P1547: ACTIVATE-KIDS: MITAPIVAT IN CHILDREN WITH PYRUVATE KINASE DEFICIENCY WHO ARE NOT REGULARLY TRANSFUSED

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Background: Pyruvate kinase (PK) deficiency is a rare, inherited disorder caused by PKLR gene mutations that is associated with chronic hemolytic anemia and lifelong complications. Clinical management includes red blood cell (RBC) transfusions and splenectomy, which only partially improves anemia. No pharmacotherapies are approved for use in children, and therapies targeting the underlying cause of hemolysis are needed. Mitapivat (AG-348), a first-in-class, oral, allosteric activator of the RBC PK enzyme, demonstrated significant and durable improvements in hemoglobin (Hb) and markers of hemolysis, hematopoiesis, and iron metabolism in adults with PK deficiency who were not regularly transfused (ACTIVATE NCT03548220, long-term extension study NCT03853798). Safety and efficacy data support the evaluation of mitapivat in children with PK deficiency who are not regularly transfused. Aims: Report the design of ACTIVATE-Kids (NCT05175105), a phase 3 study, which will evaluate the efficacy and safety of mitapivat in children with PK deficiency who are not regularly transfused. Methods: ACTIVATE-Kids, a global, multicenter, double-blind, placebo-controlled study, will stratify 30 children by age (1 to <6, 6 to <12, and 12 to <18 years); a minimum of 6 patients in each age group will be randomized (2:1) to mitapivat or placebo. The double-blind period comprises an 8-week dose-titration period and a 12-week fixed-dose period. A 5-year open-label period will follow the double-blind period. The study drug will be dosed (1–50 mg twice daily) according to patient age and weight, based on pharmacokinetic modeling data of adults with PK deficiency. Key inclusion criteria: ≥2 PKLR mutant alleles with ≥1 missense mutation, ≤5 RBC transfusions in the past year, Hb concentrations of ≤10 g/dL (12 to <18 years) or ≤9 g/dL (1 to <12 years). Key exclusion criteria: R479H homozygosity, 2 non-missense mutations without a missense mutation in PKLR, or prior stem cell transplantation. The primary endpoint is Hb response, defined as a ≥1.5 g/dL increase in Hb concentration from baseline that is sustained at ≥2 scheduled assessments at Weeks 12, 16, and 20 in the double-blind period. Secondary endpoints will evaluate the effect of mitapivat on Hb, hemolysis, erythropoiesis, iron metabolism and overload, safety, quality of life, and pharmacokinetics. Results: Global site recruitment is in-progress; an update on recruitment and patient enrollment will be provided. Summary/Conclusion: The phase 3 ACTIVATE-Kids study of children with PK deficiency who are not regularly transfused will evaluate treatment with mitapivat, a potential disease-modifying pharmacotherapy.