Trial Outcomes & Findings for A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Non-Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-NTDT) (NCT NCT04770753)

Results Overview

Hb response is defined as ≥10 grams/ liter (g/L) (1.0 gram per deciliter) (g/dL) increase in average Hb concentration from Week 12 through Week 24 compared with baseline. Hb response was tested using the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors. Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

194 participants

Primary outcome timeframe

Double-Blind Period: Baseline up to Week 12 through Week 24

Results posted on

2026-01-29

Participant Flow

Participants took part in study at study sites in the United States of America, Brazil, Bulgaria, Canada, Denmark, France, Greece, Italy, Lebanon, Malaysia, Netherlands, Saudi Arabia, Spain, Taiwan, Thailand, Turkey, United Arab Emirates and the United Kingdom. Results are reported for 24-week DB period until primary completion date. Analysis of data for OLE period is still ongoing with anticipated completion in December 2028. Results for OLE period will be reported by December 2029.

A total of 235 participants with a diagnosis of Non-Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-NTDT) were screened. Of which, 194 were enrolled and 192 were treated in this study.

Participant milestones

Participant milestones
Measure	Mitapivat Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Overall Study STARTED	130	64
Overall Study Treated	129	63
Overall Study COMPLETED	122	62
Overall Study NOT COMPLETED	8	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Mitapivat Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Overall Study Randomized, never treated	1	1
Overall Study Withdrawal by Subject	3	1
Overall Study Adverse Event	2	0
Overall Study Pregnancy	1	0
Overall Study Other un-specified	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Mitapivat n=130 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=64 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.	Total n=194 Participants Total of all reporting groups
Age, Continuous	42.4 years STANDARD_DEVIATION 13.03 • n=35 Participants	38.9 years STANDARD_DEVIATION 12.99 • n=4328 Participants	41.2 years STANDARD_DEVIATION 13.09 • n=8687 Participants
Sex: Female, Male Female	84 Participants n=35 Participants	39 Participants n=4328 Participants	123 Participants n=8687 Participants
Sex: Female, Male Male	46 Participants n=35 Participants	25 Participants n=4328 Participants	71 Participants n=8687 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	11 Participants n=35 Participants	6 Participants n=4328 Participants	17 Participants n=8687 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	118 Participants n=35 Participants	58 Participants n=4328 Participants	176 Participants n=8687 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=35 Participants	0 Participants n=4328 Participants	1 Participants n=8687 Participants
Race/Ethnicity, Customized White	73 Participants n=35 Participants	36 Participants n=4328 Participants	109 Participants n=8687 Participants
Race/Ethnicity, Customized Asian	52 Participants n=35 Participants	24 Participants n=4328 Participants	76 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	1 Participants n=35 Participants	0 Participants n=4328 Participants	1 Participants n=8687 Participants
Race/Ethnicity, Customized Unknown	2 Participants n=35 Participants	2 Participants n=4328 Participants	4 Participants n=8687 Participants
Race/Ethnicity, Customized Not reported	1 Participants n=35 Participants	1 Participants n=4328 Participants	2 Participants n=8687 Participants

PRIMARY outcome

Timeframe: Double-Blind Period: Baseline up to Week 12 through Week 24

Population: FAS included all participants who were randomized.

Hb response is defined as ≥10 grams/ liter (g/L) (1.0 gram per deciliter) (g/dL) increase in average Hb concentration from Week 12 through Week 24 compared with baseline. Hb response was tested using the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors. Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.

Outcome measures

Outcome measures
Measure	Mitapivat n=130 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=64 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Percentage of Participants Who Achieved Hemoglobin (Hb) Response From Week 12 Through Week 24 Compared With Baseline	42.3 Percentage of participants	1.6 Percentage of participants

SECONDARY outcome

Timeframe: Double-Blind Period: Baseline, Week 12 through Week 24

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

The FACIT-Fatigue subscale includes a 13-item self-reported fatigue subscale, which assesses the severity and impact of fatigue (including the impact on daily activities and functioning).The FACIT-Fatigue subscale is scored on a 5-point Likert scale: 0 (not at all) to 4 (very much). The total FACIT-Fatigue subscale score ranges from 0 to 52, with a higher score indicating better health-related quality of life (HRQOL). Baseline is defined as the last assessment before randomization for subjects randomized and not dosed or the last assessment before start of study treatment for subjects randomized and dosed.

Outcome measures

Outcome measures
Measure	Mitapivat n=109 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=54 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Change From Baseline in Average Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue Subscale Score From Week 12 Through Week 24	4.85 score on a scale Standard Error 0.732	1.46 score on a scale Standard Error 0.955

SECONDARY outcome

Timeframe: Double-Blind Period: Baseline, Week 12 through Week 24

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

Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.

Outcome measures

Outcome measures
Measure	Mitapivat n=123 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=61 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Change From Baseline in Average Hb Concentration From Week 12 Through Week 24	8.57 Gram per Liter (g/L) Standard Error 0.666	-1.06 Gram per Liter (g/L) Standard Error 0.867

SECONDARY outcome

Timeframe: Double-Blind Period: Baseline up to Week 12 through Week 24

Population: FAS included all participants who were randomized.

Hb 1.5+ response is defined as a ≥1.5 g/dL increase in average Hb concentration from Week 12 through Week 24 compared with baseline. Hb 1.5+ response will be summarized using the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors. Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.

Outcome measures

Outcome measures
Measure	Mitapivat n=130 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=64 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Percentage of Participants Who Achieved Hb 1.5+ Response From Week 12 Through Week 24 Compared With Baseline	24.6 Percentage of participants	0 Percentage of participants

SECONDARY outcome

Timeframe: Double-Blind Period: Baseline, Week 24

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

Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.

Outcome measures

Outcome measures
Measure	Mitapivat n=116 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=54 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Change From Baseline in Indirect Bilirubin at Week 24	-10.65 Micromole per Liter (umol/L) Standard Error 1.047	-0.03 Micromole per Liter (umol/L) Standard Error 1.403

SECONDARY outcome

Timeframe: Double-Blind Period: Baseline, Week 24

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

Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.

Outcome measures

Outcome measures
Measure	Mitapivat n=116 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=54 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24	-30.07 Units per Liter (U/L) Standard Error 7.131	-5.79 Units per Liter (U/L) Standard Error 9.440

SECONDARY outcome

Timeframe: Double-Blind Period: Baseline, Week 24

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

Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.

Outcome measures

Outcome measures
Measure	Mitapivat n=115 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=55 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Change From Baseline in Haptoglobin at Week 24	-0.002 Gram per Liter (g/L) Standard Error 0.0145	0.017 Gram per Liter (g/L) Standard Error 0.0199

SECONDARY outcome

Timeframe: Double-Blind Period: Baseline, Week 24

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

Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.

Outcome measures

Outcome measures
Measure	Mitapivat n=86 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=37 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Change From Baseline in Reticulocytes at Week 24	-32.11 10^9 cells per liter (10^9 cells/L) Standard Error 10.600	-14.74 10^9 cells per liter (10^9 cells/L) Standard Error 14.932

SECONDARY outcome

Timeframe: Double-Blind Period: Baseline, Week 24

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

Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.

Outcome measures

Outcome measures
Measure	Mitapivat n=103 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=47 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Change From Baseline in Erythropoietin at Week 24	19.21 International units per Liter (IU/L) Standard Error 37.773	115.71 International units per Liter (IU/L) Standard Error 49.413

SECONDARY outcome

Timeframe: Double-Blind Period: At Weeks 12, 16, 20, and 24

Population: FAS included all participants who were randomized.

PGIS-Fatigue measured participants' perception of their fatigue severity (7-day recall) on a 4-point scale ranging from '1=none' to '4=severe'. A participant was considered to have achieved the PGIS-Fatigue response at Weeks 12, 16, 20, or 24, if their baseline to postbaseline score met one of the following conditions: 'none' at baseline to 'none' postbaseline; 'mild' to 'mild' or 'none'; 'moderate' to 'mild' or 'none'; or 'severe' to 'moderate', 'mild', or 'none'.

Outcome measures

Outcome measures
Measure	Mitapivat n=130 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=64 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24 At Week 16	63.1 percentage of participants	42.2 percentage of participants
Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24 At Week 12	65.4 percentage of participants	46.9 percentage of participants
Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24 At Week 20	61.5 percentage of participants	48.4 percentage of participants
Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24 At Week 24	62.3 percentage of participants	46.9 percentage of participants

SECONDARY outcome

Timeframe: Double-Blind Period: At Weeks 12, 16, 20, and 24

Population: FAS included all participants who were randomized.

The PGIC-Fatigue assesses change over time compared with baseline on a 5-point scale ranging from 0 to 4 where 0 indicates Much better and 4 as Much worse. A participant was considered to have achieved the PGIC-Fatigue response at Weeks 12, 16, 20, or 24 if their baseline PGIS and corresponding PGIC met one of the following conditions: if the PGIS at baseline was 'none' or 'mild' and PGIC at the visit was 'no change', 'a little better', or 'much better'; or if the PGIS at baseline was 'moderate' or 'severe' and PGIC at the visit was 'a little better' or 'much better'.

Outcome measures

Outcome measures
Measure	Mitapivat n=130 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=64 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24 At Week 16	71.5 percentage of participants	50.0 percentage of participants
Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24 At Week 20	66.2 percentage of participants	56.3 percentage of participants
Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24 At Week 12	71.5 percentage of participants	53.1 percentage of participants
Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24 At Week 24	66.2 percentage of participants	53.1 percentage of participants

SECONDARY outcome

Timeframe: Double-Blind Period: Baseline, Week 24

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

The 6MWT is a well-established performance outcome (PerfO) measure that is widely used to evaluate physical activity in terms of distance walked in patients with a variety of conditions. The test measures the distance an individual can walk on a hard, flat surface in 6 minutes.

Outcome measures

Outcome measures
Measure	Mitapivat n=107 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=57 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 24	30.48 Meters Standard Error 5.651	7.11 Meters Standard Error 7.346

SECONDARY outcome

Timeframe: Double-Blind Period: Baseline, Week 24

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	Mitapivat n=116 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=56 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Change From Baseline in Serum Ferritin at Week 24	-34.75 Microgram/Liter (mcg/L) Standard Error 32.710	-32.48 Microgram/Liter (mcg/L) Standard Error 43.090

SECONDARY outcome

Timeframe: Double-Blind Period: Baseline, Week 24

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	Mitapivat n=72 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=40 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Change From Baseline in Transferrin Saturation (TSAT) at Week 24	-0.029 Ratio Standard Error 0.0212	-0.047 Ratio Standard Error 0.0262

SECONDARY outcome

Timeframe: Double-Blind Period: From the time of signing informed consent to Week 24

Population: Safety Analysis Set (SAS) includes 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.

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	Mitapivat n=129 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=63 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension 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	107 Participants	50 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	8 Participants	0 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	56 Participants	13 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	18 Participants	2 Participants

SECONDARY outcome

Timeframe: Double-Blind Period: Pre-dose at Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20

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

Outcome measures

Outcome measures
Measure	Mitapivat n=124 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Plasma Concentration of Mitapivat Pre-dose at Week 12	59.23 nanograms per milliliter (ng/mL) Standard Deviation 51.081	—
Double-Blind Period: Plasma Concentration of Mitapivat Pre-dose at Week 20	84.70 nanograms per milliliter (ng/mL) Standard Deviation 138.852	—
Double-Blind Period: Plasma Concentration of Mitapivat 30 Minutes Post-dose at Week 20	1209.00 nanograms per milliliter (ng/mL) Standard Deviation 931.211	—
Double-Blind Period: Plasma Concentration of Mitapivat 1 Hour Post-dose at Week 20	1386.35 nanograms per milliliter (ng/mL) Standard Deviation 712.996	—
Double-Blind Period: Plasma Concentration of Mitapivat 3 Hour Post-dose at Week 20	740.26 nanograms per milliliter (ng/mL) Standard Deviation 357.660	—
Double-Blind Period: Plasma Concentration of Mitapivat 5 Hour Post-dose at Week 20	359.42 nanograms per milliliter (ng/mL) Standard Deviation 269.758	—
Double-Blind Period: Plasma Concentration of Mitapivat 7 Hour Post-dose at Week 20	206.82 nanograms per milliliter (ng/mL) Standard Deviation 185.657	—

SECONDARY outcome

Timeframe: Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20

Population: Pharmacokinetic (PK) Analysis Set included a subset of the safety analysis set including all subjects with at least 1 mitapivat plasma 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	Mitapivat n=114 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of Mitapivat	4262.57 Hoursnanogram per milliliter (hng/mL) Geometric Coefficient of Variation 31.4	—

SECONDARY outcome

Timeframe: Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20

Population: Pharmacokinetic (PK) Analysis Set included a subset of the safety analysis set including all subjects with at least 1 mitapivat plasma concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Mitapivat n=114 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Time of Last Quantifiable Concentration (Tlast) of Mitapivat	6.825 hours Interval 6.5 to 7.42	—

SECONDARY outcome

Timeframe: Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20

Population: Pharmacokinetic (PK) Analysis Set included a subset of the safety analysis set including all subjects with at least 1 mitapivat plasma concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Mitapivat n=121 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat	1565.69 ng/mL Geometric Coefficient of Variation 42.4	—

SECONDARY outcome

Timeframe: Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20

Population: Pharmacokinetic (PK) Analysis Set included a subset of the safety analysis set including all subjects with at least 1 mitapivat plasma concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Mitapivat n=121 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat	1.000 Hours Interval 0.2 to 5.0	—

SECONDARY outcome

Timeframe: Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20

Population: Pharmacokinetic (PK) Analysis Set included a subset of the safety analysis set including all subjects with at least 1 mitapivat plasma concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Mitapivat n=121 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat	166.93 ng/mL Geometric Coefficient of Variation 80.1	—

SECONDARY outcome

Timeframe: Double-Blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20

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

Outcome measures

Outcome measures
Measure	Mitapivat n=122 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=59 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) At Pre-dose at Day 1	180.87 microgram/milliliter (mcg/mL) Standard Deviation 29.577	184.91 microgram/milliliter (mcg/mL) Standard Deviation 31.299
Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) Pre-dose at Week 12	242.07 microgram/milliliter (mcg/mL) Standard Deviation 45.782	176.81 microgram/milliliter (mcg/mL) Standard Deviation 33.657
Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) Pre-dose at Week 20	235.79 microgram/milliliter (mcg/mL) Standard Deviation 46.099	168.10 microgram/milliliter (mcg/mL) Standard Deviation 29.962
Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) 30 Minutes Post-dose at Week 20	417.87 microgram/milliliter (mcg/mL) Standard Deviation 102.853	457.78 microgram/milliliter (mcg/mL) Standard Deviation 89.932
Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) 1 Hour Post-dose at Week 20	417.83 microgram/milliliter (mcg/mL) Standard Deviation 105.752	457.71 microgram/milliliter (mcg/mL) Standard Deviation 104.431
Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) 3 Hour Post-dose at Week 20	409.73 microgram/milliliter (mcg/mL) Standard Deviation 96.379	454.39 microgram/milliliter (mcg/mL) Standard Deviation 107.966
Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) 5 Hour Post-dose at Week 20	412.72 microgram/milliliter (mcg/mL) Standard Deviation 94.150	464.24 microgram/milliliter (mcg/mL) Standard Deviation 97.007
Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP) 7 Hour Post-dose at Week 20	404.43 microgram/milliliter (mcg/mL) Standard Deviation 97.586	471.10 microgram/milliliter (mcg/mL) Standard Deviation 113.165

SECONDARY outcome

Timeframe: Double-Blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20

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

Outcome measures

Outcome measures
Measure	Mitapivat n=122 Participants Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=59 Participants Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) 3 Hour Post-dose at Week 20	409.73 mcg/mL Standard Deviation 96.379	454.39 mcg/mL Standard Deviation 107.966
Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) 5 Hour Post-dose at Week 20	412.72 mcg/mL Standard Deviation 94.150	464.24 mcg/mL Standard Deviation 97.007
Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) 7 Hour Post-dose at Week 20	404.43 mcg/mL Standard Deviation 97.586	471.10 mcg/mL Standard Deviation 113.165
Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) 1 Hour Post-dose at Week 20	417.83 mcg/mL Standard Deviation 105.752	457.71 mcg/mL Standard Deviation 104.431
Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) Pre-dose at Day 1	526.40 mcg/mL Standard Deviation 125.196	506.14 mcg/mL Standard Deviation 108.033
Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) Pre-dose at Week 12	434.90 mcg/mL Standard Deviation 97.901	497.68 mcg/mL Standard Deviation 112.055
Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) Pre-dose at Week 20	426.30 mcg/mL Standard Deviation 107.173	468.22 mcg/mL Standard Deviation 99.783
Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) 30 Minutes Post-dose at Week 20	417.87 mcg/mL Standard Deviation 102.853	457.78 mcg/mL Standard Deviation 89.932

SECONDARY outcome

Timeframe: Open-Label Extension Period: From week 24 up to end of study (approximately 5 years)

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

Adverse Events

Mitapivat

Serious events: 8 serious events

Other events: 80 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 33 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Mitapivat n=129 participants at risk Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=63 participants at risk Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Infections and infestations Lower respiratory tract infection	0.78% 1/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	0.00% 0/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Infections and infestations Pneumonia	0.78% 1/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	0.00% 0/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Infections and infestations Upper respiratory tract infection	0.78% 1/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	0.00% 0/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Injury, poisoning and procedural complications Craniofacial fracture	0.78% 1/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	0.00% 0/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Injury, poisoning and procedural complications Ulna fracture	0.78% 1/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	0.00% 0/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Blood and lymphatic system disorders Anaemia	0.78% 1/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	0.00% 0/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Cardiac disorders Angina pectoris	0.78% 1/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	0.00% 0/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Gastrointestinal disorders Abdominal pain	0.78% 1/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	0.00% 0/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Vascular disorders Superficial vein thrombosis	0.78% 1/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	0.00% 0/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.

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

Restriction type: OTHER

Measure	Mitapivat n=129 participants at risk Participants randomized to receive Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind period and for up to 5 years in open label extension period.	Placebo n=63 participants at risk Participants randomized to receive placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Gastrointestinal disorders Diarrhoea	8.5% 11/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	9.5% 6/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Psychiatric disorders Initial insomnia	14.0% 18/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	4.8% 3/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Psychiatric disorders Middle insomnia	6.2% 8/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	1.6% 1/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Psychiatric disorders Insomnia	5.4% 7/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	1.6% 1/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Nervous system disorders Headache	22.5% 29/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	9.5% 6/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
General disorders Fatigue	9.3% 12/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	6.3% 4/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
General disorders Pyrexia	3.1% 4/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	9.5% 6/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Musculoskeletal and connective tissue disorders Pain in extremity	6.2% 8/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	1.6% 1/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Musculoskeletal and connective tissue disorders Arthralgia	3.9% 5/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	6.3% 4/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Musculoskeletal and connective tissue disorders Back pain	2.3% 3/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	7.9% 5/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Respiratory, thoracic and mediastinal disorders Cough	3.1% 4/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	6.3% 4/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Gastrointestinal disorders Nausea	11.6% 15/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	7.9% 5/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Infections and infestations Upper respiratory tract infection	10.1% 13/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	6.3% 4/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Infections and infestations COVID-19	6.2% 8/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	7.9% 5/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.
Infections and infestations Influenza	3.9% 5/129 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.	9.5% 6/63 • Double-blind period: From the time of signing informed consent to Week 24 Adverse events: Safety analysis set was used. Participants classified according to treatment received. If participant was randomized to placebo \& received at least 1 dose of mitapivat in Double-blind Period, then participant was classified to mitapivat arm. All-Cause Mortality: FAS was used. Safety data are presented for Double-blind Period only. The OLE period is ongoing with anticipated completion in December 2028. Results for OLE will be reported separately by December 2029.