The pyruvate kinase (PK) enzyme catalyzes the last step of glycolysis—the conversion of glucose into pyruvate—and is critical for the production of cellular energy (ATP), required for the normal function and survival of the cell.
Inherited mutations in red cell PK (PKR) enzymes cause a deficit in cellular energy within the red blood cell. This is evidenced by a decline in the metabolite ATP (adenosine triphosphate) and a build-up of the metabolite 2,3-DPG (2,3-diphosphoglycerate), which leads to a rare anemia known as pyruvate kinase deficiency, or PK deficiency. Cellular energy in the form of ATP is needed for cell membrane integrity in order to withstand the stress of circulation and avoid hemolysis, which is the premature destruction of blood red cells. When ATP levels are insufficient, the membrane becomes unstable and the cells are prone to hemolysis.
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)
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)
- 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-348 is an investigational novel, first-in-class, orally available, potent, selective small molecule activator of pyruvate kinase-R (PKR) for treatment of people with pyruvate kinase deficiency, or PK deficiency.
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. The U.S. Food and Drug Administration (FDA) has granted Agios orphan drug designation and fast track designation for AG-348. Visit the Publications and Abstracts page for additional information and resources on AG-348.
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.