Pipeline

Clinical Programs

Agios is focused on discovering and developing novel investigational medicines to treat cancer and rare genetic diseases through scientific leadership in the field of cellular metabolism. In addition to an active research and discovery pipeline, Agios has multiple first-in-class investigational therapies in clinical development.
 
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.

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, cholangiocarcinoma 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. Ivosidenib is wholly owned by Agios.

DISEASE PROGRAM STUDY PHASE STATUS LEARN MORE
Acute Myeloid Leukemia ENASIDENIB or IVOSIDENIB Phase 1b Safety Study of Ivosidenib or Enasidenib in Combination With Induction and Consolidation Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 and/or IDH2 Mutation Recruiting clinicaltrials.gov
Acute Myeloid Leukemia ENASIDENIB or IVOSIDENIB Phase 1/2 Safety and Efficacy Study of Oral Ivosidenib Plus Subcutaneous Azacitidine and Oral Enasidenib Plus Subcutaneous Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia (AML) Recruiting clinicaltrials.gov
Acute Myeloid Leukemia IVOSIDENIB Phase 1 Study of Orally Administered Ivosidenib in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation Active, not recruiting clinicaltrials.gov
Acute Myeloid Leukemia IVOSIDENIB Phase 3 Study of AG-120 (Ivosidenib) vs. Placebo in Combination With Azacitidine in Patients With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation (AGILE) Recruiting clinicaltrials.gov
Acute Myeloid Leukemia IVOSIDENIB Ivosidenib Expanded Access Program in Relapsed/Refractory AML With an IDH1 Mutation Available clinicaltrials.gov
Solid Tumors (including Glioma) IVOSIDENIB Phase 1 Study of Orally Administered Ivosidenib in Subjects With Advanced Solid Tumors, Including Glioma, With an IDH1 Mutation Active, not recruiting clinicaltrials.gov
Cholangiocarcinoma IVOSIDENIB Phase 3 Study of Orally Administered Ivosidenib in Previously Treated Advanced Cholangiocarcinoma Patients With IDH1 Mutations (ClarIDHy) Recruiting clinicaltrials.gov
claridhy.com
Glioma IVOSIDENIB or AG-881 Perioperative Study of AG-120 and AG-881 in Subjects With Low Grade Glioma Recruiting clinicaltrials.gov

For additional details about these trials, please visit our Clinical Trials page or visit www.clinicaltrials.gov and search for Agios.

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.

AG-881

(Pan-IDHm inhibitor)

AG-881 is an investigational, 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. It also represents a possible second-generation molecule for ivosidenib in IDH mutant tumors.

AG-881 is part of a global research collaboration agreement with Celgene Corporation.

DISEASE PROGRAM STUDY PHASE STATUS LEARN MORE
Solid Tumors (including Glioma) AG-881 Phase 1 Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation Active, not recruiting clinicaltrials.gov
Glioma IVOSIDENIB or AG-881 Perioperative Study of AG-120 and AG-881 in Subjects With Low Grade Glioma Recruiting clinicaltrials.gov

For additional details about these trials, please visit our Clinical Trials page or visit www.clinicaltrials.gov and search for Agios.

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.

AG-348

(PKR activator)

AG-348 is an investigational novel, first-in-class, orally available, potent, selective small molecule activator of pyruvate kinase-R (PKR).

Pyruvate kinase is an enzyme involved in glycolysis: the conversion of sugar, or glucose, into energy is critical for the survival of red blood cells. PKR is the form of pyruvate kinase that is present in red blood cells. Mutations in PKR cause deficiencies in red blood cell glycolysis, which lead to a disease known as PK deficiency. PK deficiency results in a shortened lifespan for red blood cells. Agios’ pre-clinical work has demonstrated PKR activation has potential utility in other hemolytic anemias such as thalassemia and sickle cell disease. The U.S. Food and Drug Administration (FDA) has granted AG-348 Orphan Drug and Fast Track Designations for AG-348. AG-348 is wholly owned by Agios.

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Pyruvate kinase deficiency AG-348 Phase 2 DRIVE PK Study of AG-348 in Adult Patients With Pyruvate Kinase Deficiency Active, not recruiting clinicaltrials.gov
drivepktrial.com

For additional details about these trials, please visit our Clinical Trials page or visit www.clinicaltrials.gov and search for Agios

PK deficiency is an inherited disease that causes a lifelong condition called hemolytic anemia, a certain type of anemia where your body destroys red blood cells, as well as other serious complications. While many people with PK deficiency get diagnosed in their early years of life as infants or children, others – particularly adults and patients on the milder end of the spectrum of disease severity – sometimes remain undiagnosed for years. Disease manifestations may significantly affect daily activity and quality of life.

People with PK deficiency can experience a range of signs and symptoms, including:

  • Anemia (not having enough red blood cells to carry sufficient amounts of oxygen throughout the body)
  • Feeling fatigued, tired and/or weak
  • Shortness of breath
  • Exercise intolerance
  • Iron overload (having too much iron in the body) resulting from lifelong (or chronic) hemolytic anemia and as a comorbidity related to transfusions
  • Jaundice (yellow coloring of the skin and eyes)
  • Scleral icterus (yellow coloring of the whites of the eyes)
  • Abdominal pain
  • Enlarged spleen (splenomegaly)
  • Gallstones

PK deficiency is managed differently from person to person, depending on how the disease affects them. Currently, treatment is supportive and not disease-specific, and can include:

  • Blood transfusions
  • Treatment and prevention of iron overload
  • Removal of the spleen (splenectomy)
  • Removal of the gallbladder (cholecystectomy)
  • Phototherapy
  • Bone marrow transplant

Medical problems associated with PK deficiency can be caused by the disease, but can also be a result of the current treatment options themselves, including co-mordities related to splenectomy and/or chronic transfusions. A key co-morbidity is iron overload, which is caused by both the release of iron due to hemolysis and blood transfusion, which introduces additional iron into the blood stream. Treatment of iron overload with iron chelators is common in this disease.

A number of laboratory testing methods can be requested by a physician to determine if a person have PK deficiency. Typically, one or both of the following types of tests can be performed:

  • Erythrocyte (red blood cell) PK enzymatic activity (enzyme or biochemical assay)
  • Mutation analysis of the PKLR gene (molecular testing)

AG-270

(MAT2A Inhibitor)

AG-270 is an investigational, first-in-class methionine adenosyltransferase 2a (MAT2A) inhibitor.

Agios discovered that MAT2A is a component of a novel pathway in MTAP-deleted tumors which, when inhibited, results in robust anti-tumor activity. Agios scientists have demonstrated that this pathway can be modulated by small molecule inhibitors, resulting in robust anti-tumor activity in animal models. MTAP (methylthioadenosine phosphorylase) is a metabolic enzyme that is deleted in approximately 15 percent of all cancers. This deletion is readily detected by a simple genomic test, thus allowing the selection of patients predicted to be sensitive to the therapy.

AG-270 is part of a global research collaboration agreement with Celgene Corporation.

DISEASE PROGRAM STUDY PHASE STATUS LEARN MORE
Advanced Solid Tumors or Lymphoma AG-270 Phase 1 Study of AG-270 in Subjects With Advanced Solid Tumors or Lymphoma With MTAP Loss Recruiting clinicaltrials.gov

For additional details about these trials, please visit our Clinical Trials page or visit www.clinicaltrials.gov and search for Agios.