A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
Condition: Pyruvate Kinase Deficiency; Anemia, Hemolytic
MeSH terms: Anemia, Hemolytic, Congenital Nonspherocytic; Anemia, Hemolytic; Pyruvate Metabolism, Inborn Errors
Intervention: Placebo; AG-348
Intervention description: Placebo matching AG-348 tablets, administered to maintain the blind.; AG-348 tablets.
Intervention MeSH terms: Mitapivat
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 80.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Study AG348-C-006 evaluated the efficacy and safety of orally administered AG-348 as compared
      with placebo in participants with pyruvate kinase (PK) deficiency, who were not regularly
      receiving blood transfusions. Participants were randomized 1:1 to receive either AG-348 or a
      matching placebo.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Informed consent;

          -  Male or female, aged 18 years or older;

          -  Documented clinical laboratory confirmation of pyruvate kinase (PK) deficiency,
             defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which
             at least 1 is a missense mutation;

          -  Hemoglobin (Hb) concentration less than or equal to 10.0 grams per deciliter (g/dL)
             regardless of gender (average of at least 2 Hb measurements [separated by a minimum of
             7 days] during the Screening Period)

          -  Considered not regularly transfused, defined as having had no more than 4 transfusion
             episodes in the 12-month period up to the first day of study treatment and no
             transfusions in the 3 months prior to the first day of study treatment;

          -  Received at least 0.8 mg oral folic acid daily for at least 21 days prior to the first
             dose of study treatment, to be continued daily during study participation.

          -  Adequate organ function;

          -  Women of reproductive potential, have a negative serum pregnancy test;

          -  For women of reproductive potential as well as men with partners who are women of
             reproductive potential, be abstinent as part of their usual lifestyle, or agree to use
             2 forms of contraception, 1 of which must be considered highly effective, from the
             time of giving informed consent, during the study, and for 28 days following the last
             dose of study treatment for women and 90 days for men following the last dose of study
             treatment;

          -  Willing to comply with all study procedures for the duration of the study;

        Exclusion Criteria:

          -  Homozygous for the R479H mutation or have 2 non-missense mutations, without the
             presence of another missense mutation, in the PKLR gene;

          -  Significant medical condition that confers an unacceptable risk to participating in
             the study, and/or that could confound the interpretation of the study data;

          -  Splenectomy scheduled during the study treatment period or have undergone splenectomy
             within 12 months prior to signing informed consent;

          -  Currently enrolled in another therapeutic clinical trial involving ongoing therapy
             with any investigational or marketed product or placebo. Prior and subsequent
             participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK
             Deficiency Registry is permitted however, concurrent participation is not;
             participants enrolling in this current study will be expected to temporarily suspend
             participation in the NHS or Registry;

          -  Exposure to any investigational drug, device, or procedure within 3 months prior to
             the first dose of study treatment;

          -  Prior treatment with a pyruvate kinase activator;

          -  Prior bone marrow or stem cell transplant;

          -  Currently pregnant or breastfeeding;

          -  History of major surgery within 6 months of signing informed consent;

          -  Currently receiving medications that are strong inhibitors of cytochrome P450
             (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or
             digoxin (a P-gp sensitive substrate medication) that have not been stopped for a
             duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is
             longer) prior to the first dose of study treatment;

          -  Currently receiving hematopoietic stimulating agents that have not been stopped for a
             duration of at least 28 days prior to the first dose of study treatment;

          -  History of allergy to sulfonamides if characterized by acute hemolytic anemia, drug
             induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson
             syndrome, cholestatic hepatitis, or other serious clinical manifestations;

          -  History of allergy to AG-348 or its excipients;

          -  Currently receiving anabolic steroids, including testosterone preparations, within 28
             days prior to treatment.