OBJECTIVES: Pyruvate kinase deficiency (PKD) is caused by mutations in the PKLR gene encoding the red blood cell PK enzyme (PKR) leading to defective glycolysis and hemolytic anemia. Mitapivat is a first-in-class, allosteric activator of PKR. We aimed to evaluate the efficacy and safety of mitapivat in adult patients with PKD.

METHODS: Medline, Embase®, and Cochrane databases via the Ovid platform were searched on 17th June 2022 for studies assessing the efficacy and safety of Mitapivat in PKD patients. Two reviewers independently searched for the publications and extracted data, resolving differences through consensus.

RESULTS: Two studies based on three publications were included. ACTIVATE (NCT03548220) was a double-blind, phase III clinical trial that enrolled patients who were not regularly transfused and received oral mitapivat BID. Patients receiving mitapivat achieved a significantly higher sustained hemoglobin (Hb) response compared with the placebo group (40% vs 0%). The Least square mean (LSM) difference between the mitapivat and placebo arms showed statistically significant results for the mean change from baseline of Hb-concentration 1.8 g/dL (95%CI 1.2 to 2.4; p<0.0001), indirect bilirubin -26.26 μmol/L (95% CI -37.82 to -14.70; p<0.0001), reticulocyte percentage (%) -0.1011 (95%CI -0.1391 to -0.0632; p<0.0001), lactate-dehydrogenase -70.81 U/L (95%CI -115.88 to -25.74; p=0.0027), haptoglobin 0.158 g/L (95%CI 0.043 to 0.273; p=0.0079). In the long-term extension (LTE) study, patients who received a placebo in the ACTIVATE study were assigned to Mitapivat and 35% (6/17) of patients achieved Hb responses. In ACTIVATE-T (NCT03559699) single-arm study of mitapivat, 37% (10/27) of patients with regular transfusion status reported a ≥33% reduction in transfusion burden and 22% (6/22) of patients were transfusion free. No treatment-emergent adverse events (TEAEs) led to study discontinuation in both the studies.

CONCLUSIONS: Data from ACTIVATE and ACTIVATE-T studies demonstrated that mitapivat improved Hb level and reduced transfusion burden in patients with PKD.