On June 2, 2018 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported new efficacy and safety data from the ongoing Phase 1 dose-escalation and expansion study evaluating single agent oral ivosidenib (TIBSOVO; AG-120) in patients with relapsed or refractory acute myeloid leukemia (R/R AML) and an isocitrate dehydrogenase-1 (IDH1) mutation (Press release, Agios Pharmaceuticals, JUN 2, 2018, View Source [SID1234527054]). The data were presented in an oral session at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. Ivosidenib is an investigational, first-in-class, oral, targeted inhibitor of the mutant IDH1 enzyme under FDA priority review for IDH1m R/R AML patients with a PDUFA action date of August 21, 2018.

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Agios also announced the publication in the New England Journal of Medicine (NEJM) of data from the ongoing ivosidenib Phase 1 study in patients with advanced hematological malignancies and an IDH1 mutation. The NEJM manuscript, which was published online today and will appear in the June 21, 2018 print issue, provides analyses from the dataset presented at the 2017 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, with a data cutoff date of May 12, 2017.

"The findings presented at ASCO (Free ASCO Whitepaper) demonstrate that single agent ivosidenib induced durable responses, in some cases with IDH1-mutation clearance, and led to favorable responses compared with historical patient outcomes in a high-risk, molecularly-defined R/R AML population," said Daniel Pollyea, M.D., M.S., study investigator and clinical director of leukemia services at the University of Colorado School of Medicine. "Additional clinical benefits included transfusion independence and, in responding patients, reductions in advanced-grade infections and febrile neutropenia, indicating immune system recovery with functional neutrophils."

"These data provide additional clinical and translational observations beyond the 2017 ASH (Free ASH Whitepaper) presentation, including preliminary data suggesting that R/R AML patients with IDH1-mutation clearance in bone marrow who have achieved CR/CRh have prolonged remission durations and overall survival versus those without IDH1-mutation clearance," said Chris Bowden, M.D., chief medical officer of Agios. "We believe the compelling single-agent efficacy coupled with a tolerable safety profile validate the potential for ivosidenib to be a first-in-class therapy for patients with R/R AML and an IDH1 mutation."

Data Presented at ASCO (Free ASCO Whitepaper)

A total of 258 patients with advanced hematologic malignances and an IDH1 mutation were treated in the Phase 1 study. Enrollment to the study is closed. Complete safety and efficacy data are reported in 179 patients with R/R AML whose ivosidenib starting dose was 500 mg once daily. The median age is 67 (ranging from 18-87), and the median number of prior therapies is two (ranging from one to six). Of these patients, 33% had secondary AML and 24% had prior transplants. The data cutoff for the ASCO (Free ASCO Whitepaper) presentation was November 10, 2017.

Safety Data
As of the data cut-off, a safety analysis conducted for 179 treated R/R AML patients showed that ivosidenib demonstrates a favorable safety profile that is consistent with previously reported data for all 258 patients. The most common adverse events (AEs) of any grade > 25% regardless of causality were diarrhea (33.5%), leukocytosis (31.3%), nausea (31.3%), febrile neutropenia (29.1%), fatigue (28.5%) and electrocardiogram (ECG) QT prolonged (25.7%). Adverse events of interest were the following:

8% reported Grade ≥3 leukocytosis, which was managed with hydroxyurea.
10% reported Grade ≥3 ECG QT prolongation. Ivosidenib dose was reduced in two patients and held in 13 patients (for any grade of ECG QT prolongation).
10.6% reported IDH-differentiation syndrome (IDH-DS) of any grade, which was managed with corticosteroids and diuretics. Six patients had their dose temporarily held, no patients required dose reductions.
No AEs of interest lead to any permanent treatment discontinuations or deaths.
Efficacy Data
Data from 179 R/R AML patients demonstrated an overall response rate (ORR) of 41.9% (75 of 179 patients) and a combined complete remission (CR) and CR with partial hematologic recovery (CRh) rate of 31.8% [95% CI 25.1, 39.2] which is the primary endpoint of the study.

The CR rate was 24% (43 of 179 patients) [95% CI 18.0, 31.0] and the CRh rate was 7.8% (14 of 179 patients). CRh is defined as <5% of blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts (ANC >500/microliter and platelets >50,000/microliter).
Median duration of response was 10.1 months [95% CI 6.5, 22.2] for patients who achieved a CR, 8.2 months [95% CI 5.6, 12.0] for patients who achieved a CR/CRh and 6.5 months [95% CI 5.5, 10.1] for all patients who responded.
Median time to first response was 1.9 months (0.8-4.7) for all patients who responded and median time to CR/CRh was 2.0 months [95% CI 0.9, 5.6].
Transfusion independence, defined as an absence of transfusions for at least 56 consecutive days on treatment, was observed across all response categories.
Of the patients who were transfusion dependent at baseline and achieved a CR, all became independent of platelet transfusions and 88.2% became independent of RBC transfusions during any 56-day post baseline period.
Of the patients who were transfusion dependent at baseline and achieved a CRh, 75% became independent of platelet transfusions and 77.8% became independent of RBC transfusions during any 56-day post baseline period.
Achievement of transfusion independence was also seen among non-CR/CRh responders and non-responders.
Patients who achieved CR and CRh had lower rates of exposure-adjusted febrile neutropenia and Grade ≥3 infections during ivosidenib treatment than patients in other response categories.
Translational Findings
IDH1 mutation clearance, defined as absence of the IDH1 mutation with a sensitivity of 0.02–0.04% (2-4 x10-4), was observed in 23% (11/47) of patients with R/R AML who achieved CR or CRh and had molecular data available, including 28% (10/36) of patients with CR and 1/11 patients with CRh. Preliminary data suggest that R/R AML patients with IDH1-mutation clearance in bone marrow mononuclear cells who have achieved CR/CRh have prolonged remission durations and overall survival versus those without IDH1-mutation clearance.

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 the median age of diagnosis is 68. The vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 27 percent. IDH1 mutations are present in about 6 to 10 percent of AML cases.