Pipeline

IDH Program

Cancer cells undergo metabolic reprogramming to gain survival advantages as they progress into malignant tumors. Genetic mutations of isocitrate dehydrogenase (IDH), a metabolic enzyme in the tricarboxylic-acid cycle, is one pathway by which some tissues may become cancerous. IDH1 and IDH2 mutant enzymes are found in a number of tumor types, including acute myelogenous leukemia (AML), glioma, chondrosarcoma and cholangiocarcinoma.

Even though the genetic correlation of mutated IDH enzymes to these tumor subtypes was very strong, exactly how mutant IDH could reprogram cellular metabolism to drive cancer formation was a mystery. This lack of understanding of IDH cancer biology represented a major scientific stumbling block in the effort to develop drugs to treat these diseases.

The breakthrough made by Agios scientists was the discovery that mutant IDH1 (and similarly IDH2) acquires a new activity to produce an oncometabolite called 2-hydroxyglutarate (2HG) at exceedingly high levels inside these tumor cells. Subsequent investigative work in collaboration with several renowned academic researchers revealed that elevated 2HG causes changes in gene function that are independent of intrinsic DNA sequence (epigenetic regulation). This causes a block in the normal process of cellular differentiation from a precursor cell into different mature cell types, and instead leads to cancerous transformation.

The understanding of precisely how mutant IDH works, together with the gain in knowledge of metabolic and epigenetic defects, provided us with a clear roadmap for drug discovery. The therapeutic goal then is to inhibit the newly gained function of mutant IDH where the reduction of elevated 2HG would reverse the block in cellular differentiation, coaxing tumorous blast cells to differentiate into normally functioning cells. In our laboratory, our team of scientists designed and synthesized potent and selective inhibitors of mutant IDH2, which lowered 2HG levels and demonstrated efficacy in a preclinical mouse model of AML, where drug treatment showed a clear and dramatic survival benefit concomitant with changes in biomarkers of differentiation in the tumors.

IDHIFA® (Enasidenib)

(IDH2m inhibitor)

IDHIFA® (enasidenib) is designed to bind and inhibit the mutated IDH2 protein, as demonstrated in preclinical studies. IDH2 is a metabolic enzyme that is mutated in a wide range of cancers. Targeting mutated IDH2 may have the potential to benefit the subset of patients who carry IDH2 mutations.

Celgene has worldwide development and commercialization rights for IDHIFA. Agios has U.S. co-promotion and royalty rights. Agios is eligible for up to $120 million in milestone payments and royalties on any net sales.

The safety and efficacy of the agents and uses under investigation have not been established. There is no guarantee that this agent will receive health authority approval or become commercially available in any country for the uses being investigated.

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Ivosidenib

(IDH1m inhibitor)

Ivosidenib is an investigational 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.

IDH1 is a metabolic enzyme that is mutated in a wide range of cancers, including acute myeloid leukemia and solid tumor including cholangiocarcinoma, chondrosarcoma and glioma. Targeting mutated IDH1 may have the potential to benefit the subset of patients who carry IDH1 mutations. The U.S. Food and Drug Administration (FDA) has granted ivosidenib orphan drug and fast track designations. Visit the Publications and Abstracts page for additional information and resources on ivosidenib.

Ivosidenib is wholly owned by Agios.

The safety and efficacy of the agents and uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

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AG-881

(Pan-IDHm inhibitor)

AG-881 is an orally available, potent inhibitor of both the mutated IDH1 and IDH2 proteins.

IDH1 and IDH2 are metabolic enzymes that are mutated in a wide range of cancers. In preclinical studies, AG-881 has shown to penetrate the blood-brain barrier, which has potential to support ongoing development efforts to provide treatment options to patients with glioma as well as other cancers that spread to the brain. It also represents a possible second-generation molecule for both enasidenib and ivosidenib in IDH mutant tumors.

Agios has a joint worldwide development agreement with Celgene for AG-881 and 50/50 profit share collaboration. Agios is eligible to receive regulatory milestone payments up to $70 million.

The safety and efficacy of the agents and uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated

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