Background: Pyruvate kinase (PK) deficiency is a rare chronic hemolytic anemia caused by homozygous or compound heterozygous mutations in the PKLR gene. The PKLR gene encodes the red blood cell (RBC)-specific form of PK (PKR), an enzyme that is crucial in the final step of glycolysis. The clinical presentation of PK deficiency is variable, ranging from mild to severe anemia; it is associated with a spectrum of symptoms and complications which can be acute and long-term and start early in life. Registry data indicated an early age of onset of liver disease and iron overload (regardless of transfusion status), both of which were common in pediatric patients (pts). Supportive therapies in children include transfusions and splenectomy and can be associated with short- and long-term risks. No pharmacotherapies are approved for use in children with PK deficiency. Mitapivat is a first-in-class, oral, allosteric activator of PK, including the PKR and M2 (PKM2) isoforms, which act in glycolysis to generate adenosine triphosphate.

Aims: Evaluate efficacy and safety of mitapivat versus placebo in pediatric pts with PK deficiency who were not regularly transfused.  

Methods: ACTIVATE-Kids (NCT05175105) is a phase 3, randomized, global, multicenter, double-blind, placebo-controlled study. Pts aged 1–<18 years (yrs) with PK deficiency who were not regularly transfused (defined as ≤5 transfusions in the 52-week [wk] period before providing informed consent/assent and no RBC transfusions ≤12 wks before administration of the first dose of study drug) were randomized 2:1 to receive twice daily oral mitapivat (1 mg to 5 mg based on age and weight, with potential escalation up to 10 mg to 50 mg) or placebo during the double-blind period (20 wks). Randomization was stratified by age (1 to <6 yrs, 6 to <12 yrs, 12 to <18 yrs). The primary endpoint was hemoglobin (Hb) response, defined as a ≥1.5 g/dL increase in Hb concentration from baseline, sustained at ≥2 scheduled assessments at Wks 12, 16, and 20 during the double-blind period. The primary endpoint was analyzed using Bayesian methodology that incorporated Hb response information from the adult ACTIVATE (NCT03548220) study. Secondary endpoints included: average change from baseline in Hb concentration, indirect bilirubin, and lactate dehydrogenase (LDH) at Wks 12, 16, and 20, and safety.

Results: Thirty pts were randomized (mitapivat: N=19 and placebo: N=11). Mean age was 9.6 yrs. Baseline characteristics for the mitapivat and placebo arms: prior splenectomy (52.6% [10/19] and 36.4% [4/11]), prior iron chelation (21.1% [4/19] and 18.2% [2/11]), prior cholecystectomy (42.1% [8/19] and 36.4% [4/11]), mean (SD) baseline Hb (8.48 [1.085] and 8.46 [0.685] g/dL). The primary endpoint was met; observed Hb response rate was higher for pts in the mitapivat arm than in the placebo arm (31.6% [6/19] vs 0% [0/11]). Improvements in changes from baseline for Hb and markers of hemolysis were observed in the mitapivat arm compared to the placebo arm: average change from baseline at Wks 12, 16, and 20 (difference in least squares mean [95% CI]) in Hb concentration (0.90 g/dL [-0.07, 1.87]), indirect bilirubin (-27.25 umol/L [-59.65, 5.15]), and LDH (-154.08 U/L [-290.76, -17.40]). The proportion of pts with any treatment-emergent adverse events (TEAEs) was similar across treatment arms (mitapivat: 78.9% [15/19]; placebo: 90.9% [10/11]). TEAEs reported in ≥15% of pts on mitapivat include upper respiratory infection, headache, and initial insomnia. Serious TEAEs were reported in 5.3% (1/19) of pts on mitapivat and 9.1% (1/11) of pts on placebo, none were considered treatment related. No AEs led to discontinuation or death.

Conclusions: ACTIVATE-Kids is the first study to demonstrate improvements in Hb and markers of hemolysis in children with PK deficiency who are not regularly transfused. Mitapivat, in tablets and pediatric granule formulation, was generally well tolerated and consistent with the safety profile observed for adults and regularly transfused children with PK deficiency. The efficacy and safety results from ACTIVATE-Kids together with the previous ACTIVATE-KidsT (NCT05144256) study support the potential for mitapivat to provide clinically substantial benefits in children with PK deficiency and may provide insight into the development of future clinical trials for pediatric pts with other hemolytic anemias.

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2025
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