Pipeline

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.

AG-221: IDH2 mutant inhibitor in collaboration with Celgene

AG-221 is an orally available, selective, potent inhibitor of the mutated IDH2 protein, making it a highly targeted investigational medicine for the potential treatment of patients with cancers that harbor an IDH2 mutation. AG-221 has received orphan drug and fast track designations from the U.S. FDA and is currently being evaluated in multiple clinical studies, including:

  • An ongoing Phase 1 trial that includes a dose-escalation phase, four expansion cohorts of 25 patients each and a Phase 2 expansion cohort of 125 patients with IDH2 mutant-positive AML who are in second or later relapse, refractory to second-line induction or reinduction treatment, or have relapsed after allogeneic transplantation. The primary objectives of the study are to confirm the safety and clinical activity of AG-221 in a select, highly resistant AML population. 
  • The Phase 3 IDHENTIFY study of AG-221, which is an international, multi-center, open-label, randomized clinical trial designed to compare the efficacy and safety of AG-221 versus conventional care regimens in patients 60 years or older with IDH2 mutant-positive AML that is refractory or relapsed after second- or third-line therapy. 
  • For newly diagnosed AML patients eligible for intensive chemotherapy, Agios is conducting a Phase 1b combination study of either AG-221 or AG-120 with standard induction (7+3, Ara-C and idarubicin/daunorubicin) and consolidation (Ara-C, or mitoxantrone with etoposide) chemotherapy.

For additional details about these trials, please visit www.clinicaltrials.gov.  

Clinical data from the dose escalation and expansion phases of the ongoing Phase 1 trial of AG-221 in advanced hematologic malignancies presented to date provide validation of IDH2 as an important cancer target. These data 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 2015 American Society of Hematology Annual Meeting (ASH) showed a favorable safety profile and durable response rate in IDH2 mutant hematologic malignancies. As of the September 1, 2015 data analysis, AG-221 showed durable clinical activity in patients on study up to 18 months with a median duration treatment of 6.8 months. Safety data of AG-221 showed that the majority of adverse events were mild to moderate. Read the full summary of the ASH data here

AG-120: 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. AG-120 is currently being evaluated in multiple clinical studies, including:

  • An ongoing Phase 1 trial that includes a dose escalation phase and three expansion cohorts, including a homogenous population of 125 AML patients who relapsed after bone marrow transplantation, are in second or later relapse, refractory to second line induction or reinduction treatment. The study’s primary objectives are to confirm the safety and clinical activity of AG-120. 
  • An ongoing Phase 1 dose-escalation and expansion clinical trial evaluating AG-120 in patients with IDH1 mutant-positive advanced solid tumors, including glioma, chondrosarcoma and cholangiocarcinoma. 
  • The frontline combination trial as described in the AG-221 section above. 

For additional details about these trials, please visit www.clinicaltrials.gov. AG-120 has received orphan drug and fast track designations from the U.S. FDA.

Clinical data from the ongoing Phase 1 trial of AG-120 in advanced hematologic malignancies presented to date provide validation of IDH1 as an important cancer target. The data presented at EHA showed a favorable safety profile and durable clinical activity for AG-120. As of the May 1, 2015 data analysis, AG-120 showed complete and durable clinical activity in patients on study up to 11 months. Safety data showed that AG-120 is well tolerated, and the majority of adverse events were mild to moderate. Read the full summary of the EHA data here.

Clinical data from the dose-escalation portion of the ongoing Phase 1 trial of AG-120 in solid tumors were presented at AACR-NCI-EORTC in November 2015 and confirmed a well-tolerated safety profile and demonstrated signals of clinical activity that support further evaluation in patients with IDH1 mutant positive solid tumors. Read the full summary of the AACR-NCI-EORTC data here.

AG-881: 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. AG-881 is being evaluated in two Phase 1, open-label, dose-escalation and expansion studies, the first in advanced solid tumors and the second in patients with advanced IDH mutant-positive hematologic malignancies whose cancer has progressed on a prior IDH inhibitor therapy. The studies will evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-881 in advanced solid tumors and hematologic malignancies.

Celgene Collaboration Terms

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:

  • 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.

IDH1 and IDH2 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: