Agios Pharmaceuticals, Inc., a leader in the fields of cancer metabolism and rare genetic disorders of metabolism, has announced new data from the ongoing Phase 1 dose escalation study of AG-221 as a single agent in patients with IDH2-mutant positive advanced hematologic malignancies. With additional patient enrollment and longer follow-up, the data continue to show a favorable safety profile as well as durable clinical activity for AG-221, with an overall response rate of 56 percent (25 of 45 evaluable patients) in advanced hematologic malignancies. Eytan Stein, M.D., lead investigator and attending physician in the leukemia service at Memorial Sloan Kettering Cancer Center, will present the data in an oral presentation today at the 56th Annual American Society of Hematology (ASH) Annual Meeting and Exposition being held in San Francisco. AG-221 is a first-in-class, oral, selective, potent inhibitor of the mutant IDH2 (isocitrate dehydrogenase-2) enzyme being developed in collaboration with Celgene.

"The durable responses observed for AG-221 with minimal toxicity being reported are impressive in this advanced disease setting," said Dr. Stein. "These findings build upon those presented throughout the year. In addition, they continue to provide evidence that AG-221 can inhibit the IDH2 mutant protein, stop production of the oncometabolite, 2-HG, and allow for cancer cells to become mature, functioning blood cells. This approach is different from traditional chemotherapy that attempts to non-selectively kill cancer cells. I believe AG-221's unique mechanism targeting a specific mutation is the way of the future and represents a highly specific oral therapy that may transform the treatment of a devastating group of blood cancers."

As of the data cut-off on October 1, 2014, the ongoing Phase 1 study of AG-221 had enrolled 73 patients, with a documented IDH2 mutation, in a broad range of advanced hematologic malignancies. Patients enrolled included those with relapsed or refractory acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and untreated AML who decline intensive chemotherapy. At the time of the data cut- off, 45 patients were evaluable for an analysis of clinical activity. Twelve patients had initiated therapy too recently and were therefore not evaluable and 16 patients had discontinued without an evaluable day 28 assessment. The data showed that 25 out of 45 evaluable patients achieved

investigator-assessed objective responses, including six complete remissions, nine complete remissions with various degrees of hematologic recovery and ten partial remissions. An estimated 90 percent of patients who responded had responses lasting for at least three months, with durations on AG-221 for as long as eight months and ongoing. For patients who achieved a complete remission, their cancer did not progress while on therapy. AG-221 was well tolerated and the overall safety profile observed was consistent with previously reported data. A maximum tolerated dose (MTD) had not been reached. These data form the basis for the planned initiation of a global registration program in 2015.

"We are making tremendous progress for patients with our AG-221 program, as the data from the Phase 1 study have consistently shown durable activity with a favorable safety profile in patients with several types of advanced hematologic malignancies, especially AML," said Chris Bowden, M.D., chief medical officer of Agios. "While the data we are presenting today and those recently reported for AG-120, our IDH1-mutant inhibitor, are still early, we believe they validate our approach of targeting dysregulated metabolic enzymes. Along with our partner Celgene, we expect to begin a global registration program for AG-221 in 2015 in IDH2-mutant positive hematologic malignancies followed by a global registration program for AG-120 in IDH1-mutant positive hematologic malignancies by early 2016. We feel strongly that these investigational medicines with their unique mechanisms of action have the potential to profoundly impact treatment for individuals with IDH-mutant cancers, and we are pleased to share the results of the additional data for AG-221 with the medical community."

About the Ongoing Phase 1 Trial for AG-221

The primary goals of the Phase 1 trial are to establish the safety profile, determine the maximum tolerated dose and assess the preliminary clinical activity of AG-221 as a single agent administered orally in 28-day cycles. The study is only enrolling patients who have an IDH2- mutant hematologic malignancy. Secondary objectives include characterization of the pharmacokinetics (PK) and pharmacodynamics (PD), including inhibition of 2-hydroxyglutarate (or 2HG). The trial uses an open-label, dose-escalating design. Data reported are from patients receiving AG-221 in 10 dose escalation cohorts administered from 60 mg to 300 mg total daily doses as of October 1, 2014. Dose escalation continues, as the maximum tolerated dose has not been reached. The median age of these patients is 67 (range 33-90).

Safety Data

A safety analysis was conducted for all 73 treated patients as of October 1, 2014.

  • The majority of adverse events reported by investigators were mild to moderate, with the most common being nausea, pyrexia, diarrhea and fatigue.
  • The majority of serious adverse events (SAE) were disease related; SAE's possibly related to study drug were reported in 13 patients.
  • 11 deaths were reported with nine unrelated to AG-221.
  • Two deaths were reported as possibly related to study drug: one in a patient with sepsis and hypoxia and one with atrial flutter.

Efficacy Data

25 out of 45 efficacy evaluable patients achieved investigator accessed objective responses for an overall response rate of 56 percent as of the October 1, 2014 data cut-off date.

  • Of the 25 patients who achieved an objective response, there were six complete remissions, four complete remissions with incomplete platelet recovery (CRp), four marrow complete remissions (mCR), one complete remission with incomplete hematologic recovery (CRi) and 10 partial remissions (PR).
  • Responses were durable, with duration on study drug as long as eight months and ongoing. An estimated 90 percent of responses are three months or longer, with four responders on AG-221 beyond six months of treatment.
  • Ten patients with stable disease remain on AG-221, with several patients on study as long as six months and ongoing
  • There have been no relapses in patients with a complete remission.
  • Five patients were removed from the study per the protocol following decision to undergo a potentially curative bone marrow transplant.
  • Treatment with AG-221 showed substantial reduction in the plasma levels of 2-HG to the level observed in healthy volunteers.

"Throughout 2014, we made significant progress across our company, in particular the achievement of proof-of-concept for two distinct IDH inhibitors, AG-221 and AG-120," said David Schenkein, M.D., chief executive officer of Agios. "Over the coming year, we expect to expand the development programs into registration studies and in combination trials to explore the potential of broader use in patients who carry an IDH mutation. We also expect to present new data from multiple studies across our two lead IDH programs to help further define the potential of these investigational medicines to make a major impact on the treatment of cancer."