By Pavel Ryzhov, Ph.D.

Acute myeloid leukemia (AML), a type of blood cancer, is an aggressive disease affecting 3-5 people per 100,000 cases in the US. The buildup of immature blood cells as a result of bone marrow failure is very rapid and has a detrimental effect on the production of normal blood cells. The severity of the disease is currently met with chemotherapy treatments that allow many patients to enter complete remission (CR). This is where consolidation therapy (additional chemotherapy and allogeneic hematopoietic stem cell transplant) is typically prescribed in hopes of improving overall survival (OS) chances [1]. Unfortunately, many patients still relapse and die after induction treatment, thus, illustrating a clinical need that is yet to be addressed.

This is about to change with the recent FDA approval of Onureg [2], an oral formulation of epigenetic modifier azacitidine, a previously approved drug (as an intravenous injection) for the treatment of other types of blood disorders such as myelodysplastic syndrome subtypes and chronic myelomonocytic leukemia [3]. The oral formulation of the compound allows to avoid common shortcomings of chemotherapy, such as injection-site reactions, significantly improving patient convenience. Besides, the efficacy and tolerability profile of intravenous azacitidine was already previously established and further expanded to study the benefits of oral formulation in subsequent trials.

Azacitidine is a close analog of cytidine nucleoside, with nitrogen atom replacing 5-carbon to prevent methylation. This substitution leads to covalent binding and inhibition of DNA methyltransferases, leading to DNA hypomethylation and restoration of normal function for differentiation and proliferation genes [3].

According to the FDA, Onureg, manufactured by Celgene, a subsidiary of Bristol-Myers-Squibb, has been approved for continued treatment of AML patients who achieved first CR or CR with incomplete blood count recovery after induction chemotherapy but unable to complete curative therapy (such as stem cell transplant).

The approval is based mainly on the recent Phase III clinical trial – QUAZAR (NCT01757535). This multicenter, randomized, double-blind, and placebo-controlled trial enrolled 472 patients who met the inclusion criteria and randomized them 1:1 to receive either 300 mg Onureg or placebo tablets for 14 days on a 28-day cycle. In the trial, it was statistically demonstrated that median OS was 24.7 months in the Onureg arm versus 14.8 months in the placebo arm, meeting the primary endpoint. Furthermore, relapse-free survival of 10.2 months in Onureg versus 4.8 months for the placebo arm met the secondary endpoint [4].

The speedy approval of Onureg follows a Priority Review for New Drug Application that was accepted on May 1st earlier this year. It is currently waiting for EMA’s approval decision for the same indication. Onureg is also being tested for other disease indications for both solid tumors and other types of cancers.

Editor: Rajaneesh K. Gopinath, Ph.D.

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



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