Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, today presented translational data describing deep and durable molecular responses to treatment of TIBSOVO® (ivosidenib) and azacitidine and mechanisms of resistance and relapse to single agent treatment with TIBSOVO® in acute myeloid leukemia (AML) with an IDH1 mutation. The data were presented as part of the scientific program at the 2019 American Society of Hematology (ASH) Annual Meeting.

“For 10 years, we have pioneered the science behind the role of IDH mutations in AML, while bringing to patients new oral therapies for the approximately 20% of AML patients with an IDH mutation. We’re pleased to share a robust set of translational data at ASH that further elucidates our understanding of TIBSOVO® response and resistance mechanisms in patients with IDH1 mutant AML,” said Chris Bowden, M.D., chief medical officer at Agios. “These data show that combination treatment with TIBSOVO® and azacitidine in newly diagnosed IDH1 mutant AML can induce deep, durable remissions in patients with a number of molecular profiles. Our translational work has further elucidated mechanisms of relapse with IDH1 monotherapy in relapsed and refractory disease that includes both IDH-related and non-IDH related pathways.”

Treatment with TIBSOVO® and Azacitidine Results in High Rate of IDH1 Mutation Clearance and Measurable Residual Disease Negativity in Newly Diagnosed AML As of the February 19, 2019 data cutoff, 23 patients have been treated in the ongoing Phase 1/2 study of TIBSOVO® in combination with azacitidine in patients with newly diagnosed IDH1 mutant AML ineligible for intensive chemotherapy. Results from the study show a complete response (CR) rate of 61% and a CR + CR with partial hematologic recovery (CRh) rate of 70%. Responses were durable, and the median duration of CR (95% CI 9.3 months, NE) as well as CR+CRh (95% CI 12.2 months, NE) had not been reached. In patients with CR, 10 of 14 (71%) had IDH1 mutation clearance in bone marrow mononuclear cells measured by BEAMing digital PCR (limit of detection 0.02-0.04%). Additionally, the majority of CR patients with IDH1 mutation clearance demonstrated measurable residual disease (MRD) negativity by flow cytometry or next-generation sequencing. Five patients were shown to have RTK pathway mutations (KRAS, NRAS, PTPN11), and three of these patients achieved CR/CRh with TIBSOVO® and azacitidine combination therapy.

Mechanisms of Resistance to Single Agent IDH1 Inhibitors in Relapsed/Refractory AMLComprehensive genomic profiling was conducted using patient samples from the Phase 1 study of TIBSOVO® in IDH1 mutant relapsed/refractory AML to characterize the molecular predictors of response and mechanisms of relapse to TIBSOVO monotherapy. The analysis found that multiple mechanisms contribute to relapse or progression. RTK pathway mutations NRAS and PTPN11 at baseline were associated with a lower likelihood of clinical response to TIBSOVO® monotherapy in relapsed/refractory AML, while patients with JAK2 mutations were more likely to achieve a response. Acquired resistance is mediated by diverse mechanisms, and mutations are acquired in multiple pathways, most frequently in RTK and 2-HG–restoring pathways (IDH2 and second-site IDH1 mutations).

Single cell mutation profiling was conducted to explore the evolution of mutant IDH2 clones under the selective pressure of TIBSOVO® monotherapy in a subset of patients. The analysis revealed multiple evolutionary mechanisms by which mutant IDH2 contributes to relapse and reinforced the key role of 2-HG production in mutant IDH AML.

Taken together, these results inform the design of combination or sequential treatment strategies with TIBSOVO® in IDH1 mutant AML and reinforce the importance of genomic testing for both IDH1 and IDH2 mutations at relapse.

TIBSOVO® is not approved in any country for the treatment of patients with newly diagnosed AML in combination with azacitidine.

Investor Event and Webcast InformationAgios will host an investor event today at 8:00 p.m. ET in Orlando, Fla. to review the IDH and PKR data presented at ASH. The event will be webcast live and can be accessed under "Events & Presentations" in the Investors section of the company's website at www.agios.com. The archived webcast will be available on the company's website beginning approximately two hours after the event.

About TIBSOVO® (ivosidenib)TIBSOVO® is indicated for the treatment of acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in:

• Adult patients with newly-diagnosed AML who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
• Adult patients with relapsed or refractory AML.