Primary Outcomes

Measure: Percentage of Participants Achieving a Hemoglobin Response (HR) in Part 2

Time: Baseline, Part 2: Weeks 16, 20, 24

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Secondary Outcomes

Measure: Change from Baseline in Hb Concentration at Weeks 16, 20 and 24 in Part 2

Time: Baseline, Part 2: Weeks 16, 20, 24

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Measure: Maximum Change from Baseline in Hb Concentration

Time: Baseline, Part 2, up to Week 24

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Measure: Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More

Time: Baseline, Part 2, up to Week 24

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Measure: Change from Baseline in Bilirubin at Weeks 16, 20 and 24 in Part 2

Time: Baseline, Part 2: Weeks 16, 20, 24

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Measure: Change from Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24 in Part 2

Time: Baseline, Part 2: Weeks 16, 20, 24

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Measure: Change from Baseline in Haptoglobin at Weeks 16, 20 and 24 in Part 2

Time: Baseline, Part 2: Weeks 16, 20, 24

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Measure: Change from Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24 in Part 2

Time: Baseline, Part 2: Weeks 16, 20, 24

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Measure: Change from Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score

Time: Baseline, up to Week 24

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Measure: Change from Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score

Time: Baseline, up to Week 24

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Measure: Percentage of Participants Experiencing an Adverse Event

Time: Through 4 weeks after last dose (approximately Part 2, Week 31)

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Measure: Percentage of Participants Experiencing an Adverse Event of Special Interest (AESI)

Time: Through 4 weeks after last dose (approximately Part 2, Week 31)

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Measure: Change from Baseline in Bone Mineral Density Z-Score at Week 24 in Part 2

Time: Baseline, Part 2: Week 24

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Measure: Change from Baseline in Bone Mineral Density T-Score at Week 24 in Part 2

Time: Baseline, Part 2: Week 24

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Measure: Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12

Time: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose

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Measure: Maximum Plasma Concentration (Cmax) for AG-348

Time: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose

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Measure: Time to Cmax (Tmax) for AG-348

Time: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose

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Measure: Time to Last Measurable Concentration (Tlast) for AG-348

Time: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose

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Primary Outcomes

Measure: Percentage of Participants Achieving a Reduction in Transfusion Burden in Part 2

Time: From Part 2, Day 1 to the end of the study (Part 2, Week 24)

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Secondary Outcomes

Measure: Number of RBC Units Transfused During the Study

Time: From Part 1, Day 1 to the end of the study (Part 2, Week 24)

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Measure: Number of Transfusion Episodes in Part 2

Time: Part 2, Day 1 to the end of study (Part 2, Week 24)

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Measure: Percentage of Transfusion-Free Participants in Part 2

Time: Part 2, Day 1 to the end of study (Part 2, Week 24)

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Measure: Percentage of Participants Achieving Normal Hemoglobin (Hb) Concentrations in Part 2

Time: Part 2, Day 1 to the end of study (Part 2, Week 24)

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Measure: Bone Mineral Density T-Score

Time: Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24

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Measure: Bone Mineral Density Z-Score

Time: Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24

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Measure: Percentage of Participants Experiencing an Adverse Event

Time: Through 4 weeks after last dose (approximately Part 2, Week 31)

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Measure: Percentage of Participants Experiencing an Adverse Event of Special Interest (AESI)

Time: Through 4 weeks after last dose (approximately Part 2, Week 31)

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