IDH Mutant Inhibitors

Isocitrate dehydrogenase (IDH) 1 and 2 are metabolic enzymes that are mutated in a wide range of hematologic and solid tumor malignancies, including acute myelogenous leukemia (AML) and glioma, a type of aggressive brain tumor with poor prognosis. Normally, IDH enzymes help to break down nutrients and generate energy for cells. When mutated, IDH creates a molecule that alters the cells’ genetic programming, and instead of maturing, the cells remain primitive and proliferate quickly. Agios believes that inhibition of these mutated proteins may lead to clinical benefit for the subset of cancer patients whose tumors carry them. Agios has identified novel investigational medicines that target the mutated forms of IDH1 and IDH2.

IDH2 mutant inhibitor in collaboration with Celgene

AG-221 is also being evaluated in a Phase 1/2 study of AG-221 in advanced solid tumors, including gliomas, as well as angioimmunoblastic T-cell lymphoma (AITL) that carry an isocitrate dehydrogenase-2 (IDH2) mutation. For additional details about these trials, please visit www.clinicaltrials.gov.

Initial clinical data from the ongoing Phase 1 trial of AG-221 in hematologic malignancies presented at medical meetings in 2014 provide early validation 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 the 56th Annual American Society of Hematology (ASH) Annual Meeting in 2014 continue showed a favorable safety profile as well as durable clinical activity for AG-221. As of the October 1, 2014 data analysis, AG-221 showed complete and durable clinical activity in patients on study up to eight months in some patients, clinical activity in patients beyond AML and no patient relapses on therapy. Safety data showed that AG-221 is well tolerated in a relapse or refractory AML patient population, and the majority of adverse events were mild to moderate. Read the full summary of the 2014 American Association for Cancer Research (AACR) Annual Meeting data here, the 19th Congress of the European Hematology Association (EHA) data here and the ASH data here

IDH1 mutant inhibitor in collaboration with Celgene 

AG-120 is a first-in-class, orally available, selective, potent inhibitor of the mutated IDH1 protein, and is a highly targeted investigational medicine 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.

The first reported clinical data from the ongoing Phase 1 trial of AG-120 in hematologic malignancies were presented at the 26th Annual EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics on November 19, 2014. As of October 17, 2014, the trial had enrolled 17 patients with a documented IDH1 mutation whose cancer relapsed or failed to respond (refractory) to at least one prior treatment regimen. At the time of the data cut, 14 patients with relapsed and/or refractory AML were evaluable; three patients recently initiated therapy and were not evaluable. The initial data showed investigator assessed objective responses in seven out of 14 evaluable patients, including four complete remissions with early evidence of durability. AG-120 was well tolerated, and the majority of adverse events (AEs) reported by investigators were grade 1 and 2 and most commonly included nausea, fatigue and dyspnea. Serious AEs were reported in eight patients and were primarily related to disease progression. Read the full summary of the EORTC data here.

Brain-penetrant, pan IDH mutant inhibitor in collaboration with Celgene 

AG-881 is an orally available inhibitor of the mutated IDH1 and IDH2 proteins. In preclinical studies, it has shown to fully penetrate the blood-brain barrier, which has potential to support ongoing development efforts to provide treatment options to patients with glioma. It also represents a possible second-generation molecule for both AG-221 and AG-120 in IDH mutant tumors. Agios plans to initiate Phase 1 clinical development of AG-881 in the second quarter of 2015.

AG-221, AG-120 and AG-881 are part of the global strategic collaboration with Celgene Corporation. Each of these investigational medicines carries different financial terms and rights under the collaboration, including:

  • AG-221: Celgene has worldwide development and commercialization rights for AG-221. Agios is eligible for up to $120 million in milestone payments and royalties on any net sales. 
  • AG-120: Agios retains U.S. development and commercialization rights, while Celgene will lead development and commercialization outside the U.S. Agios is eligible to receive royalties on any net sales outside the U.S. and up to $120 million in payments. Celgene is eligible to receive royalties on any net sales in the U.S.
  • AG-881: Joint worldwide development and 50/50 profit share collaboration. Agios is eligible to receive regulatory milestone payments up to $70 million.

IDH2 and IDH1 Research

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 hematologic malignancies such as AML 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 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.

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