A small but significant study of Agios Pharmaceuticals’ AG-221, partnered with Celgene, caused a stir at the American Society of Hematology meeting in San Francisco earlier this week.

The drug, which targets the metabolic pathways of tumour cells by inhibiting the catalytic activity of mutated versions of the enzyme isocitrate dehydrogenase-2 (IDH2) has achieved response rates of 56% in a cohort of heavily pretreated patients with acute myeloid leukaemia (AML).

“I think this is a big deal,” said AG-221 study investigator Eytan Stein of the Memorial Sloan Kettering Cancer Center in New York. “A response rate – a durable response rate like this in refractory AML patients where you’re not killing cells and causing profound cytopenia, I think is a very big deal.”

AG-221 works by preventing the mutant form of IDH2, found in 9-13% of AML cases, from converting isocitrate to 2-hydroxyglutarate (2HG), rather than the usual product of alpha keto glutarate, a molecule necessary to the production of energy in non-malignant cells.

This molecular switch-up causes epigenetic changes in the setting of AML, changes that block the cell’s ability to differentiate into a normal healthy adult cells. “Essentially these cells get stuck at the myeloblast stage of differentiation,” said Dr. Stein, “And the accumulating myeloblasts lead to eventual bone marrow failure.”

The hypothesis supporting the development of AG-221 is that if the production of 2HG can be abrogated, allowing the malignant cells to return to the process of normal differentiation and mature into normal healthy adult neutrophils.

Dr Stein reported his interim analysis of the Phase I, first-in-man study of AG-221, an oral agent, in a cohort of relapsed/refractory AML, untreated AML, or myelodysplastic syndrome patients (N=73).

To determine the maximum tolerated dose of AG-221, patients were treated with one of four levels of the drug, which was given either once, or twice a day in a 28-day cycle.

Results of this investigation showed that 15 patients experienced a complete remission of their disease after receiving AG-221. Ten patients had a partial remission, defined as a 50% decrease in blast cells in the marrow with a normalization of platelet, and neutrophil count, and 17 seventeen patients achieved measures of stable disease. The drug was considered well tolerated, and few serious adverse events were reported.

“One serious adverse event that occurred in three patients that is very interesting from a scientific perspective is leukocytosis (a white blood cell count above the normal range),” Dr Stein said. “We think that’s part of the differentiation effect of the drug, so, you get your drug, the myeloblasts start differentiating, and the white count goes up – and all the patients that had this problem went on to a complete or partial remission of disease. “

Dr Stein emphasised that the results were particularly striking given the condition of patients on study entry: 13 patients had already failed a bone marrow transplant, and, according to Dr. Stein the balance of the cohort were unlikely to have responded to further approved treatment regimens.

“It’s certainly a big deal for the patients. My patients, many of who were on this trial – their lives have been transformed. They are leading essentially healthy normal lives, not being in the hospital, and taking an oral medication.”