Agios Announces New Clinical Data from Dose-Escalation Portion of Phase 1 Trial of Single Agent AG-120 Showing Durable Molecular Responses in Patients with Advanced Hematologic Malignancies
- Overall Response Rate of 38% and Complete Remission Rate of 18% with Patients on Study up to 24.2 Months -
- For Relapsed/Refractory Acute Myeloid Leukemia Patients, Overall Response Rate of 33% and Complete Remission Rate of 16% with 6.5 Month Median Duration of Response -
- First Demonstration that Treatment with
In order to study the depth of response to single agent AG-120, molecular detection of the mutant IDH1 burden in blood and bone marrow samples (collected at pre-treatment and at least one on-treatment time point) were analyzed using next generation sequencing (NGS, FoundationOne® Heme assay) in 67 patients from the dose-escalation portion of the study. Molecular clearance was defined as reduction of the IDH1 mutation below the limit of detection of the assay (1% for IDH). Molecular data show that treatment with AG-120 resulted in clearance of the IDH1 mutation in 36% of patients (5 of 14) in complete remission compared to 4% of patients (2 of 53) that did not achieve complete remission (p-value=0.003). This is the first demonstration that treatment with single agent AG-120 can result in mIDH1 clearance.
“AG-120 continues to demonstrate an impressive single-agent efficacy and safety profile in this cohort of high-risk relapsed or refractory AML patients, with some responses maintained for approximately two years,” said
“We are encouraged by the durable clinical activity of AG-120 and are working to bring this medicine to waiting patients with IDH1 mutant positive AML whose disease has progressed after standard treatments,” said
Updated Phase 1 Dose-Escalation Data for AG-120 in Advanced Hematologic Malignancies
Clinical and molecular data reported are from 78 patients treated with AG-120 in the dose escalation phase of the ongoing Phase 1; data from the ongoing expansions were not reported. Doses were administered from 200 mg to 1,200 mg total daily doses. As of
A safety analysis conducted for all 78 treated patients as of the data cut-off shows that AG-120 continues to demonstrate a favorable safety profile.
- The majority of adverse events reported by investigators were mild to moderate, with the most common regardless of causality being fatigue, nausea, diarrhea, pyrexia and peripheral edema.
- Fifty-three patients experienced at least one serious adverse event (SAE), the majority being disease related.
- The maximum tolerated dose was not reached. The recommended Phase 2 dose was 500 mg once daily, which is being studied in the ongoing expansion phase of the trial.
- Nine patients discontinued from the study due to death, including one reported as possibly related to AG-120.
- All cause mortality at 30 and 60 days were 12% and 21%, respectively.
Thirty out of 78 treated patients achieved investigator-assessed objective responses for an overall response rate of 38%.
- Of the 30 patients who achieved an objective response, there were 14 (18%) complete remissions (CR), eight CRs with incomplete neutrophil recovery or platelet recovery (CRi/CRp), six marrow CR (mCR)/morphologic leukemia-free state (MLFS) and two partial remissions (PR).
- Of the 63 patients with R/R AML, 21 (33%) achieved an objective response, including 10 (16%) CRs, eight CRi/CRp, two MLFS and one PR.
- Responses were durable, with a median response duration of 10.2 months (3.7- not estimable (NE)) overall and 6.5 months (3.7-NE) in the subset of patients with R/R AML.
- Median duration of treatment is 3.2 months (ranging from 0.1 to 24.2 months).
IDH1 Mutational Clearance
Longitudinal mIDH1 VAF data were reported for 67 patients. Patients with IDH1 mutational clearance (IDH1-MC) were defined as having:
- mIDH1 detected at screening (any sample type), and
- no reported mIDH1 mutation in at least one on-study time point (FoundationOne® Heme sensitivity of 1%).
Importantly, IDH1-MC was observed in 36% of CRs (5 of 14) and 4% of non-CRs (2 of 53). IDH1-MC was enriched in patients achieving CR (p-value = .003). The median time to mutational clearance was 2.7 months (ranging from 1.1 to 3.8 months). This is the first demonstration that treatment with single agent AG-120 can result in mIDH1 clearance. Agios is continuing to study the potential relationship between IDH1-MC and clinical benefit for patients with AML.
About the Ongoing Phase 1 Trial for AG-120 in Advanced Hematologic Malignancies
AG-120 is being evaluated in an ongoing Phase 1 trial that includes a dose-escalation phase and four expansion arms, including:
- Arm 1: 125 IDH1 mutant positive AML patients who relapsed after bone marrow transplantation, are in second or later relapse, refractory to initial induction or reinduction treatment, or who relapse within one year of initial treatment, excluding patients with favorable-risk status
- Arm 2: 25 untreated IDH1 mutant positive AML patients who are not candidates for standard-of-care chemotherapy
- Arm 3: 25 patients with other non-AML IDH1 mutant, relapsed or refractory advanced hematologic malignancies
- Arm 4: 25 patients with relapsed IDH1 mutant positive AML not eligible for arm 1 who have failed or are unable to receive standard of care
About Variant Allele Frequency (VAF)
Sequencing studies have demonstrated that most tumors exhibit extensive intra-tumor genetic heterogeneity characterized by individual cells that have different somatic mutations. For single-nucleotide mutations, or variants, the VAF is defined as the fraction of DNA sequence reads covering the variant position that contains the variant allele. This technique makes it possible to infer the subpopulations of tumor cells by counting the number of DNA sequence reads that contain a specific somatic mutation.
About IDH Mutations and Cancer
IDH1 and IDH2 are two metabolic enzymes that are mutated in a wide range of hematologic and solid tumor malignancies. Normally, IDH enzymes help to break down nutrients and generate energy for cells. When mutated, IDH increases production of an oncometabolite 2-hydroxyglutarate (2HG) that alters the cells’ epigenetic programming, thereby promoting cancer. 2HG has been found to be elevated in several tumor types. Agios believes that inhibition of the mutated IDH proteins may lead to clinical benefit for the subset of cancer patients whose tumors carry them.
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. Immature white blood cells known as myeloblasts, or “blasts” proliferate in the bone marrow rather than mature into normal blood cells. The decrease in normal blood cells can result in severe complications for patients including infections and dependence on blood product transfusions. AML incidence significantly increases with age, and according to the
Agios is focused on discovering and developing novel investigational medicines to treat cancer and rare genetic metabolic disorders 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.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding: the potential benefits of Agios' product candidates targeting IDH mutations, including AG-120; Agios’ plans for the further clinical development of AG-120; Agios’ potential NDA submission for AG-120; and Agios’ strategic plans and prospects. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “would,” “could,” “potential,” “possible,” “hope” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios' current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios is developing will successfully commence or complete necessary preclinical and clinical development phases; that positive safety and efficacy findings observed in early stage clinical trials will be replicated in later stage trials; that a submitted NDA will be accepted; that an accepted NDA will be approved; or that development of any of Agios' product candidates will successfully continue. There can be no guarantee that any positive developments in Agios' business will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other important factors, including: Agios' results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S.
Kendra Adams, 617-844-6407 Senior Director, Investor & Public Relations Kendra.Adams@agios.com Renee Leck, 617-649-8299 Senior Manager, Investor & Public Relations Renee.Leck@agios.com Media: Dan Budwick, 973-271-6085 Senior Vice President, Media Relations Pure Communications Inc.email@example.com