Study with Novel Drug AG-221 Shows Positive Early Results in AML


In a first-in-human study, the drug AG-221 generated long-lasting remissions in patients with acute myeloid leukemia (AML).

In a first-in-human study, the drug AG-221 generated long-lasting remissions in patients with acute myeloid leukemia (AML). The drug targets a mutation of the IDH2 gene, which, left unchecked, can result in an overproduction of immature white blood cells. Researchers are excited about the novel drug class, which could represent a new, chemotherapy-free approach for AML.

The agent demonstrated tolerability and efficacy in treating patients with AML—whether previously treated or not—and with myelodysplastic syndromes (MDS) among participants with IDH2-positive disease, said lead researcher of the study, Eytan M. Stein, of Memorial Sloan Kettering Cancer Center, said at a press briefing during the American Society of Hematology (ASH) meeting in San Francisco.

The IGH2 mutation prevents immature white blood cells from developing into healthy infection-fighting adult white cells. In addition, these immature leukemic white cells continue to increase and eventually crowd out normal red cells and platelets, a hallmark of AML.

For patients with AML or pre-leukemia, such as MDS, chronic myelomonocytic leukemia and myeloproliferative neoplasms, who are affected by the mutation, the novel drug AG-221 could eventually represent a better-tolerated alternative to conventional chemotherapy, stated ASH. Up to 13 percent of patients with AML and up to 6 percent of patients with MDS harbor IDH2 mutations, Stein said.

“These early results in this hard-to-treat population demonstrate that, when we inhibit mutant IDH2, we can transform leukemia cells into healthy, normal adult white blood cells and eradicate disease without the use of traditional chemotherapy,” Stein said. “This approach to treat leukemia is revolutionary and 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.”

The primary objectives of the ongoing trial are safety and determination of maximum tolerated dose, and to select a dose and schedule for the expansion cohorts and future phase 2 studies.

Initially, the study tested the use of the oral agent once or twice daily at escalating doses up to 150 mg and 200 mg, respectively, for 28-day cycles. More recently, four additional dose cohorts were added, with the highest cumulative daily dose being 300 mg, and four expansion cohorts were added at a daily dose of 100 mg, Stein said. The lowest dose being tested is 60 mg. A maximum tolerated dose has not been reached, he said.

Among the 45 patients who have been on the study long enough to be evaluable, responses have been observed in 25 patients (56 percent), including various classifications of complete remission in 15 patients and partial remissions in 10 participants, Stein reported.

There have been no relapses in patients who have experienced a complete remission, according to Agios Pharmaceuticals, Inc, which is developing the drug in collaboration with Celgene. In addition, 17 patients have experienced stable disease, and two patients have had disease progression while participating in the study. Responses have been durable, Stein said, with some patients who have experienced partial response being on the study as long as nine months so far, and some patients with complete response being on the study as long as seven months to date.

Therapy has been well tolerated, with the majority of reported adverse events (AEs) being grades 1 and 2, most typically including nausea, fever, diarrhea and fatigue—AEs that might have come from the disease itself, Stein noted. Thirteen patients have experienced 21 severe AEs that were possibly treatment related, Stein added. The most common severe AEs have included tumor lysis syndrome and leukocytosis, although leukocytosis appears to be a differentiation effect of the drug, and all the patients who experienced it went on to achieve complete or partial remission, he said.

There have been 11 deaths reported, nine unrelated to the study drug and two possibly related. One death was due to oxygen depletion (in a patient who also had unrelated sepsis and fungal pneumonia) and the other to atrial flutter.

AG-221 is “well tolerated in patients with advanced hematologic malignancies, and triggers the differentiation of leukemic blast cells that ultimately leads to objective durable responses, including complete remissions,” the researchers noted in the ASH abstract for the meeting. “These data provide continued validation of mutant IDH2 as a therapeutic cancer target.”

Eventually, AG-221 might be applicable as a treatment for other tumor types, including glioblastoma, Stein added.

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