The FDA recently approved Agios’ Pyrukynd (mitapivat, AG-348), a first-in-class, allosteric activator of pyruvate kinase (PK), for treatment of hemolytic anemia in adults with the genetic condition, pyruvate kinase deficiency. The drug is given orally with a starting dose of 5 mg BID, titrating up to 50 mg BID depending on hemoglobin (Hb) levels.
See our overview of all 36 of the novel small molecule and large molecule FDA approvals for 2022 here.
Pyruvate kinase is not that kind of kinase – structurally it is related to protein kinases in having a hinge-element, alpha helix, etc. but is functionally distinct. Rather than catalyze phosphate transfer from ATP to a substrate (the definition of a kinase), PK catalyzes the opposite – irreversible phosphate transfer from phosphoenolpyruvate (PEP) to ADP, forming ATP in the last step of glycolysis.
Inherited mutations in PK exert pathology through reduced activity of PK-R, the isoform of PK in red blood cells. Since PK-R catalyzes the final step in glycolysis (PEP to pyruvate with formation of ATP), reduced PK-R activity leads to cellular energy deficiency and anemia, since mature RBCs lack mitochondria and are unable to generate significant ATP through non-glycolysis mechanisms.
The molecule increases the activity of both WT and mutant PK enzymes in patient red blood cells, restoring glycoytic activity in patients with PK deficiency. It has been shown to bind to PK-R crystallographically, inducing an active state of the PK-R tetramer. PK-R has a natural agonist ligand, fructose biphosphate (FBP), and mitapivat leads to greater PK activity than achieved with FBP. Little has been disclosed to date about the drug discovery strategy.
Importantly, since PK deficiency is caused by hundreds of different mutations, the Agios team found that mitapivat had activity against a broad range of PKLR genotypes based on enzymatic and cell activity. Since the molecule also activates WT-PK, it is conceivable that it could be beneficial in other forms of genetic anemias, such as sickle cell disease and thalassemias. Several clinical trials in other anemias are ongoing (e.g. NCT04610866).
The primary endpoints for approval were increases in hemoglobin for patients who are not regularly transfused, and clinically meaningful reduction in transfusion burden for patients who are regularly transfused. Side effects were mainly low-grade and temporary, with the most common serious side effects being hemolytic anemia and pharyngitis (2 patients in Ph. I).
Mitapivat is the first disease-modifying treatment for PK deficiency.
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