FDA Grants Priority Review to Enasidenib for IDH2-Mutant AML

David Schenkein, MD

The FDA has granted a priority review to a new drug application (NDA) for enasidenib (AG-221) as a treatment for patients with relapsed or refractory IDH2-mutated acute myeloid leukemia (AML), according to a statement from Celgene and Agios, the codevelopers of the targeted therapy.

The priority review is based on data from the phase I/II AG221-C-001 study, which was presented at the 2015 ASH Annual Meeting. In the single-arm trial, the objective response rate (ORR) with enasidenib was 41% in patients with relapsed or refractory IDH2-mutant AML. The complete response (CR) rate was 18% and 1.6% had a CR with incomplete platelet recovery (CRp) or incomplete blood count recovery (CRi). Additionally, 6% of patients had a marrow CR (mCR).

Under the priority review program, the FDA will decide on the NDA for enasidenib within 6 months compared with the standard 10-month review. The accelerated review timeline follows a fast track designation for enasidenib, which was granted in 2014 and allowed for a rolling submission of data to the FDA. Under the Prescription Drug User Fee Act (PDUFA), the FDA is scheduled to decide on the NDA by August 30, 2017.

“Having received NDA acceptance and priority review for enasidenib, we look forward to working with our partner Celgene and the FDA to advance a first-in-class therapy for relapsed or refractory AML with an IDH2 mutation,” David Schenkein, MD, chief executive officer at Agios, said in a statement. “We hope that the continued adoption of molecular profiling and availability of new targeted therapies such as enasidenib will have a significant impact on patients living with AML.”

The phase I/II study treated 198 patients with enasidenib at escalating doses that started at 30 mg or 50 mg daily or twice daily. The highest dose received was 450 mg daily, although a maximum tolerated dose was not reached. The dose selected for future studies was 100 mg once daily.

The median age of patients enrolled was 69 years, and the median number of prior therapies was 2 (range, 1-6). Patients had relapsed/refractory AML (70%), untreated AML (17%), myelodysplastic syndrome (7%), or another IDH2-mutant hematologic malignancy (6%). In those specifically with relapsed/refractory AML, 64% of patients had received ≥2 prior therapies, which included intensive therapy, bone marrow transplant, and hypomethylating agents. The median baseline absolute neutrophil count (ANC) was 0.4 x 10⁹/L.

Across all patients in the study, 181 were evaluable for efficacy, which included 128 patients with relapsed/refractory AML. In all patients, the ORR was 41% and the CR rate was 17%, with a CRi rate of 1%, a CRp rate of 2%, and a mCR rate of 8%. Additionally, 14% of patients had a partial response.

The median duration of response in the full population was 6.9 months. In those with relapsed/refractory AML, the duration of response was 6.0 months (95% CI, 3.7-9.2). Overall, 8 patients went on to receive a transplant, 5 of whom had relapse/refractory AML.

There were improvements in baseline ANC for 56% of patients with relapsed/refractory AML. These improvements were noted after the first cycle of therapy and continued through cycle 6. Patients with improvements in ANC experienced lower rates of infection and febrile neutropenia compared with those who did not have an ANC improvement.

The most common treatment-related adverse events (AEs) were indirect hyperbilirubinemia (19%) and nausea (18%). Serious AEs in the study were mostly associated with the underlying disease; however, 18% of patients did experience a treatment-related serious AE, primarily leukocytosis (3.5%)

“We accelerated this application—submitting the NDA just 3 years after the first patient was treated in the enasidenib pivotal investigational trial–because we believe that there is a significant unmet need for people with relapsed or refractory AML,” Michael Pehl, president, Hematology/Oncology for Celgene, said in a statement. “The acceptance of the enasidenib NDA is a significant milestone in what we hope will be a new era of molecularly targeted therapies for patients with this devastating disease.”

Abbott has also applied for premarket approval with the FDA for a diagnostic to detect patients with the IDH2 mutation. The assay, named the m2000 RealTime System, utilizes PCR testing to detect IDH2 mutations, which occur in 8% to 19% of patients with AML.

A phase III study, known as IDHENTIFY, is comparing enasidenib with standard regimens in older patients with relapsed/refractory IDH2-mutant AML. The trial, which is still enrolling, plans to include 280 participants with an estimated primarily completion date in April 2019. In this study, conventional therapy will consist of azacitidine and low- or intermediate-dose cytarabine. All patients will receive best supportive care (NCT02577406).

Stein EM, DiNardo C, Altman JK, et al. Safety and Efficacy of AG-221, a Potent Inhibitor of Mutant IDH2 That Promotes Differentiation of Myeloid Cells in Patients with Advanced Hematologic Malignancies: Results of a Phase 1/2 Trial. Blood. 2015;126:323.