AG-221 Clinical Results Promise “Revolutionary” Approach in AML

Early clinical findings with AG-221 – a first-in-class potent, selective oral inhibitor of mutated isocitrate dehydrogenase 2 (IDH2) – reveal durable responses, including complete remissions, in patients with advanced hematologic malignancies associated with IDH2 mutations.

Approximately 15 percent of patients with acute myeloid leukemia (AML) harbor a mutation of either the IDH1 or IDH2 gene. These somatic mutations in IDH1 and IDH2 confer gain-of-function activity in cancer cells, noted lead AG-221 study author Eytan M. Stein, MD, assisting attending physician at Memorial Sloan Kettering Cancer Center, in an oral presentation at the 2014 ASH Annual Meeting. The genetic abnormality leads to altered enzyme activity and increased production of the oncometabolite 2-hydroxyglutarate (2-HG), which alters epigenetic patterns and prevents differentiation of immature white blood cells. AG-221 works by inhibiting the mutated IDH2 enzyme and eliminating production of 2-HG.

“I am extremely enthusiastic about the data to date,” Dr. Stein said. “The early results with AG-221 are truly remarkable for a population with relapsed and refractory AML.”

Dr. Stein presented data from 73 patients enrolled in the ongoing first-in-human, phase 1, open-label, dose-escalation study of AG-221. Of the 73 patients, 55 have relapsed/refractory AML and 13 have undergone prior bone marrow transplant, making them unlikely to respond to chemotherapy, Dr. Stein said. Five of the patients have untreated AML, while six have MDS. All enrolled patients have IDH2 mutations and are receiving AG-221 orally as a single-agent either once- or twice-daily, in 28-day cycles.

The dose in the first cohort was twice-daily 30 mg, and testing of sequentially higher dose levels is now ongoing, with once- and twice-daily dosing regimens up to 150 mg and 200 mg, respectively. The maximum tolerated dose has not yet been reached. Bone marrow is examined on days 15, 29, 57, and every 56 days thereafter.

As of October 1, 2014, 45 patients had 28-day bone marrow samples and were evaluable for treatment efficacy – 16 patients discontinued treatment before day 28, and 12 others had been on study for fewer than 28 days. Investigators observed objective responses in 25 of the evaluable subjects (56%), including 15 complete responses (6 CRs, and an additional 9 CRs with incomplete blood count recovery) and 10 partial responses. Seventeen subjects with stable disease remain on AG-221, and two patients have had disease progression while participating in the study.

Responses, Dr. Stein said, are durable and include CRs of up to 9 months. Some subjects have been on study for eight 28-day treatment cycles. Five CR patients have moved forward to bone marrow transplantation.

The results, Dr. Stein said, confirm that AG-221’s triggering of leukemic blast cell differentiation leads ultimately to objective durable responses and some complete remissions. The current findings encourage further testing of AG-221 and validate IDH2 as a therapeutic target in cancer.

AG-221 was “remarkably well tolerated”, with patients experiencing adverse events typical for this population (e.g., nausea, fever, diarrhea, fatigue). One treatment-emergent event was leukocytosis, which is of special interest. “We actually think that is a response to the therapy with AG-221,” Dr. Stein explained. “When it causes the leukemic blasts to begin to differentiate into normal neutrophils, in some patients you get a burst of activity and a rise in the white count.”

By inhibiting mutant IDH2 with AG-221, Dr. Stein added, “we can transform leukemia cells into healthy, normal adult white blood cells and eradicate disease without the use of traditional chemotherapy.

“This revolutionary approach to treat leukemia represents the future of treatment for hematologic diseases. Our goal is to treat patients with therapy that is targeted to the specific genotype of their disease, thereby increasing efficacy, extending patients’ life spans, and minimizing toxicity.”


Stein EM, Altman JK, Collins R, et al. “AG-221, an oral, selective, first-in-class, potent inhibitor of the IDH2 mutant metabolic enzyme, induces durable remissions in a phase I study in patients with IDH2 mutation positive advanced hematologic malignancies.” Abstract #115. Presented at the American Society of Hematology Annual Meeting. December 7, 2014.