Mutant IDH2 Inhibitor Looks Promising in AML

AG-221, a first-in-class oral agent to inhibit the mutated isocitrate dehydrogenase-2 (IDH2) protein, appears promising in patients with relapsed or refractory acute myeloid leukemia (AML), according to preliminary results from an ongoing phase I trial presented on April 6 at the American Association for Cancer Research Annual Meeting 2014 in San Diego, CA.

Six of 10 patients with IDH2-mutated AML achieved an objective response, including two complete remissions, three complete remissions with incomplete platelet count recovery, and one partial remission. Of the remaining four patients, one experienced disease progression and three died of sepsis unrelated to the drug.

“If the early preliminary data hold up, this drug has the potential to provide remarkable clinical benefit for patients with relapsed or refractory AML,” said principal investigator Eytan Stein, MD, assistant attending physician on the leukemia service at Memorial Sloan Kettering Cancer Center in New York, NY. Treatment for AML has not changed in the past 40 years, Stein added.

Made by Agios Pharmaceuticals (Cambridge, MA), AG-221 blocks mutant IDH2. The normal version of this enzyme is involved in chemical reactions that produce energy for cell activities. However, mutant IDH2 produces high levels of the metabolite 2-hydroxyglutarate (2-HG), which previous research suggests leads to epigenetic changes that block the ability of cells such as myeloblasts to differentiate, thus causing cancer.

AG-221 is the first mutant IDH inhibitor tested in humans. Another such drug from Agios called AG-120 targets IDH1 mutations. Phase I testing of that drug began in March.

In the study, researchers have so far tested two doses of AG-221—30 mg and 50 mg twice daily—over continuous 28-day cycles. The drug reduced 2-HG plasma levels by up to 97%. “Not only does this drug reduce the levels of 2-HG, but that reduction in 2-HG leads to profound [myeloblast] differentiation and meaningful clinical benefit,” Stein said.

No dose-limiting toxicities have occurred. Severe adverse events were reported in two patients, one with grade 2 hyperleukocytosis (severely elevated white blood cell counts) and the other with grade 3 confusion.

According to the National Cancer Institute, nearly 19,000 adults in the United States are diagnosed with AML each year. About 10% to 15% of them harbor an IDH2 mutation, according to research.

Patients with advanced myelodysplastic syndromes (MDS) are also being enrolled in the AG-221 study. About 5% of patients with MDS have an IDH2 mutation, which has also been identified in chondrosarcoma and glioblastoma.

Investigators are also testing doses of 75 mg twice a day and 100 mg once a day. Updated findings will be presented at a future major medical conference, Stein said.