On December 9, 2013 Agios Pharmaceuticals reported that data from its lead programs were highlighted at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting this week in New Orleans (Press release Agios Pharmaceuticals, DEC 9, 2013, View Source;p=irol-newsArticle&ID=1883336&highlight= [SID:1234500778]).
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Two presentations featured in vivo efficacy data in acute myelogenous leukemia (AML) for the company’s lead cancer metabolism programs targeting IDH1 and IDH2 mutations. In AML and other cancers, IDH1 and IDH2 mutations initiate and drive cancer growth by blocking maturation of primitive cells. The data presented at ASH (Free ASH Whitepaper) demonstrate preclinical single agent and combination efficacy of Agios’ IDH mutant inhibitors in patient-derived primary models of AML. Agios also presented data on AG-348, its lead inborn errors of metabolism (IEM) program candidate focused on pyruvate kinase deficiency (PK deficiency), a rare, inherited hemolytic anemia with no approved therapeutic options.
"We are excited to present data highlighting our IDH and PKR programs, which focus on genetically identified patient populations with limited or no therapeutic options," said Scott Biller, Ph.D., chief scientific officer at Agios. "These results highlight the potential for all three programs to provide significant clinical benefit to patients in the future."
Agios Presentations
"AG-221 offers a survival advantage in a primary human IDH2 mutant AML xenograft model," an oral presentation, provides strong preclinical in vivo evidence of AG-221’s potential clinical benefit for patients with tumors that harbor an IDH2 mutation. AG-221 is a potent, selective, orally available IDH2 mutant inhibitor currently in clinical trials for patients with hematologic malignancies. In this study, Agios scientists evaluated the efficacy of AG-221 as a single agent in a primary human model of aggressive AML carrying an IDH2 mutation. AG-221 caused a potent reduction in 2HG, the oncometabolite produced by the mutant IDH2 protein, found in the bone marrow, plasma and urine of engrafted mice. Treatment also induced a dose-dependent, statistically significant survival benefit in which all mice in the high-dose treatment group survived to the end of the study.
"IDH1 mutant inhibitor induces cellular differentiation and offers a combination benefit with Ara-C in a primary human IDH1 mutant AML xenograft model," a poster, evaluates the use of AGI-14100, a potent, selective, orally available IDH1 mutant inhibitor. Agios scientists treated a primary human mutant AML model with AGI-14100, either alone or in combination with low-dose chemotherapy (Ara-C). Researchers observed a significant decrease in tumor burden in peripheral blood in the model treated with AGI-14100 alone, and a more pronounced response, as measured by a simultaneous decrease in the bone marrow tumor burden, in the model that received combination therapy. The duration of response continued for three weeks after dosing of both drugs had been terminated. These data suggest that this combination therapeutic approach could be an important option for patients, to be explored in future clinical trials.
"Small Molecule Activation of Pyruvate Kinase Normalizes Metabolic Activity in Red Cells From Patients With Pyruvate Kinase Deficiency-associated Hemolytic Anemia," a poster, presents preclinical data supporting Agios’ lead IEM clinical candidate, AG-348, as a potentially effective approach to correcting the underlying pathology of PK deficiency. The results demonstrate that AG-348 potently activates a spectrum of PKR mutant proteins, the isoform of pyruvate kinase that is present in red blood cells, leading to a normalization of metabolic balance in patient-derived blood samples. These data support the hypothesis that drug intervention with AG-348 may restore glycolytic pathway activity and normalize red cell metabolism in vivo.