A Study to Evaluate the Efficacy and Safety of Mitapivat in Pediatric Participants With Pyruvate Kinase Deficiency (PKD) Who Are Not Regularly Transfused, Followed by a 5-Year Extension Period

Inclusion Criteria:

• Written informed consent from the participant, or the participant's legallyauthorized representative, parent(s), or legal guardian, and the participant'sassent, where applicable (informed consent/assent) must be obtained before anystudy-related procedures are conducted, and participants must be willing to complywith all study procedures for the duration of the study;

• Aged 1 to <18 years. Participants between 12 and 24 months of age must weigh aminimum of 7 kilograms (kg);

• Clinical laboratory confirmation of pyruvate kinase deficiency (PKD), defined asdocumented presence of at least 2 mutant alleles in the pyruvate kinase L/R (PKLR)gene, of which at least 1 is a missense mutation, as determined per the genotypingperformed by the study central genotyping laboratory;

• No more than 5 red blood cell (RBC) transfusions in the 52-week period beforeproviding informed consent/assent and no RBC transfusions ≤12 weeks beforeadministration of the first dose of study drug;

• Hemoglobin concentration ≤10 grams per deciliter (g/dL) for participants 12 to <18years of age or ≤9 g/dL for participants 1 to <12 years of age during the screeningperiod. Hb concentration must be based on an average of at least 2 Hb concentrationmeasurements (separated by ≥7 days) collected during the screening period;

• Receiving folic acid supplementation as part of routine clinical care for at least 21 days before administration of the first dose of study drug, to be continuedduring study participation;

• Female participants who have attained menarche and/or breast development in TannerStage 2 must be abstinent of sexual activities that may induce pregnancy as part oftheir usual lifestyle, or agree to use 2 forms of contraception, 1 of which must beconsidered highly effective, from the time of informed consent/assent, throughoutthe study, and for 28 days after the last dose of study drug (including the timerequired to dose taper). The second form of contraception can include an acceptablebarrier method.

Exclusion Criteria:

• Pregnant or breastfeeding;

• Homozygous for the R479H mutation or have 2 nonmissense mutations, without thepresence of another missense mutation, in the PKLR gene as determined per thegenotyping performed by the study central genotyping laboratory;

• History of malignancy;

• History of active and/or uncontrolled cardiac or pulmonary disease or clinicallyrelevant QT prolongation within 6 months before providing informed consent/assent;

• Hepatobiliary disorders including, but not limited to:

• Liver disease with histopathological evidence of cirrhosis or severe fibrosis;

• Clinically symptomatic cholelithiasis or cholecystitis (participants with priorcholecystectomy are eligible);

• History of drug-induced cholestatic hepatitis;

• Aspartate aminotransferase >2.5×upper limit of normal (ULN) (unless due tohemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5×ULN (unless due to hepatic iron deposition);

• Renal dysfunction as defined by an estimated glomerular filtration rate <60milliliters per minute (mL/min)/1.73 m^2;

• Nonfasting triglycerides >440 milligrams per deciliter (mg/dL) (5 millimoles perliter [mmol/L]);

• Active uncontrolled infection requiring systemic antimicrobial therapy;

• Participants with known active hepatitis B or hepatitis C virus infection;

• Participants with known human immunodeficiency virus (HIV) infection;

• History of major surgery (including splenectomy) ≤6 months before providing informedconsent/assent and/or planning on undergoing a major surgical procedure during thescreening or double-blind period;

• Current enrollment or past participation (within 90 days before the first dose ofstudy drug or a time frame equivalent to 5 half-lives of the investigational studydrug, whichever is longer) in any other clinical study involving an investigationalstudy drug or device;

• Prior exposure to gene therapy, or bone marrow or stem cell transplantation;

• Currently receiving hematopoietic stimulating agents; the last dose must have beenadministered at least 28 days or a time frame equivalent to 5 half-lives (whicheveris longer) before randomization;

• Receiving products that are strong inhibitors of CYP3A4/5 that have not been stoppedfor ≥5 days or a time frame equivalent to 5 half-lives (whichever is longer), orstrong inducers of CYP3A4 that have not been stopped for ≥28 days or a time frameequivalent to 5 half-lives (whichever is longer), before randomization;

• Receiving anabolic steroids, including testosterone preparations, that have not beenstopped for at least 28 days before randomization;

• Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate,mannitol, Opadry® II Blue [hypromellose, titanium dioxide, lactose monohydrate,triacetin, and Food, Drug, and Cosmetics blue dye number 2 (FD&C Blue #2)], Opadry®II White [hypromellose, titanium dioxide, lactose monohydrate, and triacetin], andmagnesium stearate);

• Any medical, hematologic, psychological, or behavioral condition(s) or prior orcurrent therapy that, in the opinion of the Investigator, may confer an unacceptablerisk to participating in the study and/or could confound the interpretation of thestudy data; also included are:

• Participants who are institutionalized by regulatory or court order.

• Participants with any condition(s) that could create undue influence (includingbut not limited to incarceration, involuntary psychiatric confinement, andfinancial or familial affiliation with the Investigator or Sponsor).

• Receiving a pyruvate kinase activator that has not been stopped for ≥52 weeks beforeproviding informed consent/assent.