Pyruvate Kinase Deficiency
Conditions
Brief summary
This is an open-label, multicenter, extension study to evaluate the long-term safety, tolerability, and efficacy of treatment with mitapivat in participants who were previously enrolled in Study AG348-C-006 or Study AG348-C-007.
Interventions
DRUGMitapivat
Tablets
Sponsors
Agios Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Be willing and able to comply with study visits and procedures. * Have signed written informed consent prior to participating in this extension study. * Have completed either antecedent study AG348-C-006 or AG348-C-007 through the Part 2 Week 24 Visit. * Cohorts 2 and 3: Have demonstrated clinical benefit from mitapivat treatment in the antecedent study, in the opinion of the Investigator. * For women of reproductive potential, have a negative pregnancy test during screening of this extension study. * 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 drug for women and 90 days following the last dose of study drug for men.
Exclusion criteria
* Have a significant medical condition (including clinically significant laboratory abnormality) that developed during his/her antecedent AG- 348 study that confers an unacceptable risk to participating in this extension study, that could confound the interpretation of the study data, and/or that compromises the ability of the participant to complete study visits and procedures. * Are currently pregnant or breastfeeding. * Have a splenectomy scheduled during the study treatment period. * Meet the withdrawal criteria of his/her antecedent mitapivat study during screening of this extension study. * Are currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4 that have not been stopped for a duration of at least 5 days or a time frame equivalent to 5 half-lives (whichever is longer) before start of study drug; or strong inducers of CYP3A4 that have not been stopped for a duration of at least 28 days or a time frame equivalent to 5 half-lives (whichever is longer) before start of study drug on this extension study. * Have received anabolic steroids, including testosterone preparations, within 28 days prior to start of study drug on this extension study. * Have received hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony stimulating factors, thrombopoietins) within 28 days prior to start of study drug on this extension study. * Have exposure to any investigational drug other than mitapivat, device, or procedure within 3 months prior to start of study drug on this extension study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Up to 197 weeks | 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. |
| All Cohorts: Number of Participants With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation | Up to 197 weeks | 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. |
| All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Up to 197 weeks | 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. |
| All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs | Up to 197 weeks | 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. |
| All Cohorts: Number of Participants With Clinically Significant Abnormalities in Bone Mineral Density (BMD) | Up to 192 weeks | 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. |
| All Cohorts: Change From Baseline in Adjusted Spine T-score | Baseline, Week 192 | 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. |
| All Cohorts: Change From Baseline in Adjusted Spine Z-score | Baseline, Week 192 | 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. |
| All Cohorts: Change From Baseline in Femoral Total T-score | Baseline, Week 192 | 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. |
| All Cohorts: Change From Baseline in Femoral Total Z-score | Baseline, Week 192 | 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. |
| All Cohorts: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters Reported as TEAEs | Up to 197 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohorts 1 and 2: Change From Baseline in Indirect Bilirubin | Baseline, Week 192 | 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. |
| Cohorts 1 and 2: Change From Baseline in Lactate Dehydrogenase (LDH) | Baseline, Week 192 | 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. |
| Cohorts 1 and 2: Change From Baseline in Haptoglobin Levels | Baseline, Week 192 | 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. |
| Cohorts 1 and 2: Change From Baseline in Reticulocytes/Erythrocytes Ratio | Baseline, Week 192 | 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. |
| Cohort 1: Percentage of Participants Who Achieved a Hemoglobin (Hb) Response | Baseline up to Week 24 | 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. |
| Cohort 3: Change From Baseline in Number of Red Blood Cell (RBC) Units Transfused | Baseline, Week 192 | 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. |
| All Cohorts: Change From Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD) | Baseline, Week 24 | 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. |
| All Cohorts: Change From Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA) | Baseline, Week 24 | 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. |
| Cohort 3: Change From Baseline in Number of Transfusion Episodes | Baseline, Week 192 | 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. |
| Cohort 1: Average Change From Baseline in Hb Concentration at Weeks 16, 20, and 24 | Baseline, Weeks 16, 20, and 24 | 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. |
| Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to 8-hours Post-dose (AUC0-8) of Mitapivat | Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12 | — |
| Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Mitapivat | Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12 | — |
| Cohort 1: Maximum Observed Plasma Concentration (Cmax) of Mitapivat | Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12 | — |
| Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat | Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12 | — |
| Cohort 1: Time of Last Quantifiable Concentration (Tlast) of Mitapivat | Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12 | — |
| Cohort 1: Plasma Concentration (Ctrough) at the End of a Dosing Interval of Mitapivat | Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12 | — |
| Cohort 1: Exposure-response (E-R) Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters | First dose to up to 24 weeks | — |
| Cohorts 1 and 2: Change From Baseline in Hb Concentration | Baseline, Week 192 | 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. |
Countries
Brazil, Canada, Denmark, France, Germany, Ireland, Italy, Japan, Netherlands, South Korea, Spain, Switzerland, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at 42 investigative sites in Denmark, France, Italy, Spain, Germany, United Kingdom, Netherlands, Ireland, Switzerland, United States, Canada, Japan, Korea, Thailand, Brazil and Turkey from 21 March 2019 to 03 July 2024.
Pre-assignment details
A total of 90 participants who had completed Study AG348-C-006 (NCT03548220) or AG348-C-007 (NCT03559699), were enrolled in this extension study to receive mitapivat treatment. Participants were assigned to Cohorts 1, 2 or 3 depending on the previous treatment received in the antecedent studies.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Participants who received placebo in Study AG348-C-006 and met the eligibility criteria of this extension study were enrolled to receive mitapivat tablets, 5 mg, BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined at Week 12, and participants then received that optimized dose for a period of 12 weeks (Weeks 13-24) as a fixed dose and from Week 25 to Week 193, until study withdrawal, or the study was closed. | 38 |
| Cohort 2 Participants who received mitapivat at a dose of 5 mg, 20 mg, or 50 mg, BID, in the fixed dose period of Study AG348-C-006 and met the eligibility criteria of this extension study continued to receive the same mitapivat dose up to Week 193 or until study withdrawal, or the study was closed. | 35 |
| Cohort 3 Participants who received mitapivat at a dose of 5 mg, 20 mg, or 50 mg, BID, in the fixed dose period of Study AG348-C-007 and met the eligibility criteria of this extension study continued to receive the same mitapivat dose up to Week 193 or until study withdrawal, or the study was closed. | 17 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Approved Drug Available for Indication | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Other un-specified | 0 | 0 | 2 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 4 | 0 | 0 | 5 | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Total | Cohort 3 |
|---|---|---|---|---|
| Adjusted Spine: T-Score | -1.143 T-score STANDARD_DEVIATION 1.0926 | -1.808 T-score STANDARD_DEVIATION 1.1589 | -1.400 T-score STANDARD_DEVIATION 1.144 | -1.161 T-score STANDARD_DEVIATION 1.0469 |
| Adjusted Spine: Z-score | -0.804 Z-score STANDARD_DEVIATION 1.2529 | -1.536 Z-score STANDARD_DEVIATION 1.2469 | -1.092 Z-score STANDARD_DEVIATION 1.2506 | -0.848 Z-score STANDARD_DEVIATION 1.042 |
| Age, Continuous | 38.0 Years STANDARD_DEVIATION 15.95 | 36.9 Years STANDARD_DEVIATION 15.77 | 37.4 Years STANDARD_DEVIATION 15.56 | 36.9 Years STANDARD_DEVIATION 15.09 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 23 Participants | 68 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 10 Participants | 19 Participants | 5 Participants |
| Femoral Total: T-score | -0.834 T-score STANDARD_DEVIATION 1.1182 | -1.139 T-score STANDARD_DEVIATION 1.0995 | -0.946 T-score STANDARD_DEVIATION 1.0416 | -0.813 T-score STANDARD_DEVIATION 0.6748 |
| Femoral Total: Z-score | -0.548 Z-score STANDARD_DEVIATION 1.1574 | -0.916 Z-score STANDARD_DEVIATION 1.0657 | -0.685 Z-score STANDARD_DEVIATION 1.056 | -0.529 Z-score STANDARD_DEVIATION 0.7137 |
| Race/Ethnicity, Customized Asian | 3 Participants | 5 Participants | 10 Participants | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not reported | 3 Participants | 6 Participants | 11 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 31 Participants | 23 Participants | 67 Participants | 13 Participants |
| Sex: Female, Male Female | 23 Participants | 20 Participants | 55 Participants | 12 Participants |
| Sex: Female, Male Male | 15 Participants | 15 Participants | 35 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 | 0 / 36 | 0 / 2 | 0 / 3 | 1 / 30 | 0 / 0 | 0 / 1 | 0 / 16 |
| other Total, other adverse events | 0 / 1 | 1 / 1 | 35 / 36 | 2 / 2 | 2 / 3 | 27 / 30 | 0 / 0 | 1 / 1 | 14 / 16 |
| serious Total, serious adverse events | 1 / 1 | 0 / 1 | 10 / 36 | 0 / 2 | 2 / 3 | 6 / 30 | 0 / 0 | 0 / 1 | 4 / 16 |
Outcome results
Primary
All Cohorts: Change From Baseline in Adjusted Spine T-score
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.
Time frame: Baseline, Week 192
Population: The safety analysis set included all participants who received at least 1 dose of study treatment. Here, overall number of participants analyzed indicates the number of participants who were evaluable for this OM. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent studies AG348-C-006 (NCT03548220) and AG348-C-007 (NCT03559699), it was pre-specified in the SAP to report data for this OM by Cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | All Cohorts: Change From Baseline in Adjusted Spine T-score | 0.046 T-score | Standard Deviation 0.4874 |
| Cohort 2 | All Cohorts: Change From Baseline in Adjusted Spine T-score | 0.234 T-score | Standard Deviation 0.4383 |
| Cohort 3 | All Cohorts: Change From Baseline in Adjusted Spine T-score | 0.416 T-score | Standard Deviation 1.109 |
Primary
All Cohorts: Change From Baseline in Adjusted Spine Z-score
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.
Time frame: Baseline, Week 192
Population: The safety analysis set included all participants who received at least 1 dose of study treatment. Here, overall number of participants analyzed indicates the number of participants who were evaluable for this OM. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent studies AG348-C-006 (NCT03548220) and AG348-C-007 (NCT03559699), it was pre-specified in the SAP to report data for this OM by Cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | All Cohorts: Change From Baseline in Adjusted Spine Z-score | 0.152 Z-score | Standard Deviation 0.4585 |
| Cohort 2 | All Cohorts: Change From Baseline in Adjusted Spine Z-score | 0.332 Z-score | Standard Deviation 0.4002 |
| Cohort 3 | All Cohorts: Change From Baseline in Adjusted Spine Z-score | 0.530 Z-score | Standard Deviation 1.2409 |
Primary
All Cohorts: Change From Baseline in Femoral Total T-score
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.
Time frame: Baseline, Week 192
Population: The safety analysis set included all participants who received at least 1 dose of study treatment. Here, overall number of participants analyzed indicates the number of participants who were evaluable for this OM. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent studies AG348-C-006 (NCT03548220) and AG348-C-007 (NCT03559699), it was pre-specified in the SAP to report data for this OM by Cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | All Cohorts: Change From Baseline in Femoral Total T-score | -0.020 T-score | Standard Deviation 0.2612 |
| Cohort 2 | All Cohorts: Change From Baseline in Femoral Total T-score | 0.047 T-score | Standard Deviation 0.3893 |
| Cohort 3 | All Cohorts: Change From Baseline in Femoral Total T-score | 0.114 T-score | Standard Deviation 0.505 |
Primary
All Cohorts: Change From Baseline in Femoral Total Z-score
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.
Time frame: Baseline, Week 192
Population: The safety analysis set included all participants who received at least 1 dose of study treatment. Here, overall number of participants analyzed indicates the number of participants who were evaluable for this OM. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent studies AG348-C-006 (NCT03548220) and AG348-C-007 (NCT03559699), it was pre-specified in the SAP to report data for this OM by Cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | All Cohorts: Change From Baseline in Femoral Total Z-score | 0.054 Z- score | Standard Deviation 0.2468 |
| Cohort 2 | All Cohorts: Change From Baseline in Femoral Total Z-score | 0.126 Z- score | Standard Deviation 0.3631 |
| Cohort 3 | All Cohorts: Change From Baseline in Femoral Total Z-score | 0.214 Z- score | Standard Deviation 0.5099 |
Primary
All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3
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.
Time frame: Up to 197 weeks
Population: The safety analysis set included all participants who received at least 1 dose of study treatment. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent studies AG348-C-006 (NCT03548220) and AG348-C-007 (NCT03559699), it was pre-specified in the SAP to report data for this outcome measure (OM) by Cohort.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with TEAEs | 37 Participants |
| Cohort 1 | All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with TEAEs related to study drug | 22 Participants |
| Cohort 1 | All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with Serious TEAEs | 11 Participants |
| Cohort 1 | All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with any TEAE of Grade ≥ 3 | 16 Participants |
| Cohort 2 | All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with TEAEs | 33 Participants |
| Cohort 2 | All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with Serious TEAEs | 8 Participants |
| Cohort 2 | All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with TEAEs related to study drug | 14 Participants |
| Cohort 2 | All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with any TEAE of Grade ≥ 3 | 10 Participants |
| Cohort 3 | All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with Serious TEAEs | 4 Participants |
| Cohort 3 | All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with TEAEs | 15 Participants |
| Cohort 3 | All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with any TEAE of Grade ≥ 3 | 5 Participants |
| Cohort 3 | All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with TEAEs related to study drug | 4 Participants |
Primary
All Cohorts: Number of Participants With Clinically Significant Abnormalities in Bone Mineral Density (BMD)
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.
Time frame: Up to 192 weeks
Population: The safety analysis set included all participants who received at least 1 dose of study treatment. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent studies AG348-C-006 (NCT03548220) and AG348-C-007 (NCT03559699), it was pre-specified in the SAP to report data for this OM by Cohort.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Bone Mineral Density (BMD) | 0 Participants |
| Cohort 2 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Bone Mineral Density (BMD) | 1 Participants |
| Cohort 3 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Bone Mineral Density (BMD) | 0 Participants |
Primary
All Cohorts: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters Reported as TEAEs
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.
Time frame: Up to 197 weeks
Population: The safety analysis set included all participants who received at least 1 dose of study treatment. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent studies AG348-C-006 (NCT03548220) and AG348-C-007 (NCT03559699), it was pre-specified in the SAP to report data for this OM by Cohort.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters Reported as TEAEs | 0 Participants |
| Cohort 2 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters Reported as TEAEs | 1 Participants |
| Cohort 3 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters Reported as TEAEs | 0 Participants |
Primary
All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs
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.
Time frame: Up to 197 weeks
Population: The safety analysis set included all participants who received at least 1 dose of study treatment. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent studies AG348-C-006 (NCT03548220) and AG348-C-007 (NCT03559699), it was pre-specified in the SAP to report data for this OM by Cohort.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Anaemia | 3 Participants |
| Cohort 1 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Blood triglycerides increased | 1 Participants |
| Cohort 1 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Haemolysis | 1 Participants |
| Cohort 1 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Alanine aminotransferase increased | 0 Participants |
| Cohort 1 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Hypertriglyceridaemia | 1 Participants |
| Cohort 1 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Aspartate aminotransferase increased | 2 Participants |
| Cohort 1 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Blood bilirubin increased | 0 Participants |
| Cohort 2 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Aspartate aminotransferase increased | 1 Participants |
| Cohort 2 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Blood bilirubin increased | 0 Participants |
| Cohort 2 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Alanine aminotransferase increased | 0 Participants |
| Cohort 2 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Haemolysis | 2 Participants |
| Cohort 2 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Blood triglycerides increased | 0 Participants |
| Cohort 2 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Hypertriglyceridaemia | 0 Participants |
| Cohort 2 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Anaemia | 1 Participants |
| Cohort 3 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Hypertriglyceridaemia | 0 Participants |
| Cohort 3 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Blood triglycerides increased | 0 Participants |
| Cohort 3 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Anaemia | 0 Participants |
| Cohort 3 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Haemolysis | 0 Participants |
| Cohort 3 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Alanine aminotransferase increased | 1 Participants |
| Cohort 3 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Aspartate aminotransferase increased | 1 Participants |
| Cohort 3 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs | Blood bilirubin increased | 1 Participants |
Primary
All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs
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.
Time frame: Up to 197 weeks
Population: The safety analysis set included all participants who received at least 1 dose of study treatment. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent studies AG348-C-006 (NCT03548220) and AG348-C-007 (NCT03559699), it was pre-specified in the SAP to report data for this OM by Cohort.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs | Hypotension | 1 Participants |
| Cohort 1 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs | Weight decreased | 0 Participants |
| Cohort 1 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs | Hypertension | 1 Participants |
| Cohort 1 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs | Hot flush | 2 Participants |
| Cohort 2 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs | Hypotension | 0 Participants |
| Cohort 2 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs | Hot flush | 0 Participants |
| Cohort 2 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs | Weight decreased | 1 Participants |
| Cohort 2 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs | Hypertension | 2 Participants |
| Cohort 3 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs | Hot flush | 2 Participants |
| Cohort 3 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs | Weight decreased | 1 Participants |
| Cohort 3 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs | Hypertension | 0 Participants |
| Cohort 3 | All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs | Hypotension | 0 Participants |
Primary
All Cohorts: Number of Participants With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation
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.
Time frame: Up to 197 weeks
Population: The safety analysis set included all participants who received at least 1 dose of study treatment. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent studies AG348-C-006 (NCT03548220) and AG348-C-007 (NCT03559699), it was pre-specified in the SAP to report data for this OM by Cohort.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | All Cohorts: Number of Participants With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation | Participants with TEAEs Leading to Interruption | 3 Participants |
| Cohort 1 | All Cohorts: Number of Participants With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation | Participants with TEAEs Leading to Dose Reduction | 2 Participants |
| Cohort 1 | All Cohorts: Number of Participants With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation | Participants with TEAEs Leading to Discontinuation | 2 Participants |
| Cohort 2 | All Cohorts: Number of Participants With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation | Participants with TEAEs Leading to Interruption | 4 Participants |
| Cohort 2 | All Cohorts: Number of Participants With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation | Participants with TEAEs Leading to Dose Reduction | 2 Participants |
| Cohort 2 | All Cohorts: Number of Participants With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation | Participants with TEAEs Leading to Discontinuation | 1 Participants |
| Cohort 3 | All Cohorts: Number of Participants With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation | Participants with TEAEs Leading to Dose Reduction | 1 Participants |
| Cohort 3 | All Cohorts: Number of Participants With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation | Participants with TEAEs Leading to Discontinuation | 0 Participants |
| Cohort 3 | All Cohorts: Number of Participants With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation | Participants with TEAEs Leading to Interruption | 0 Participants |
Secondary
All Cohorts: Change From Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD)
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.
Time frame: Baseline, Week 24
Population: FAS included all participants who received at least 1 dose of study treatment. Here, overall number of participants analyzed indicates the number of participants who were evaluable for this OM. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent studies AG348-C-006 (NCT03548220) and AG348-C-007 (NCT03559699), it was pre-specified in the SAP to report data for this OM by Cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | All Cohorts: Change From Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD) | -3.75 score on a scale | Standard Deviation 5.805 |
| Cohort 2 | All Cohorts: Change From Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD) | -6.09 score on a scale | Standard Deviation 7.617 |
| Cohort 3 | All Cohorts: Change From Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD) | -5.04 score on a scale | Standard Deviation 12.273 |
Secondary
All Cohorts: Change From Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA)
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.
Time frame: Baseline, Week 24
Population: FAS included all participants who received at least 1 dose of study treatment. Here, overall number of participants analyzed indicates the number of participants who were evaluable for this OM. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent studies AG348-C-006 (NCT03548220) and AG348-C-007 (NCT03559699), it was pre-specified in the SAP to report data for this OM by Cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | All Cohorts: Change From Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA) | -3.9 score on a scale | Standard Deviation 7.38 |
| Cohort 2 | All Cohorts: Change From Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA) | -6.6 score on a scale | Standard Deviation 8.75 |
| Cohort 3 | All Cohorts: Change From Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA) | -5.4 score on a scale | Standard Deviation 12.83 |
Secondary
Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to 8-hours Post-dose (AUC0-8) of Mitapivat
Time frame: Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12
Population: PK analysis population: all participants who were enrolled \& received at least 1 dose of mitapivat with at least 1 nonzero plasma concentration of mitapivat at Week 12 visit. Overall number of participants analyzed: number of participants who received 50 mg BID mitapivat in Cohort 1 and were evaluable for this OM. As per planned analysis, data for this OM was reported by cohort and for Cohort 1 only based on FAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to 8-hours Post-dose (AUC0-8) of Mitapivat | 3016 hour*nanograms per milliliter (hr*ng/mL) | Geometric Coefficient of Variation 27.5 |
Secondary
Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Mitapivat
Time frame: Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12
Population: PK analysis population: all participants who were enrolled \& received at least 1 dose of mitapivat with at least 1 nonzero plasma concentration of mitapivat at Week 12 visit. Overall number of participants analyzed: number of participants who received 50 mg BID mitapivat in Cohort 1 and were evaluable for this OM. As per planned analysis, data for this OM was reported by cohort and for Cohort 1 only based on FAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Mitapivat | 2990 hr*ng/mL | Geometric Coefficient of Variation 26.3 |
Secondary
Cohort 1: Average Change From Baseline in Hb Concentration at Weeks 16, 20, and 24
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.
Time frame: Baseline, Weeks 16, 20, and 24
Population: FAS included all participants who received at least 1 dose of study treatment. Overall number of participants analyzed indicates number of participants were evaluable for this OM. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent study AG348-C-006 (NCT03548220), it was pre-specified in the SAP to report data for this OM by Cohort. As per planned analysis, data for this OM was reported for Cohort 1 only based on FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Cohort 1: Average Change From Baseline in Hb Concentration at Weeks 16, 20, and 24 | 16.45 grams per liter | Standard Deviation 15.634 |
Secondary
Cohort 1: Exposure-response (E-R) Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters
Time frame: First dose to up to 24 weeks
Population: After the dose optimization period, the 5 mg and 20 mg doses each had a single participant and the 50 mg dose had 36 participants. The exposure-relationship analysis planned cannot be performed with a single participant in multiple groups.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 | Cohort 1: Exposure-response (E-R) Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters | NA Percent probability |
| Cohort 2 | Cohort 1: Exposure-response (E-R) Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters | NA Percent probability |
| Cohort 3 | Cohort 1: Exposure-response (E-R) Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters | NA Percent probability |
Secondary
Cohort 1: Maximum Observed Plasma Concentration (Cmax) of Mitapivat
Time frame: Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12
Population: PK analysis population: all participants who were enrolled \& received at least 1 dose of mitapivat with at least 1 nonzero plasma concentration of mitapivat at Week 12 visit. Overall number of participants analyzed: number of participants who received 50 mg BID mitapivat in Cohort 1 and were evaluable for this OM. As per planned analysis, data for this OM was reported by cohort and for Cohort 1 only based on FAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Cohort 1: Maximum Observed Plasma Concentration (Cmax) of Mitapivat | 1018 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 22.5 |
Secondary
Cohort 1: Percentage of Participants Who Achieved a Hemoglobin (Hb) Response
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.
Time frame: Baseline up to Week 24
Population: FAS included all participants who received at least 1 dose of study treatment. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent Study AG348-C-006 (NCT03548220), it was pre-specified in the SAP to report data for this OM by Cohort. As per planned analysis, data for this OM was reported for Cohort 1 only based on FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Cohort 1: Percentage of Participants Who Achieved a Hemoglobin (Hb) Response | 39.5 percentage of participants |
Secondary
Cohort 1: Plasma Concentration (Ctrough) at the End of a Dosing Interval of Mitapivat
Time frame: Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12
Population: PK analysis population: all participants who were enrolled \& received at least 1 dose of mitapivat with at least 1 nonzero plasma concentration of mitapivat at Week 12 visit. Overall number of participants analyzed: number of participants who received 50 mg BID mitapivat in Cohort 1 and were evaluable for this OM. As per planned analysis, data for this OM was reported by cohort and for Cohort 1 only based on FAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Cohort 1: Plasma Concentration (Ctrough) at the End of a Dosing Interval of Mitapivat | 62.8 ng/mL | Geometric Coefficient of Variation 72.7 |
Secondary
Cohort 1: Time of Last Quantifiable Concentration (Tlast) of Mitapivat
Time frame: Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12
Population: PK analysis population: all participants who were enrolled \& received at least 1 dose of mitapivat with at least 1 nonzero plasma concentration of mitapivat at Week 12 visit. Overall number of participants analyzed: number of participants who received 50 mg BID mitapivat in Cohort 1 and were evaluable for this OM. As per planned analysis, data for this OM was reported by cohort and for Cohort 1 only based on FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Cohort 1: Time of Last Quantifiable Concentration (Tlast) of Mitapivat | 7.61 hours |
Secondary
Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat
Time frame: Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12
Population: PK analysis population: all participants who were enrolled \& received at least 1 dose of mitapivat with at least 1 nonzero plasma concentration of mitapivat at Week 12 visit. Overall number of participants analyzed: number of participants who received 50 mg BID mitapivat in Cohort 1 and were evaluable for this OM. As per planned analysis, data for this OM was reported by cohort and for Cohort 1 only based on FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat | 1.00 hours |
Secondary
Cohort 3: Change From Baseline in Number of Red Blood Cell (RBC) Units Transfused
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.
Time frame: Baseline, Week 192
Population: FAS included all participants who received at least 1 dose of study treatment. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent study AG348-C-007 (NCT03559699), it was pre-specified in the SAP to report data for this OM by Cohort. As per planned analysis, data for this OM was reported for Cohort 3 only based on FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Cohort 3: Change From Baseline in Number of Red Blood Cell (RBC) Units Transfused | 7.25 number of RBC units transfused | Standard Deviation 7.915 |
Secondary
Cohort 3: Change From Baseline in Number of Transfusion Episodes
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.
Time frame: Baseline, Week 192
Population: FAS included all participants who received at least 1 dose of study treatment. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent study AG348-C-007 (NCT03559699), it was pre-specified in the SAP to report data for this OM by Cohort. As per planned analysis, data for this OM was reported for Cohort 3 only based on FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Cohort 3: Change From Baseline in Number of Transfusion Episodes | 4.14 number of transfusion episodes | Standard Deviation 5.487 |
Secondary
Cohorts 1 and 2: Change From Baseline in Haptoglobin Levels
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.
Time frame: Baseline, Week 192
Population: FAS included all participants who received at least 1 dose of study treatment. Here, overall number of participants analyzed indicates the number of participants who were evaluable for this OM. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent study AG348-C-006 (NCT03548220), it was pre-specified in the SAP to report data for this OM by Cohort. As per planned analysis, data for this OM was reported for Cohort 1 and 2 only based on FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Cohorts 1 and 2: Change From Baseline in Haptoglobin Levels | 0.254 grams per liter | Standard Deviation 0.434 |
| Cohort 2 | Cohorts 1 and 2: Change From Baseline in Haptoglobin Levels | 0.250 grams per liter | Standard Deviation 0.4689 |
Secondary
Cohorts 1 and 2: Change From Baseline in Hb Concentration
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.
Time frame: Baseline, Week 192
Population: FAS included all participants who received at least 1 dose of study treatment. Here, overall number of participants analyzed indicates the number of participants who were evaluable for this OM. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent study AG348-C-006 (NCT03548220), it was pre-specified in the SAP to report data for this OM by Cohort. As per planned analysis, data for this OM was reported for Cohort 1 and 2 only based on FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Cohorts 1 and 2: Change From Baseline in Hb Concentration | 22.39 grams per liter | Standard Deviation 21.211 |
| Cohort 2 | Cohorts 1 and 2: Change From Baseline in Hb Concentration | 21.32 grams per liter | Standard Deviation 20.721 |
Secondary
Cohorts 1 and 2: Change From Baseline in Indirect Bilirubin
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.
Time frame: Baseline, Week 192
Population: FAS included all participants who received at least 1 dose of study treatment. Here, overall number of participants analyzed indicates the number of participants who were evaluable for this OM. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent study AG348-C-006 (NCT03548220), it was pre-specified in the SAP to report data for this OM by Cohort. As per planned analysis, data for this OM was reported for Cohort 1 and 2 only based on FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Cohorts 1 and 2: Change From Baseline in Indirect Bilirubin | -57.50 micromoles per liter (μmol/L) | Standard Deviation 54.542 |
| Cohort 2 | Cohorts 1 and 2: Change From Baseline in Indirect Bilirubin | -36.73 micromoles per liter (μmol/L) | Standard Deviation 35.511 |
Secondary
Cohorts 1 and 2: Change From Baseline in Lactate Dehydrogenase (LDH)
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.
Time frame: Baseline, Week 192
Population: FAS included all participants who received at least 1 dose of study treatment. Here, overall number of participants analyzed indicates the number of participants who were evaluable for this OM. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent study AG348-C-006 (NCT03548220), it was pre-specified in the SAP to report data for this OM by Cohort. As per planned analysis, data for this OM was reported for Cohort 1 and 2 only based on FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Cohorts 1 and 2: Change From Baseline in Lactate Dehydrogenase (LDH) | -46.10 Units per Liter (U/L) | Standard Deviation 75.31 |
| Cohort 2 | Cohorts 1 and 2: Change From Baseline in Lactate Dehydrogenase (LDH) | -130.80 Units per Liter (U/L) | Standard Deviation 275.424 |
Secondary
Cohorts 1 and 2: Change From Baseline in Reticulocytes/Erythrocytes Ratio
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.
Time frame: Baseline, Week 192
Population: FAS included all participants who received at least 1 dose of study treatment. Here, overall number of participants analyzed indicates the number of participants who were evaluable for this OM. Due to limited number of participants with optimal dose of 5 mg or 20 mg in antecedent study AG348-C-006 (NCT03548220), it was pre-specified in the SAP to report data for this OM by Cohort. As per planned analysis, data for this OM was reported for Cohort 1 and 2 only based on FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Cohorts 1 and 2: Change From Baseline in Reticulocytes/Erythrocytes Ratio | -0.1696 Reticulocytes/Erythrocytes Ratio | Standard Deviation 0.16243 |
| Cohort 2 | Cohorts 1 and 2: Change From Baseline in Reticulocytes/Erythrocytes Ratio | -0.1565 Reticulocytes/Erythrocytes Ratio | Standard Deviation 0.14631 |