Pyruvate Kinase Deficiency: Current Challenges and Future Prospects

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• supportive measures, iron chelation, and splenectomy. In the last 10 years, a novel era of therapies directed at boosting enzyme activity, by directly activating PK or by substituting the defective gene, has begun

• Mitapivat, previously AG-348

• The drug showed a favorable safety profile, with mainly low-grade adverse events (AEs) including headache (24 patients), insomnia (22), and nausea (21), mostly transient and resolving within 7 days of treatment. Further two Phase 3 trials assessed mitapivat in PKD patients.

• oral allosteric activator of RBC PK

• Ten cases (37%) met the primary endpoint (>33% reduction in transfusion burden), and 6 (22%) became transfusion independent. Mitapivat was again well tolerated, with increased alanine aminotransferase (37%) and headache (37%) as most common AEs. Responders maintained transfusion independence across the LTE study45.

• . Interestingly, mitapivat and etavopivat, a new allosteric PK activator (FT-4202), are currently under study in sickle cell disease (SCD) and thalassemia (NCT04610866, NCT03692052, NCT03815695, NCT04624659, NCT04987489).46–48 These conditions share with PKD features of chronic hemolysis with reduced RBC life span, and ineffective erythropoiesis and further highlight the potential of boosting RBC energy machinery in congenital anemias.