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Agios Begins Studying AG-221 for IDH2-Mutated Hematologic Cancer in Phase I Dosing Trial


Agios Pharmaceuticals has administered the agent AG-221 to the first patient enrolled in a Phase I trial investigating the drug as a treatment for advanced blood cancers characterized by the IDH2 gene mutation.

AG-221 is an oral agent that has shown the ability to inhibit the mutated IDH2 protein. The IDH2 protein is a metabolic enzyme in the citric acid cycle, chemical reactions that generate energy and play a critical role in cellular metabolism. Scientists from Agios have conducted research showing that mutated IDH1 and IDH2 block cells' ability to differentiate and cause various forms of cancer.

Research at Agios is primarily focused on unraveling the role of cellular metabolism in cancer, and on developing drugs that interrogate markers associated with these metabolic mechanisms. Investigators at the company reported in a 2009 Nature paper that IDH1 mutations cause the body to produce and accumulate 2HG, a metabolite that has shown to cause various cancers. Initially, Johns Hopkins researchers linked IDH1 mutations to brain cancers, but more recently investigators from Agios and elsewhere have reported that targeted inhibition of IDH2 mutations could have application for treating acute myelogenous leukemia.

"These insights revealed the potential of IDH1 and IDH2 mutations as novel therapeutic targets in cancer," Scott Biller, Agios' chief scientific officer, told PGx Reporter this week.

Previously conducted research has suggested that IDH2 mutations are prevalent in approximately 15 percent of adults with AML. The mutations have also been observed in smaller subsets of patients with other types of hematologic cancers, such as in 2 percent of patients with myelodysplastic syndromes and myeloproliferative neoplasms.

The Phase I trial Agios has launched will investigate the safety and tolerability of AG-221 given to around 60 patients twice daily at increasing doses over a 28-day cycle. Study participants who have an IDH2-mutant hematologic malignancy, including AML and myelodysplastic syndrome, will be enrolled in the trial. The primary objective will be to identify the maximum tolerated dose for AG-221 and the incidence of adverse events. Researchers will also measure dose-limiting toxicities, pharmacokinetics, pharmacodynamics, and the drug's clinical activity.

Biller noted that if AG-221 progresses into later stage clinical trials, the drug will be developed with a companion diagnostic that identifies patients with IDH2-mutated hematologic malignancies. Anticipating this, in March this year, Agios partnered with Foundation Medicine, which will conduct genomic analysis for Agios' lead programs on cancer metabolism inhibitors

"These [lead] programs focus on developing new cancer metabolism inhibitors targeting tumors carrying mutations in either the IDH1 or IDH2 metabolic enzymes," Biller said. "Foundation Medicine and Agios are collaborating to identify tumor genomic alterations that can be used to identify which patients are most likely to respond to Agios’ IDH1 and IDH2 drug candidates, and to develop and potentially commercialize diagnostic products for these programs."

Foundation Medicine has partnerships with a number of other drug developers, including AstraZeneca, Eisai, Novartis, and Clovis Oncology, to use its next-generation sequencing capabilities to explore the genomic mechanisms associated with response to various drugs in their pipelines.

Biller noted, however, that Agios has not settled on a long-term diagnostic partner for commercializing a companion test with regulatory approval into the market for the AG-221 program.

AG-221 is an agent that Agios is advancing under a global alliance with Celgene, a leading biotechnology company. Under the terms of the agreement inked in 2010, Agios is responsible for R&D efforts through Phase I. At the end of Phase I or when an IND designation has been awarded, Celgene has an initial period of exclusivity during which it can choose to further develop any of the agents from Agios' cancer metabolism inhibitor program.

"Agios retains rights to develop one out of every three drugs in the US territory," Biller said.

In addition to AG-221, its most advanced product, Agios is also developing AG-120 in IDH1 mutant cancers, also under collaboration with Celgene.