On June 14, 2014, Agios Pharmaceuticals reported new clinical data from the ongoing Phase I study of AG-221, which includes 35 patients with IDH2 mutant positive hematologic malignancies. These data confirm and build upon previously presented data on AG-221’s clinical activity, safety profile and unique mechanism of action (Press release Agios Pharmaceuticals, JUN 14, 2014, View Source;p=RssLanding&cat=news&id=1939863 [SID:1234500651]). The data were presented today in a late-breaker oral presentation at the 19th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Milan, Italy by Stéphane de Botton, M.D., the principal investigator at the Institut de Cancérologie Gustave Roussy, Villejuif, France.

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The new data show objective responses in 14 out of 25 evaluable patients on AG-221 and an additional five patients with stable disease. In six patients who achieved a complete remission (CR), evidence of durability was observed, ranging from one to four months in duration. All responses are ongoing. AG-221 continues to show favorable drug exposure and pharmacokinetics at all doses tested with substantial reductions in plasma levels of the oncometabolite 2-hydroxyglutarate (2HG). Safety data show that AG-221 is well tolerated, with the majority of adverse events reported as mild to moderate. There were no discontinuations of AG-221 due to adverse events, and the maximum tolerated dose has not been reached. These promising safety and efficacy data support the company’s plan to initiate four expansion cohorts in the second half of 2014. Agios also expects to submit additional data from the ongoing Phase 1 trial for potential presentation at the 2014 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

"These data demonstrate that treatment with AG-221 leads to a profound differentiation effect and is associated with durable complete remissions in patients who are extremely ill and have limited treatment options," said Dr. de Botton. "We believe these data support comprehensive investigation of AG-221 in IDH2-mutant positive cancers and look forward to participating in Agios’ planned expansion cohorts and future clinical trials."

"AML is a devastating disease with a dismal prognosis, and AG-221 is the first targeted agent showing clinical activity in patients with IDH2-mutant disease," said David Schenkein, M.D., chief executive officer of Agios. "We are encouraged for patients that AG-221 has shown durable clinical activity, and no patients have relapsed after having a response. We are also encouraged by the clinical activity and safety profile that continue to emerge as doses escalate and patient numbers increase. The durability of responses observed to date and unique mechanism of action hold promise that AG-221 may change the paradigm for the treatment of these cancers."

AG-221 is an orally available, selective, potent inhibitor of the mutated IDH2 protein. In the ongoing Phase 1 study, patients have been enrolled in six study cohorts to receive AG-221 administered at 30 mg twice a day, 50 mg twice a day, 75 mg twice a day, 100 mg once a day, 100 mg twice a day and 150 mg once a day. As of May 23, 2014, the study had enrolled 35 patients with IDH2 mutant positive advanced hematological malignancies, including relapsed or refractory AML, myelodysplastic syndrome (MDS) and one patient with chronic myelomonocytic leukemia (CMML). The median age of these patients is 68 (range 48-81).

Safety Data

A safety analysis was conducted as of April 25, 2014 and showed that the majority of adverse events (AEs) reported by investigators were Grade 1 and 2 and most common include nausea, pyrexia, and thrombocytopenia. As of May 23, 2014, possible drug-related severe AEs were reported in four patients, which included confusion, respiratory failure (in the setting of disease-related infection), leukocytosis, anorexia, nausea, and diarrhea. There were seven patient deaths, all unrelated to study drug. Dose escalation continues, as the maximum tolerated dose has not been achieved.

Efficacy Data

Of the 25 evaluable patients, 14 patients achieved objective responses, including six complete remissions, two complete remissions with incomplete platelet recovery (CRp), one complete remission with incomplete hematologic recovery (CRi) and five partial responses. Five patients have stable disease and remain on AG-221. These data include clinical activity beyond AML: four patients diagnosed with MDS achieved objective responses, including one CR and one CRp. There have been no patient relapses once objective response was achieved. Of the 14 responding patients, 12 remain on AG-221, with duration of responses ranging from 15 days to four months and ongoing as of May 23, 2014. One patient with a CR was removed from the study to undergo a bone marrow transplant, and one patient with a CRp died from a surgical complication unrelated to AG-221.

The mechanism of response is consistent with preclinical studies, including 2HG inhibition leading to cellular differentiation, normalization of cell counts in the bone marrow and blood and ultimately complete remissions. This differentiation effect is a distinct mechanism of action as compared to traditional chemotherapy, which is the current standard of care for AML patients.