Efficacy and Safety Evaluation of Mitapivat in Pediatric Patients with Pyruvate Kinase Deficiency Not Receiving Regular Transfusions: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-Controlled Study

The primary objective of this Phase 3, multicenter, randomized, double-blind, placebo-controlled study is to determine the **efficacy** of treatment with **mitapivat** compared with placebo. This is assessed by the increase in hemoglobin (Hb) concentrations in pediatric subjects with **pyruvate kinase deficiency** who are not regularly transfused. The clinical relevance of this objective lies in addressing the unmet need for effective treatment options in this patient population, potentially improving their hematological parameters and overall quality of life.

The clinical trial involves a total of **18 participants** diagnosed with **Pyruvate Kinase Deficiency**. The study population includes both male and female subjects, aged between 1 and less than 18 years. Participants are required to have a clinical laboratory confirmation of the deficiency, characterized by the presence of at least two mutant alleles in the PKLR gene, with at least one being a missense mutation. The trial includes individuals who are not regularly transfused, with no more than five red blood cell transfusions in the year prior to the study and none within 12 weeks before the first dose of the study drug. Participants must have a hemoglobin concentration of ≤10 g/dL for those aged 12 to <18 years or ≤9 g/dL for those aged 1 to <12 years, based on an average of at least two measurements during the screening period. All subjects are required to be on folic acid supplementation as part of their routine clinical care for at least 21 days before the study and continue throughout the trial. Female participants who have reached menarche or are in Tanner Stage 2 must adhere to specific contraceptive measures. The trial population was selected based on these criteria to ensure the safety and efficacy of the treatment being evaluated.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of **mitapivat** in pediatric subjects with **pyruvate kinase deficiency** who are not regularly transfused. The trial is structured in two phases: an initial double-blind period followed by a 5-year open-label extension. The primary objective is to assess the increase in hemoglobin concentrations, with the primary endpoint being a ≥1.5 g/dL increase in hemoglobin concentration from baseline, sustained at two or more scheduled assessments at Weeks 12, 16, and 20 during the double-blind period. The trial is expected to conclude by December 2029, with recruitment having started in April 2022.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, genetic confirmation of pyruvate kinase deficiency, and hemoglobin levels. The screening period will include at least two hemoglobin concentration measurements separated by at least seven days. Following successful screening, participants will be randomized to receive either mitapivat or placebo. The double-blind treatment phase will involve regular follow-up visits to monitor hemoglobin levels and other safety parameters. Upon completion of the double-blind phase, participants will have the option to enter the open-label extension, where all subjects will receive mitapivat for an additional five years.

The expected duration of participant involvement in the study is approximately seven years, including both the double-blind and open-label phases. Conditions that may lead to early termination from the study include non-compliance with study procedures, withdrawal of consent, or adverse events that, in the opinion of the investigator, warrant discontinuation of the study drug. The study is designed to ensure rigorous monitoring and assessment of both efficacy and safety outcomes throughout the trial duration.

The clinical trial involves the administration of **Mitapivat**, a chemical compound with the active substance name **Mitapivat**. The pharmaceutical form of Mitapivat is available as both **granules** and **tablets**. The granules are identified by the product code AG-348 and are manufactured by Agios Pharmaceuticals. The route of administration for Mitapivat is oral use. The dosage is measured in milligrams, although specific dosing amounts are not provided. The maximum treatment period for Mitapivat is specified as 1111 days. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to Mitapivat, a **placebo** is used as a comparator treatment in this study. The placebo is designed to match the appearance of the Mitapivat granules and tablets but does not contain any active substance. The placebo is administered orally, similar to the experimental medication, to maintain the double-blind nature of the trial. The use of a placebo allows for the assessment of the efficacy and safety of Mitapivat by providing a control group for comparison.

The efficacy of **mitapivat** in the clinical trial will be assessed by evaluating the increase in hemoglobin (Hb) concentrations in pediatric subjects with pyruvate kinase deficiency who are not regularly transfused. The primary endpoint for efficacy is defined as an Hb response, which is characterized by a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline. This increase must be sustained at two or more scheduled assessments at Weeks 12, 16, and 20 during the Double-blind Period. The baseline Hb concentration for each subject is determined as the average of all available Hb concentrations collected during the Screening Period up to the first dose of the study drug.