The isocitrate dehydrogenase (IDH) protein is a critical enzyme in the citric acid cycle, also known as the tricarboxylic acid, or Krebs, cycle. The Krebs cycle is centrally important to many biochemical pathways, and is one of the earliest established components of cellular metabolism. IDH1 and IDH2 appear to be mutated in cancers, and catalyze the same reaction but in different cellular compartments: IDH1 is found in the cytoplasm of the cell, and IDH2 in the mitochondria.

Agios has identified selective development candidates that target the mutated forms of IDH1 and IDH2, which are each found in a wide range of solid and hematologic cancers. AG-221 is an orally available, selective, potent inhibitor of the mutated IDH2 protein, making it a highly targeted therapeutic candidate for the treatment of patients with cancers that harbor an IDH2 mutation. In September 2013, Agios initiated a Phase 1 multicenter, open-label, dose escalation clinical trial of AG-221 designed to assess the safety and tolerability of AG-221. For additional details about the trial, please visit www.clinicaltrials.gov. Agios plans to potentially evaluate AG-221 in the genetic neurometabolic disorder called Type II D-2 hydroxyglutaric aciduria (Type II D-2-HGA). 

AG-120 is an orally available, selective, potent inhibitor of the mutated IDH1 protein, and is a highly targeted therapeutic candidate for the treatment of patients with cancers that harbor an IDH1 mutation. In March 2014, Agios initiated two Phase 1 multicenter, open-label, dose escalation clinical trials of AG-120 designed to assess the safety and tolerability of AG-120 in patients with advanced hematologic malignancies and advanced solid tumors. 

Agios and its collaborators have demonstrated that IDH1 and IDH2 mutations initiate and drive cancer growth by blocking differentiation, also referred to as maturation, of primitive cells, which leads to tumor formation and maintenance. Agios believes that inhibition of these mutated proteins may lead to clinical benefit for the subset of cancer patients whose tumors carry these mutations.

Groundbreaking research by Agios' scientists (published in the November 22, 2009 edition of the journal Nature) established for the first time that the mutated metabolic gene IDH1 has novel enzyme activity consistent with a cancer-causing gene or oncogene. This discovery shows that the mutated form of IDH1 produces a metabolite, 2-hydroxyglutarate (2HG), which may contribute to the formation and malignant progression of including hematologic malignancies such as acute myeloid leukemia and solid tumors such as gliomas (the most common type of brain cancer), chondrosarcomas and cholangiocarcinomas. This discovery appears to reverse the previously held belief that IDH1 did not have an impact on cancer-causing activity. This research also represents one of the first reported cases wherein a metabolic enzyme is shown to play a role in cancer formation, in this case through altered metabolic activity.

IDH Mutation as Gain of Function; 2HG as

More recently, mutations in both IDH1 and a related enzyme IDH2 have been observed in patients with acute myelogenous leukemia (AML), one of the most common types of leukemia in adults. Agios scientists have shown that these mutations also produce high levels of 2HG (published in 2010 in the Journal of Experimental Medicine). Furthermore, a new study published in Nature in July 2012 provided added evidence of the link between AML and the oncometabolite 2HG and IDH. Recent research suggests that 2HG leads to epigenetic changes that block the normal differentiation of cells, leading to cancer. Inhibiting IDH mutations to stop production of 2HG could reverse that block. In addition, taken together, data from two recent Science papers provide compelling evidence that IDH1 and IDH2 mutant inhibitors induce differentiation in both cell based models and primary patient samples.

Early clinical data from the ongoing Phase 1 study of AG-221 presented at the 2014 American Association for Cancer Research (AACR) Annual Meeting in April and the 19th Congress of the European Hematology Association (EHA) in June provide corroboration of IDH2 as an important cancer target and support Agios’ hypothesis that precision medicine has the potential to shift the treatment paradigm for patients with fatal hematologic cancers, including acute myeloid leukemia (AML). Specifically, the data presented at EHA were the first to show AG-221’s durability and build upon and confirm data presented at AACR. AG-221 is shaping up to have a promising profile with complete and durable clinical activity out to four months in some patients, clinical activity in patients beyond AML and no patient relapses on therapy as of the May 23, 2014 data analysis. Safety data show that AG-221 is well tolerated in a relapse/refractory AML patient population. The majority of adverse events were mild to moderate, and there were no dose-limiting toxicities. Furthermore, the data support the initiation of multiple expansion cohorts in the second half of 2014, and the potential for an accelerated development path. Read the full summary of the AACR data here and the EHA data here

Scientific publications about IDH research from Agios and its collaborators include: