Updated Data from Phase 1 Trial of Oral IDHIFA® (enasidenib) Demonstrate Complete Responses and Duration of Response in Patients with Relapsed or Refractory AML and an IDH2 Mutation
40.3% Overall Response Rate (ORR) with Median Duration of Response of 5.8 Months and 19.3% Complete Response (CR) Rate with Median Duration of Response of 8.8 Months in Patients With a CR
Overall Safety Profile was Consistent with Previously Reported Data
"The updated results, including duration of response, from the Phase 1
study reinforce the potential for enasidenib as a first-in-class therapy
for patients with relapsed or refractory AML and an IDH2 mutation," said
As of
The overall safety profile observed for enasidenib was consistent with previously reported data. Twenty-four percent of patients had treatment-related serious adverse events (SAEs), notably IDH differentiation syndrome (8%), leukocytosis (4%), tumor lysis syndrome (3%) and hyperbilirubinemia (2%). The most common treatment-emergent AEs were nausea (46%) hyperbilirubinemia (45%), diarrhea (40%) and fatigue (40%).
Data from 176 R/R AML patients with an IDH2 mutation demonstrated a 40.3 percent (71 of 176 patients) overall response rate, which was the primary endpoint of the study. Further, the complete response rate was 19.3 percent (34 of 176 patients). Median duration of response was 5.8 months [95% CI 3.9, 7.4] for all patients who responded and 8.8 months [95% CI 6.4, NR] for patients who achieved a CR. Median time to first response was 1.9 months (0.5-9.4) and median time to CR was 3.8 months (0.5-11.2). Median overall survival (OS) for R/R AML patients as observed in the study was 9.3 months [95% CI 8.2, 10.9]. Additional results including qualitative improvement in response over time, improvement in hematological parameters over time, OS for patients achieving a CR and transfusion independence were also reported.
"In addition to the complete response in this study, we also observed
changes in responses and hematologic parameters over time," said
"Targeting IDH mutations is thought to allow for the differentiation of
malignant cells and introduces a new paradigm in the treatment of AML,"
said
Additional Data Available - IDH Differentiation Syndrome & Translational Analyses
A separate analysis of IDH-inhibitor-associated differentiation syndrome (IDH-DS) associated with enasidenib was also presented as a poster discussion during the ASCO meeting and detailed the findings of an independent Differentiation Syndrome Review Committee (DSRC). The committee reviewed investigator reported IDH-DS cases and determined that 13 of the 27 potential cases were consistent with IDH-DS (11.9% of 109 patients). These data demonstrate that the signs and symptoms of IDH-DS are recognizable. IDH-DS represents a novel clinical finding in patients with mutated IDH2 AML treated with enasidenib, and is likely due to its purported mechanism of action, differentiation of leukemic cells.
In addition to the clinical data publication, additional analyses describing the mechanism of action of enasidenib were also published online in Blood. An analysis of patient samples confirmed that the preclinical efficacy and mechanism of action of mutated IDH2 inhibition by enasidenib is through differentiation of AML cells. The authors conclude that the data provide insights into enasidenib resistance to inform future mechanism-based combination treatment studies.
Clinical Development
Enasidenib continues to be studied in the following ongoing clinical trials:
- Phase III IDHENTIFY study evaluating the efficacy and safety of enasidenib versus conventional care regimens in older patients with R/R AML with an IDH2 mutation (NCT02577406)
- Phase 1b study of either enasidenib or ivosidenib in combination with standard induction and consolidation chemotherapy in newly diagnosed AML (NCT02632708)
- Phase 1/2 study of either enasidenib or ivosidenib in combination with azacitidine in newly diagnosed AML (NCT02677922)
The New Drug Application (NDA) for IDHIFA is currently under Priority
Review with the
Ivosidenib (AG-120, wholly owned by Agios) is an investigational, oral, targeted inhibitor of the mutant IDH1 enzyme.
About AG221-C-001
Study AG221-C-001 includes three parts: a Phase 1 dose escalation, a part 1 (Phase 1) expansion and a Phase 2 expansion.
The Phase 1 dose escalation study was designed to determine the maximum tolerated dose and recommended Phase 2 dose, and to evaluate efficacy and safety of enasidenib (AG-221/CC-90007) in subjects with advanced hematologic malignancies with an IDH2 mutation. The Part 1 expansion further evaluated the safety, tolerability, and efficacy of enasidenib in subjects with R/R AML, untreated AML, myelodysplastic syndrome or other advanced hematologic malignancies with an IDH2 mutation. Based on the clinical activity observed in R/R AML subjects, the Phase 2 expansion was designed to assess efficacy of enasidenib at recommended 100 mg daily dose and to further evaluate safety in subjects with R/R AML and with IDH2 mutation. The study was not designed or statistically powered to reach a conclusion on OS. A phase 3 randomized controlled trial with OS as a primary endpoint has been initiated.
About Acute Myelogenous Leukemia (AML)
AML, a cancer of blood and bone marrow characterized by rapid disease
progression, is the most common acute leukemia affecting adults.
Undifferentiated blast cells proliferate in the bone marrow rather than
mature into normal blood cells. AML incidence significantly increases
with age, and according to the
About Agios
Agios is focused on discovering and developing novel investigational medicines to treat cancer and rare genetic diseases through scientific leadership in the field of cellular metabolism. In addition to an active research and discovery pipeline across both therapeutic areas, Agios has multiple first-in-class investigational medicines in clinical and/or preclinical development. All Agios programs focus on genetically identified patient populations, leveraging our knowledge of metabolism, biology and genomics. For more information, please visit the company's website at www.agios.com.
About
About Agios/Celgene Collaboration
IDHIFA® (enasidenib) and AG-881 are part of Agios' global
strategic collaboration with
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