Mitapivat for the Treatment of Pyruvate Kinase Deficiency

Pyruvate kinase (PK) deficiency is an inherited, rare chronic form of hemolysis resulting in anemia and, potentially, pigmented gallstones and iron overload, among other complications. Mutations involving the PKLR gene are common, though there are many pathogenic variants involving this gene. Treatment is typically supportive and includes transfusions, splenectomy, and cholecystectomy for those with gallstones.

In a prior phase 2 study of mitapivat, an activator of red cell pyruvate kinase, roughly half the patients experienced an increase in hemoglobin level of at least 1 g/dL. Now, in an industry-sponsored phase 3 study (ACTIVATE), researchers compared mitapivat to placebo in 80 patients with PK deficiency. Included patients had PKLR mutations, baseline hemoglobin ≤10 g/dL, and lack of transfusion dependence. The primary endpoint was a sustained increase in hemoglobin of at least 1.5 g/dL.

Among the findings:

• Patients had a mean age of 36 (mitapivat) and 37 years (placebo) and mean baseline hemoglobin level of 8.6 and 8.5 g/dL, respectively.
• Most patients had undergone splenectomy as well as cholecystectomy.
• The most common genetic profile in both groups was missense/missense.
• The primary endpoint was met in 16 of 40 patients treated with mitapivat, compared with none of 40 patients in the placebo group.
• Among responders, the mean change in hemoglobin level was 3.5 ± 1.4 g/dL.
• The most common adverse events in the mitapivat group included nausea in 7 patients (18%) and headache in 6 (15%) — incidences similar to or lower than those in the placebo group.