A Study Evaluating the Efficacy and Safety of AG-348 in 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: AG-348
Intervention description: Part 1 (Dose Optimization Period): Participants began by receiving 5 mg orally, BID. Each participant's dose of AG-348 was sequentially increased to 20 mg BID followed by 50 mg BID depending on their response to AG-348 and their tolerance.
Part 2 (Fixed Dose Period): Optimized dose determined in Part 1.
Intervention MeSH terms: Mitapivat
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 27.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Study AG348-C-007 was a multicenter study designed to evaluate the efficacy and safety of
      treatment with AG-348 in a minimum of 20, with up to 40, participants with pyruvate kinase
      (PK) deficiency, who were regularly receiving blood transfusions. The study was composed of
      two parts. During Part 1, Dose Optimization Period, participants started on a dose of 5 mg
      AG-348 administered twice daily. Over the course of Part 1 each participant's dose of AG-348
      was sequentially increased to 20 mg twice a day, followed by 50 mg twice a day depending on
      their tolerance. During Part 2, Fixed-Dose Period, participants received AG-348 at their
      optimized dose from Part 1.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Informed consent;

          -  Male or female, aged 18 or older;

          -  Presence of at least 2 mutant alleles in the Pyruvate Kinase Liver and RBC (PKLR)
             gene, of which at least 1 is a missense mutation;

          -  History of a minimum of 6 transfusion episodes in the 52-week period prior to date of
             informed consent;

          -  Complete records of transfusion history for the 52 weeks prior to the date of informed
             consent, including all transfusion dates, number of blood units transfused for all the
             transfusions, and Hb concentrations within 1 week prior to transfusion for at least
             80% of the transfusions;

          -  Have received at least 0.8 mg of oral folic acid daily for at least 21 days prior to
             the first dose of study drug, to be continued daily during study participation;

          -  Have adequate organ function;

          -  Negative serum pregnancy test for women of reproductive potential;

          -  For women of reproductive potential as well as fertile men and their partners who are
             women of reproductive potential: be abstinent 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 AG-348;

          -  Willing to comply with all study procedures, in particular the individual transfusion
             trigger (TT) calculated based on 52 weeks of transfusion history, 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 participate in the
             study, and/or that could confound the interpretation of the study data;

          -  History of transfusions occurring on average more frequently than once every 3 weeks
             during the 52 weeks prior to date of informed consent;

          -  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. Prior participation in the
             PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is
             permitted;

          -  Exposure to any investigational drug, device, or procedure within 3 months prior to
             the first dose of study drug;

          -  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 CYP3A4, 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
             5 times their half-lives (whichever is longer) prior to start of study drug;

          -  Currently receiving hematopoietic stimulating agents (eg, erythropoietins [EPOs],
             granulocyte colony stimulating factors, thrombopoietins) that have not been stopped
             for a duration of at least 28 days prior to the first dose of study drug;

          -  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;

          -  Allergy to AG-348 or its excipients;

          -  Currently receiving anabolic steroids, including testosterone preparations, within 28
             days prior to the first dose of study drug.