Extension Study of AG-348 in Adult Participants With Pyruvate Kinase Deficiency Previously Enrolled in AG-348-006 or AG348-C-007

A clinical adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study drug. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and include both serious and non-serious TEAEs. Severity of AEs was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE.

A clinical AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study drug. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and include both serious and non-serious TEAEs. Number of participants with TEAEs leading to dose reduction, treatment interruption and treatment discontinuation are reported.

Clinical laboratory assessments including hematology, clinical chemistry, triglycerides, urate, coagulation, urinalysis, and liver function tests were performed in the study. Clinically significant treatment-emergent laboratory abnormalities were graded according to the NCI CTCAE; Version 4.03: grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE. Clinical significance was determined based on the judgment of the Investigator.

Vital signs and physical examinations including height, weight, body mass index (BMI), systolic blood pressure, diastolic blood pressure, pulse rate, temperature were assessed. Number of participants who experienced clinically significant abnormalities in vital signs and physical examinations as TEAEs were reported. Clinical significance was determined based on the judgment of the Investigator.

BMD was measured by dual-energy X-ray absorptiometry (DXA) scans during the study. Number of participants with clinically significant abnormalities were reported. Clinical significance was determined based on the judgment of the Investigator.

T-score of adjusted spine were assessed by DXA scans. The T-score is the number of standard deviations that bone density is above or below the average. A score of ≥ -1 indicates normal bone density; score between < -1 and > -2.5 indicates a sign of osteopenia (bone density below normal), and score of ≤ -2.5 indicates a sign of osteoporosis.

The Z-score is a statistical measure to describe whether a value was above or below the standard. A Z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.

T-score of femoral total were assessed by DXA scans. The T-score is the number of standard deviations that bone density is above or below the average. A score of ≥ -1 indicates normal bone density; score between < -1 and > -2.5 indicates a sign of osteopenia (bone density below normal), and score of ≤ -2.5 indicates a sign of osteoporosis.

The Z-score is a statistical measure to describe whether a value was above or below the standard. A Z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.

The following ECG parameters including RR, PR, heart rate-corrected QT interval using the Fridericia's formula (QRS), QT, and QTc were assessed during the study. Number of Participants with clinically significant abnormalities in ECG parameters as TEAEs were reported. Clinical significance was determined based on the judgment of the Investigator.

The Hb response was defined as a greater than or equal to (≥)1.5 grams per deciliter (g/dL) (0.93 millimoles per liter [mmol/L]) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments, excluding those within 2 months (61 days) of transfusion. The baseline value for cohort 1 participants was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment is available.

The baseline value for participants was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment is available. The mean of average change from baseline in Hb concentration across Weeks 16, 20 and 24 is reported.

The baseline value for cohort 1 participant was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment was available. The baseline value for cohort 2 was from Study AG348-C-006.

The baseline value for cohort 1 participant was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment is available. The baseline value for cohort 2 was from Study AG348-C-006.

The baseline value for cohort 1 participant was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment was available. The baseline value for cohort 2 was from Study AG348-C-006.

The baseline value for Cohort 1 participant was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment was available. The baseline value for Cohort 2 was from Study AG348-C-006.

The baseline value for Cohort 1 participants was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment was available. The baseline value for Cohort 2 was from Study AG348-C-006.

Number of transfusions at baseline was determined based on the transfusion data during the 52 weeks before informed consent for Cohort 3. Number of on-study transfusions was based on transfusions collected up to the end of the fixed dose period and standardized to 52 weeks. The change from baseline in number of transfusions was summarized for Cohort 3.

Annualized total number of RBC units transfused (units/52-week) during the study, including data up to end of study (EOS), was the total number of RBC units transfused during the entire study*52 / [(date of EOS - date of start of study treatment + 1)/7]. Number of RBC units were determined based on the transfusion data during the 52 weeks before informed consent of the antecedent study for Cohort 3. Number of on-study RBC units was based on transfusion data collected up to the end of the fixed dose period and standardized to 52 weeks.

The PKDD is a validated, daily 7-item PRO instrument with a recall period of 24 hours that measures the core signs and symptoms associated with pyruvate kinase deficiency in adults. The symptoms include tiredness, jaundice, bone pain, shortness of breath, and energy level. PKDD daily scores were calculated based on the participant's response to the PKDD questionnaire. Score ranges from 25 to 76, with higher scores indicating more severe symptoms and a higher disease burden. The change from baseline in weekly mean scores was summarized. A negative change from baseline indicates a lower disease burden. Baseline of weekly mean score was defined as average of daily scores collected within 7 days before start of study treatment (mitapivat). For Cohort 1, last measurement before the start of study treatment in AG348-C-011 was used as baseline; if baseline was missing, then baseline value from AG348-C-006 was used. For Cohorts 2 & 3 baseline values from -006 and-007, respectively, were used.

PKDIA is a 12-item PRO measure of common impacts of PK deficiency on activities of daily living. Participants rated how PK deficiency has impacted aspects of daily living in past 7 days, including impacts on relationships & leisure and social, mental, and physical activities. PKDIA score at each visit was based on 8 items that were retained after in-trial psychometric validation and calculated at each visit based on participant's response to PKDIA questionnaire. Score ranges from 30 to 76, with higher scores indicating higher disease burden. Negative change from baseline indicates lower disease burden. Baseline was defined as the last complete assessment (with no missing item in response) before start of study treatment. For Cohort 1, last measurement before start of study treatment in AG348-C-011 was used as baseline; if baseline was missing, then baseline value from AG348-C-006 was used. For Cohorts 2 and 3, the baseline values from 006 and 007, respectively, were used.