ATLANTA—In December, Agios Pharmaceuticals Inc. presented data from two separate studies evaluating ivosidenib (AG-120) and an investigational use of Idhifa (enasidenib) in patients with newly diagnosed acute myeloid leukemia (AML) and an isocitrate dehydrogenase (IDH) mutation—either IDH1 or IDH2—as part of the scientific program at the 59th American Society of Hematology Annual Meeting in Atlanta.
The first presentation, given by Dr. Eytan Stein, evaluated ivosidenib or enasidenib in combination with standard induction chemotherapy in patients with newly diagnosed AML and an IDH1 or IDH2 mutation, where patients received either 500 mg of ivosidenib and 7+3 standard chemotherapy, or 100 mg of enasidenib and 7+3 standard chemotherapy. Of these patients, 69 percent in the ivosidenib arm and 57 percent in the enasidenib arm had de-novo AML, while the remaining patients had secondary AML (sAML). For patients with sAML, 40 percent in the ivosidenib arm and 63 percent in the enasidenib arm had received prior hypomethylating agent therapy.
After induction, patients could receive up to four cycles of consolidation chemotherapy while continuing ivosidenib or enasidenib. Patients who achieved a complete response (CR) or a complete response with incomplete neutrophil or platelet recovery (CRi/CRp) after consolidation could continue to take single agent ivosidenib or enasidenib daily for up to two years from day one of induction. The results demonstrated an overall best response of CR+CRi/CRp rate for all patients of 62 percent.
“The early results from these studies of ivosidenib and enasidenib in combination with traditional frontline AML treatment are highly encouraging and support the strategy to advance IDHm inhibitors into the newly diagnosed setting,” said Dr. Chris Bowden, chief medical officer of Agios. “We are focused on evaluating the IDHm inhibitors in late-stage studies that span the entire frontline setting with our ongoing Phase 3 AGILE study of ivosidenib in combination with azacitidine versus azacitidine and a planned Phase 3 study of ivosidenib and enasidenib in combination with 7+3 intensive chemotherapy.”
The second presentation, given by Dr. Courtney DiNardo, evaluated an investigational use of enasidenib or ivosidenib in combination with azacitidine in patients with newly diagnosed AML unable to receive intensive chemotherapy. For this study, patients received either 100 mg or 200 mg of enasidenib daily plus azacitidine or 500 mg of ivosidenib plus azacitidine. At the data cutoff, 11 patients remained on the study (three enasidenib, eight ivosidenib). Four of six patients receiving the enasidenib combination had a response, including two CRs, one partial response (PR) and one morphologic leukemia-free state (MLFS). Of patients receiving the ivosidenib combination, eight of 11 patients had a response, including four CRs, one CRi, one PR and two MLFS.
Initially, enasidenib and ivosidenib were studied in relapsed/refractory AML (R/R AML), and results demonstrated that both medicines were well tolerated, as approximately 40 percent of patients achieved durable responses. Enasidenib was approved by the FDA for treatment of patients with R/R AML and an IDH2 mutation in Aug. 2017, and a new drug application for ivosidenib was submitted in December for treatment of patients with R/R AML and an IDH1 mutation.
Agios is focused on cellular metabolism to treat cancer and rare genetic diseases. In addition to an active research and discovery pipeline across both therapeutic areas, Agios has an approved oncology precision medicine and multiple first-in-class investigational therapies in clinical and/or preclinical development. All Agios programs focus on genetically identified patient populations, leveraging the company’s knowledge of metabolism, biology and genomics.
Idhifa is part of Agios’ global strategic collaboration with Celgene Corp. focused on cancer metabolism. Under the terms of the 2010 collaboration agreement, Celgene has worldwide development and commercialization rights for Idhifa. Agios continues to conduct certain clinical development activities within the Idhifa development program and is eligible to receive reimbursement for those development activities and up to $95 million in remaining payments, assuming achievement of certain milestones and royalties on any net sales.
Celgene and Agios are currently co-commercializing Idhifa in the United States. Celgene will reimburse Agios for costs incurred for its co-commercialization efforts. Idhifa is indicated for the treatment of adult patients with R/R AML with an IDH2 mutation as detected by an FDA-approved test. Neither Idhifa nor ivosidenib are approved for the treatment of patients with newly diagnosed AML or approved in combination with azacitidine.
Currently, newly diagnosed patients are either given intensive chemotherapy or a less-intensive cytotoxic therapy like azacitidine. Ivosidenib and enasidenib are not cytotoxic agents, but targeted therapies that were designed to inhibit a cancer-causing mutation in order for cells to grow and mature normally. Additionally, both are administered via a daily pill, which is substantially different from the intravenous delivery of chemotherapy.
According to Bowden, now that results have demonstrated that full doses of enasidenib and ivosidenib can be safely combined with standard-of-care treatment in the frontline setting, the company is moving into late-stage clinical development. A randomized Phase 3 study (AGILE) of ivosidenib combined with azacitidine is ongoing, and a Phase 3 study of ivosidenib or enasidenib and intensive chemotherapy is planned to initiate in the fourth quarter of 2018.
“For Agios,” Bowden stated in an interview with DDNews, “the response we’ve seen with our IDHm inhibitors validates our drug discovery platform and the scientific expertise we’ve created in-house. We believe we’re well equipped to create additional meaningful medicines for patients using the same approach and tools that we used to identify mutant IDH, create a medicine to inhibit it and bring these drugs to patients.”
