Trial Outcomes & Findings for A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-TDT) (NCT NCT04770779)

Last Updated: 2026-01-29

Results Overview

TRR is defined as ≥50% reduction in transfused red blood cells (RBC) units with a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline transfusion burden standardized to 12 weeks. Baseline transfusion burden standardized to 12 weeks= (12/24) × total number of RBC units transfused during 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 12 (Day 85) were considered nonresponders.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

258 participants

Primary outcome timeframe

Double-blind Period: Baseline through Week 48

Results posted on

2026-01-29

Participant Flow

Participants took part at 81 study sites in Malaysia,Taiwan,Thailand,Bulgaria,Brazil,Lebanon,Saudi Arabia,Turkey,United Arab Emirates,Canada, the United States,Denmark,France,Germany,Greece,Italy,Netherlands,Spain and the United Kingdom.Results are reported for 48-week DB period until primary completion date.Analysis of data for OLE period is still ongoing with anticipated completion in June 2029.Results for OLE period will be reported by June 2030.

A total of 305 participants with a diagnosis of Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-TDT) were screened. Of which, 258 were randomized and 257 received study treatment in this study.

Participant milestones

Participant milestones
Measure	Mitapivat Participants randomized to receive mitapivat 100 milligrams (mg), orally, twice daily (BID) for 48 weeks in double-blind period.	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in double-blind period.
Overall Study STARTED	171	87
Overall Study Safety Analysis Set	172	85
Overall Study COMPLETED	155	83
Overall Study NOT COMPLETED	16	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Mitapivat Participants randomized to receive mitapivat 100 milligrams (mg), orally, twice daily (BID) for 48 weeks in double-blind period.	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in double-blind period.
Overall Study Randomized, never treated	0	1
Overall Study Adverse Event	9	1
Overall Study Withdrawal by Subject	7	1
Overall Study Pregnancy	0	1

Baseline Characteristics

A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-TDT)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Mitapivat n=171 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in double-blind period.	Placebo n=87 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in double-blind period.	Total n=258 Participants Total of all reporting groups
Age, Continuous	35.8 years STANDARD_DEVIATION 11.61 • n=35 Participants	34.7 years STANDARD_DEVIATION 9.77 • n=4328 Participants	35.5 years STANDARD_DEVIATION 11.02 • n=8687 Participants
Sex: Female, Male Female	93 Participants n=35 Participants	43 Participants n=4328 Participants	136 Participants n=8687 Participants
Sex: Female, Male Male	78 Participants n=35 Participants	44 Participants n=4328 Participants	122 Participants n=8687 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=35 Participants	3 Participants n=4328 Participants	8 Participants n=8687 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	158 Participants n=35 Participants	79 Participants n=4328 Participants	237 Participants n=8687 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	8 Participants n=35 Participants	5 Participants n=4328 Participants	13 Participants n=8687 Participants
Race/Ethnicity, Customized White	99 Participants n=35 Participants	56 Participants n=4328 Participants	155 Participants n=8687 Participants
Race/Ethnicity, Customized Asian	56 Participants n=35 Participants	22 Participants n=4328 Participants	78 Participants n=8687 Participants
Race/Ethnicity, Customized Black or African American	1 Participants n=35 Participants	1 Participants n=4328 Participants	2 Participants n=8687 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=35 Participants	0 Participants n=4328 Participants	0 Participants n=8687 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=35 Participants	0 Participants n=4328 Participants	0 Participants n=8687 Participants
Race/Ethnicity, Customized Multiracial	2 Participants n=35 Participants	0 Participants n=4328 Participants	2 Participants n=8687 Participants
Race/Ethnicity, Customized Unknown	7 Participants n=35 Participants	3 Participants n=4328 Participants	10 Participants n=8687 Participants
Race/Ethnicity, Customized Not reported	6 Participants n=35 Participants	5 Participants n=4328 Participants	11 Participants n=8687 Participants

PRIMARY outcome

Timeframe: Double-blind Period: Baseline through Week 48

Population: FAS included all participants who were randomized.

Outcome measures

Outcome measures
Measure	Placebo n=87 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=171 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Percentage of Participants Who Achieved Transfusion Reduction Response (TRR)	12.6 percentage of participants	30.4 percentage of participants

SECONDARY outcome

Timeframe: Double-blind period: Baseline through Week 48

Population: FAS included all participants who were randomized.

TRR2, defined as a ≥50% reduction in transfused RBC units in any consecutive 24-week period through Week 48 compared with the 24-week baseline transfusion burden, is reported. Baseline transfusion burden standardized to 24 weeks is the total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 24 (Day 169) were considered nonresponders.

Outcome measures

Outcome measures
Measure	Placebo n=87 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=171 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Percentage of Participants Who Achieved TRR2	2.3 percentage of participants	13.5 percentage of participants

SECONDARY outcome

Timeframe: Double-blind period: Baseline up to Week 13 through Week 48

Population: FAS included all participants who were randomized.

TRR3, defined as a ≥33% reduction in transfused RBC units from Week 13 through Week 48 compared with the baseline transfusion burden standardized to 36 weeks, is reported. Baseline transfusion burden standardized to 36 weeks= (36/24) × total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 48 were considered nonresponders.

Outcome measures

Outcome measures
Measure	Placebo n=87 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=171 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Percentage of Participants Who Achieved TRR3	1.1 percentage of participants	14.6 percentage of participants

SECONDARY outcome

Timeframe: Double-blind period: Baseline up to Week 13 through Week 48

Population: FAS included all participants who were randomized.

TRR4, defined as a ≥50% reduction in transfused RBC units from Week 13 through Week 48 compared with the baseline transfusion burden standardized to 36 weeks, is reported. Baseline transfusion burden standardized to 36 weeks = (36/24) × total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 48 were considered nonresponders.

Outcome measures

Outcome measures
Measure	Placebo n=87 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=171 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Percentage of Participants Who Achieved TRR4	1.1 percentage of participants	7.6 percentage of participants

SECONDARY outcome

Timeframe: Double-blind Period: Baseline, Week 13 through Week 48

Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.

Transfusion burden from Week 13 through Week 48 standardized to 36 weeks is defined as number of transfused RBC units from Day 85 through Week 48 in the Double-blind Period ×36/(Number of days from Day 85 through Week 48 in the Double-blind Period/7). Baseline transfusion burden standardized to 36 weeks= (36/24)× is the total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or within 168 days before the start of study treatment for participants randomized and dosed.

Outcome measures

Outcome measures
Measure	Placebo n=83 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=155 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Percent Change From Baseline in Transfused RBC Units	3.32 percent change Standard Error 2.846	10.96 percent change Standard Error 2.149

SECONDARY outcome

Timeframe: Double-blind Period: Baseline through Week 48

Population: FAS included all participants who were randomized.

Transfusion-independence is defined as transfusion-free for ≥8 consecutive weeks through Week 48 in the double-blind period.

Outcome measures

Outcome measures
Measure	Placebo n=87 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=171 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Percentage of Participants Who Achieved Transfusion-Independence	1.1 percentage of participants	9.9 percentage of participants

SECONDARY outcome

Timeframe: Double-blind Period: Baseline through Week 48

Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.

Iron metabolism was assessed based on Iron levels.

Outcome measures

Outcome measures
Measure	Placebo n=75 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=149 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Change From Baseline in Iron Levels	2.06 micromoles per liter (µmol/L) Standard Error 1.280	-4.57 micromoles per liter (µmol/L) Standard Error 0.949

SECONDARY outcome

Timeframe: Double-blind Period: Baseline through Week 48

Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.

Iron metabolism was assessed based on serum ferritin levels.

Outcome measures

Outcome measures
Measure	Placebo n=75 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=148 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Change From Baseline in Serum Ferritin Levels	76.3 micrograms per liter (µg/L) Standard Error 119.84	45.3 micrograms per liter (µg/L) Standard Error 88.90

SECONDARY outcome

Timeframe: Double-blind Period: Baseline through Week 48

Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.

Iron metabolism was assessed based on total iron binding capacity.

Outcome measures

Outcome measures
Measure	Placebo n=41 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=80 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Change From Baseline in Total Iron Binding Capacity	-1.23 µmol/L Standard Error 5.053	-21.80 µmol/L Standard Error 3.597

SECONDARY outcome

Timeframe: Double-blind Period: Baseline through Week 48

Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.

Iron metabolism was assessed based on TSAT levels. Transferrin saturation is reported by dividing value of serum iron by total iron binding capacity.

Outcome measures

Outcome measures
Measure	Placebo n=40 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=80 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Change From Baseline in Transferrin Saturation (TSAT) Levels	-0.013 Ratio Standard Error 0.0371	0.079 Ratio Standard Error 0.0261

SECONDARY outcome

Timeframe: Double-blind Period: From first dose of study drug up to week 48

Population: Safety Analysis Set (SAS) included all participants who had received at least 1 dose of study treatment. Participants were classified according to the treatment received. If a participant was randomized to placebo and received at least 1 dose of mitapivat in the double-blind period, then the participant was classified to the mitapivat arm. One subject, randomized to placebo, received mitapivat and was classified in the mitapivat arm in the safety analysis set.

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and includes both serious \& 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.

Outcome measures

Outcome measures
Measure	Placebo n=85 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=172 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 Participants with TEAEs	71 Participants	155 Participants
Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 Participants with serious TEAEs	13 Participants	19 Participants
Double-blind Period: Number of Participants With 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	16 Participants	65 Participants
Double-blind Period: Number of Participants With 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	12 Participants	32 Participants

SECONDARY outcome

Timeframe: Open-Label Extension Period: From Week 48 up to end of study (approximately 5 years)

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and includes both serious \& non-serious TEAEs. Severity of abnormalities 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Double-blind Period: Pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36

Population: Pharmacokinetic (PK) Analysis Set included a subset of the safety analysis set and included all participants with at least 1 mitapivat plasma concentration measurement ≥ lower limit of quantification (LLQ). Number analyzed signifies those participants who were evaluable at specified time point.

Outcome measures

Outcome measures
Measure	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=165 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Plasma Concentrations of Mitapivat 7 Hours Post-dose at Week 36	—	221.78 nanograms per milliliter (ng/mL) Standard Deviation 172.845
Double-blind Period: Plasma Concentrations of Mitapivat Pre-dose at Week 24	—	96.55 nanograms per milliliter (ng/mL) Standard Deviation 184.835
Double-blind Period: Plasma Concentrations of Mitapivat Pre-dose at Week 36	—	129.31 nanograms per milliliter (ng/mL) Standard Deviation 260.610
Double-blind Period: Plasma Concentrations of Mitapivat 0.5 Hour Post-dose at Week 36	—	1282.21 nanograms per milliliter (ng/mL) Standard Deviation 1007.068
Double-blind Period: Plasma Concentrations of Mitapivat 1 Hour Post-dose at Week 36	—	1468.69 nanograms per milliliter (ng/mL) Standard Deviation 713.248
Double-blind Period: Plasma Concentrations of Mitapivat 3 Hours Post-dose at Week 36	—	765.32 nanograms per milliliter (ng/mL) Standard Deviation 372.719
Double-blind Period: Plasma Concentrations of Mitapivat 5 Hours Post-dose at Week 36	—	371.11 nanograms per milliliter (ng/mL) Standard Deviation 232.556
Double-blind Period: Plasma Concentrations of Mitapivat Pre-dose at Week 12	—	122.90 nanograms per milliliter (ng/mL) Standard Deviation 252.666

SECONDARY outcome

Timeframe: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36

Population: PK analysis set is a subset of the safety analysis set and included all participants with at least 1 plasma mitapivat concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.

Area under the concentration-time curve from time zero to Tlast on dosing day, calculated using the linear-log trapezoidal rule.

Outcome measures

Outcome measures
Measure	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=141 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of Mitapivat	—	4365.84 hoursnanograms per milliliter (hng/mL) Geometric Coefficient of Variation 35.9

SECONDARY outcome

Timeframe: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36

Outcome measures

Outcome measures
Measure	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=149 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat	—	1603.00 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 45.6

SECONDARY outcome

Timeframe: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36

Outcome measures

Outcome measures
Measure	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=149 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Time to Reach of Maximum Observed Plasma Concentration (Tmax) of Mitapivat	—	1.000 Hours Interval 0.42 to 5.0

SECONDARY outcome

Timeframe: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36

Outcome measures

Outcome measures
Measure	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=147 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Time of Last Quantifiable Concentration (Tlast) of Mitapivat	—	6.750 Hours Interval 4.83 to 7.17

SECONDARY outcome

Timeframe: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36

Clast is the last quantifiable concentration after a single dose or within the dosing interval (tau) for multiple doses.

Outcome measures

Outcome measures
Measure	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=147 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat	—	175.76 ng/mL Geometric Coefficient of Variation 85.1

SECONDARY outcome

Timeframe: Double-blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36

Population: Pharmacodynamic (PD) analysis set is a subset of the safety analysis set and included all participants with at least 1 blood 2,3-diphosphoglycerate (DPG) or ATP concentration measurement ≥ LLQ. Number analyzed signifies those participants who were evaluable at specified time point.

Outcome measures

Outcome measures
Measure	Placebo n=85 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=169 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) Pre-dose at Day 1	236.23 µg/mL Standard Deviation 47.368	224.33 µg/mL Standard Deviation 40.031
Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) Pre-dose at Week 12	204.19 µg/mL Standard Deviation 33.207	283.39 µg/mL Standard Deviation 59.217
Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) Pre-dose at Week 24	200.84 µg/mL Standard Deviation 30.333	279.16 µg/mL Standard Deviation 53.652
Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) Pre-dose at Week 36	210.47 µg/mL Standard Deviation 43.330	280.72 µg/mL Standard Deviation 61.834
Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) 0.5 Hour Post-dose at Week 36	206.83 µg/mL Standard Deviation 39.389	274.75 µg/mL Standard Deviation 63.513
Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) 1 Hour Post-dose at Week 36	209.92 µg/mL Standard Deviation 38.597	277.45 µg/mL Standard Deviation 58.668
Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) 3 Hours Post-dose at Week 36	213.63 µg/mL Standard Deviation 43.949	281.70 µg/mL Standard Deviation 61.262
Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) 5 Hours Post-dose at Week 36	208.18 µg/mL Standard Deviation 40.965	283.76 µg/mL Standard Deviation 61.216
Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) 7 Hours Post-dose at Week 36	212.02 µg/mL Standard Deviation 45.767	281.47 µg/mL Standard Deviation 57.163

SECONDARY outcome

Timeframe: Double-blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36

Population: PD analysis set is a subset of the safety analysis set and included all participants with at least 1 blood 2,3-diphosphoglycerate (2,3-DPG) or adenosine triphosphate (ATP) concentration measurement ≥LLQ. Number analyzed signifies those participants who were evaluable at specified time point.

Outcome measures

Outcome measures
Measure	Placebo n=85 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.	Mitapivat n=169 Participants Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.
Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) 1 Hour Post-dose at Week 36	368.67 µg/mL Standard Deviation 66.037	281.73 µg/mL Standard Deviation 80.276
Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) 3 Hours Post-dose at Week 36	383.00 µg/mL Standard Deviation 91.727	280.93 µg/mL Standard Deviation 76.916
Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) 5 Hours Post-dose at Week 36	359.09 µg/mL Standard Deviation 72.144	272.73 µg/mL Standard Deviation 65.327
Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) 7 Hours Post-dose at Week 36	369.19 µg/mL Standard Deviation 75.546	268.17 µg/mL Standard Deviation 65.942
Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) Pre-dose at Day 1	417.13 µg/mL Standard Deviation 87.448	426.67 µg/mL Standard Deviation 75.055
Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) Pre-dose at Week 12	365.88 µg/mL Standard Deviation 67.238	274.25 µg/mL Standard Deviation 76.114
Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) Pre-dose at Week 24	355.57 µg/mL Standard Deviation 59.420	275.60 µg/mL Standard Deviation 78.307
Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) Pre-dose at Week 36	368.81 µg/mL Standard Deviation 71.481	289.11 µg/mL Standard Deviation 78.658
Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) 0.5 Hour Post-dose at Week 36	367.74 µg/mL Standard Deviation 62.673	286.06 µg/mL Standard Deviation 73.409

Adverse Events

Mitapivat

Serious events: 19 serious events

Other events: 122 other events

Deaths: 0 deaths

Placebo

Serious events: 13 serious events

Other events: 50 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Agios Medical Affairs

Agios Pharmaceuticals, Inc.

Phone: 833-228-8474

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Mitapivat n=172 participants at risk Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in the double-blind period.	Placebo n=85 participants at risk Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the double-blind period.
General disorders Influenza like illness	5.2% 9/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	2.4% 2/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Infections and infestations Upper respiratory tract infection	15.7% 27/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	16.5% 14/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Infections and infestations Influenza	8.1% 14/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	4.7% 4/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Infections and infestations Nasopharyngitis	6.4% 11/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	4.7% 4/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Infections and infestations Urinary tract infection	6.4% 11/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	0.00% 0/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Infections and infestations COVID-19	4.7% 8/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	9.4% 8/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Nervous system disorders Headache	26.7% 46/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	11.8% 10/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
General disorders Fatigue	10.5% 18/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	2.4% 2/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
General disorders Pyrexia	9.9% 17/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	7.1% 6/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
General disorders Asthenia	5.8% 10/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	4.7% 4/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Gastrointestinal disorders Diarrhoea	11.0% 19/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	8.2% 7/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Gastrointestinal disorders Nausea	7.6% 13/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	5.9% 5/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Gastrointestinal disorders Vomiting	4.7% 8/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	8.2% 7/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Psychiatric disorders Initial insomnia	14.0% 24/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	4.7% 4/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Psychiatric disorders Middle insomnia	5.8% 10/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	3.5% 3/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Musculoskeletal and connective tissue disorders Arthralgia	7.6% 13/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	5.9% 5/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Musculoskeletal and connective tissue disorders Back pain	5.8% 10/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	4.7% 4/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Musculoskeletal and connective tissue disorders Myalgia	3.5% 6/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	5.9% 5/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.
Respiratory, thoracic and mediastinal disorders Cough	8.7% 15/172 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.	3.5% 3/85 • Double-blind period: From first dose of study drug up to week 48 AEs: Safety Analysis Set (SAS) was used. One participant, randomized to placebo, received mitapivat and is classified in the mitapivat arm in the SAS. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in June 2029. Results for OLE will be reported separately by June 2030.