Trial Outcomes & Findings for A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD) (NCT NCT03548220)

Last Updated: 2022-05-24

Results Overview

Hemoglobin response (HR) is defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24. The baseline Hb concentration is the average of all available Hb concentrations for a participant during the Screening Period up to the first dose of study treatment. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

80 participants

Primary outcome timeframe

Baseline, Weeks 16, 20, 24

Results posted on

2022-05-24

Participant Flow

A total of 80 participants were randomized in the study, which was conducted across multiple sites in 14 countries: Brazil, Canada, Denmark, France, Germany, Italy, Japan, Republic of Korea, Netherlands, Spain, Switzerland, Turkey, United Kingdom, and United States. The study was conducted from 9 August 2018 to 9 October 2020.

Screening was done for a period of 42 days after the participant provided the informed consent. Investigators determined if the participants met all the inclusion criteria and none of the exclusion criteria to receive AG-348 or placebo to determine the optimized dose to be received for 12 weeks as fixed-dose.

Participant milestones

Participant milestones
Measure	Placebo Comparator: Placebo Participants received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 5 mg Participants received AG-348 tablets, 5 milligrams (mg) twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348, 20 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348, 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Overall Study STARTED	40	2	3	35
Overall Study COMPLETED	39	2	3	35
Overall Study NOT COMPLETED	1	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Comparator: Placebo Participants received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 5 mg Participants received AG-348 tablets, 5 milligrams (mg) twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348, 20 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348, 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Overall Study Lost to Follow-up	1	0	0	0

Baseline Characteristics

A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo Comparator: Placebo n=40 Participants Participants received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348, 5 mg n=2 Participants Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348, 20 mg n=3 Participants Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348, 50 mg n=35 Participants Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Total n=80 Participants Total of all reporting groups
Age, Continuous	37.2 years STANDARD_DEVIATION 15.92 • n=99 Participants	21.5 years STANDARD_DEVIATION 4.95 • n=107 Participants	48.0 years STANDARD_DEVIATION 26.21 • n=206 Participants	35.8 years STANDARD_DEVIATION 14.07 • n=7 Participants	36.6 years STANDARD_DEVIATION 15.47 • n=31 Participants
Sex: Female, Male Female	24 Participants n=99 Participants	0 Participants n=107 Participants	2 Participants n=206 Participants	22 Participants n=7 Participants	48 Participants n=31 Participants
Sex: Female, Male Male	16 Participants n=99 Participants	2 Participants n=107 Participants	1 Participants n=206 Participants	13 Participants n=7 Participants	32 Participants n=31 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	2 Participants n=7 Participants	3 Participants n=31 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	34 Participants n=99 Participants	1 Participants n=107 Participants	2 Participants n=206 Participants	25 Participants n=7 Participants	62 Participants n=31 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	5 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants	8 Participants n=7 Participants	15 Participants n=31 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants	0 Participants n=31 Participants
Race (NIH/OMB) Asian	3 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	5 Participants n=7 Participants	8 Participants n=31 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	1 Participants n=7 Participants	1 Participants n=31 Participants
Race (NIH/OMB) Black or African American	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants	0 Participants n=31 Participants
Race (NIH/OMB) White	32 Participants n=99 Participants	2 Participants n=107 Participants	3 Participants n=206 Participants	23 Participants n=7 Participants	60 Participants n=31 Participants
Race (NIH/OMB) More than one race	1 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants	1 Participants n=31 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	6 Participants n=7 Participants	10 Participants n=31 Participants

PRIMARY outcome

Timeframe: Baseline, Weeks 16, 20, 24

Population: Full analysis set included all participants who were randomized.

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=40 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=40 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR)	0 percentage of participants	40.0 percentage of participants	—	—

SECONDARY outcome

Timeframe: Baseline, Weeks 16, 20, 24

Population: Full analysis set included all participants who were randomized.

This is the change in Hb concentration at Weeks 16, 20 and 24 compared to baseline. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=40 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=40 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24	-1.48 grams per liter (g/L) Standard Error 2.082	16.73 grams per liter (g/L) Standard Error 2.075	—	—

SECONDARY outcome

Timeframe: Baseline, up to Week 24

Population: Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.

This is the maximum change from baseline in Hb concentration up to Week 24. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=39 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=39 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Maximum Change From Baseline in Hb Concentration	4.76 g/L Standard Deviation 4.217	23.94 g/L Standard Deviation 21.367	—	—

SECONDARY outcome

Timeframe: Baseline, up to Week 24

Population: Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.

This is the time taken to first achieve an increase of hemoglobin concentration of 1.5 g/dL or more from baseline. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=17 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More	—	7.66 weeks Standard Deviation 4.050	—	—

SECONDARY outcome

Timeframe: Baseline, Weeks 16, 20, 24

Population: Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.

The change from baseline in indirect bilirubin levels was summarized. Indirect bilirubin is a marker for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=39 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=37 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24	5.10 micromoles per liter (μmol/L) Standard Error 4.061	-21.16 micromoles per liter (μmol/L) Standard Error 4.228	—	—

SECONDARY outcome

Timeframe: Baseline, Weeks 16, 20, 24

Population: Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.

The change from baseline in LDH levels was summarized. LDH is a marker for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=40 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=39 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24	-21.18 units per litre (U/L) Standard Error 16.040	-91.99 units per litre (U/L) Standard Error 16.222	—	—

SECONDARY outcome

Timeframe: Baseline, Weeks 16, 20, 24

Population: Full analysis set included all participants who were randomized.

The change from baseline in haptoglobin levels was summarized. Haptoglobin levels are markers for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=40 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=40 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24	0.012 g/L Standard Error 0.0412	0.169 g/L Standard Error 0.0408	—	—

SECONDARY outcome

Timeframe: Baseline, Weeks 16, 20, 24

Population: Full analysis set included all participants who were randomized.

The change from baseline in reticulocyte percentage was summarized. Reticulocyte levels are markers for hematopoietic activity. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=40 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=40 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24	0.0038 Reticulocyte percentages Standard Error 0.01390	-0.0973 Reticulocyte percentages Standard Error 0.01401	—	—

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.

The PKDD is a 7-item patient reported outcome (PRO) measure of the core signs and symptoms associated with PK deficiency in adults. Participants rate their experience with symptoms of PK deficiency on the present day. The symptoms include those associated with tiredness, jaundice, bone pain, shortness of breath, and energy level. The score ranges from 25 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDD weekly scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=36 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=37 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24	-2.05 score on a scale Standard Error 0.976	-5.16 score on a scale Standard Error 0.955	—	—

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.

The PKDIA is a 12-item patient reported outcome (PRO) measure of the common impacts of PK deficiency on activities of daily living. Participants rate how PK deficiency has impacted aspects of daily living in the past 7 days, including impacts on relationships; perceived appearance; work performance; and leisure, social, mental, and physical activities. The score range is 30 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDIA scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=39 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=39 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24	-1.39 score on a scale Standard Error 1.157	-4.65 score on a scale Standard Error 1.123	—	—

SECONDARY outcome

Timeframe: From signing of informed consent form to the end of study, including follow-up (up to Day 197)

Population: Safety analysis set included all participants who received at least 1 dose of study treatment.

An AE is any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=39 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=2 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg n=3 Participants Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg n=35 Participants Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Percentage of Participants With Adverse Events	89.7 percentage of participants	50.0 percentage of participants	100 percentage of participants	88.6 percentage of participants

SECONDARY outcome

Timeframe: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)

Population: Pharmacokinetic analysis population consisted of all participants who were enrolled and received a dose of study medication (mitapivat) with at least 1 non-zero pharmacokinetic plasma concentration of mitapivat at the Week 12 visit. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=2 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=3 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg n=24 Participants Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12	565.9 h*ng/mL Geometric Coefficient of Variation NA Data was not reported due to small size of sample.	1481.2 h*ng/mL Geometric Coefficient of Variation 26.9	2973.3 h*ng/mL Geometric Coefficient of Variation 35.6	—

SECONDARY outcome

Timeframe: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=2 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=3 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg n=26 Participants Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Maximum Plasma Concentration (Cmax) for AG-348	156.9 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation NA Data not reported due to small size of sample.	373.1 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 13.6	1033 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 31.2	—

SECONDARY outcome

Timeframe: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=2 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=3 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg n=26 Participants Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Time to Cmax (Tmax) for AG-348	0.75 hours (h) Interval 0.5 to 1.0	1.02 hours (h) Interval 0.92 to 2.17	0.50 hours (h) Interval 0.42 to 1.92	—

SECONDARY outcome

Timeframe: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=2 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=3 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg n=24 Participants Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Time to Last Measurable Concentration (Tlast) for AG-348	7.787 hours (h) Geometric Coefficient of Variation NA Data not reported due to small size of sample.	7.809 hours (h) Geometric Coefficient of Variation 4.2	7.162 hours (h) Geometric Coefficient of Variation 28.0	—

SECONDARY outcome

Timeframe: From first dose of mitapivat to the end of study, including follow-up (up to Day 197)

Population: Safety Set: Participants who were administered the study drug. Participants who received mitapivat in studies: study AG348-C-003 (NCT02476916): 52 participants; study AG348-C-006 (NCT03548220): 40 participants; study AG348-C-007 (NCT03559699): 27 participants; and study AG348-C-011 (NCT03853798): 36 participants, were pooled for the analysis of this outcome measure.

Predicted probability of experiencing all grade hot flush at the doses of 5, 20, and 50 mg mitapivat BID based on exposure-response model.

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=2 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=3 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg n=150 Participants Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters	3.37 Percent probability Interval 1.22 to 7.35	4.03 Percent probability Interval 1.61 to 8.36	5.5 Percent probability Interval 2.48 to 10.5	—

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: Safety Set: Participants who were administered the study drug. Male participants who received mitapivat in studies: study AG348-C-003 (NCT02476916): 32 participants; study AG348-C-006 (NCT03548220):15 participants; study AG348-C-007 (NCT03559699): 7 participants; and study AG348-C-011 (NCT03853798): 14 participants were pooled for analysis of this outcome measure.

Predicted percent change from baseline at Week 24 in the sex hormone measures (total testosterone, free testosterone, and estrone) at the doses of 5, 20, and 50 mg mitapivat BID in male participants.

Outcome measures

Outcome measures
Measure	Placebo Comparator: Placebo n=2 Participants Participants received matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 n=3 Participants Participants received AG-348 tablets, 5 mg for 4 weeks followed by the respective optimized dose of 5 mg or 20 mg or 50 mg BID as determined by the investigator, administered orally, up to Weeks 8 and 12 respectively, as an optimized dose and continued to receive the same dose for a period of 12 weeks as a fixed-dose.	Experimental: AG-348 20 mg n=63 Participants Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters Total Testosterone	0.877 Percent change Interval 0.41 to 1.43	3.18 Percent change Interval 1.49 to 5.4	7.59 Percent change Interval 3.29 to 13.7	—
Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters Free Testosterone	6.01 Percent change Interval 1.66 to 13.2	14.1 Percent change Interval 4.0 to 27.5	26 Percent change Interval 7.14 to 55.1	—
Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters Estrone	-31.5 Percent change Interval -51.0 to -21.1	-56.5 Percent change Interval -67.3 to -48.4	-68.2 Percent change Interval -74.5 to -62.6	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Through 4 weeks after last dose (approximately Week 31)

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Week 24

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Week 24

Outcome measures

Outcome data not reported

Adverse Events

Placebo Comparator: Placebo

Serious events: 2 serious events

Other events: 35 other events

Deaths: 0 deaths

Experimental: AG-348, 5 mg

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Experimental: AG-348, 20 mg

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Experimental: AG-348, 50 mg

Serious events: 3 serious events

Other events: 31 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo Comparator: Placebo n=39 participants at risk Participants received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.	Experimental: AG-348, 5 mg n=2 participants at risk Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348, 20 mg n=3 participants at risk Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.	Experimental: AG-348, 50 mg n=35 participants at risk Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Infections and infestations Gastroenteritis	0.00% 0/39 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	0.00% 0/2 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	0.00% 0/3 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	2.9% 1/35 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.
Infections and infestations Metapneumovirus infection	2.6% 1/39 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	0.00% 0/2 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	0.00% 0/3 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	0.00% 0/35 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.
Cardiac disorders Atrial fibrillation	0.00% 0/39 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	0.00% 0/2 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	0.00% 0/3 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	2.9% 1/35 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.
Injury, poisoning and procedural complications Rib fracture	0.00% 0/39 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	0.00% 0/2 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	0.00% 0/3 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	2.9% 1/35 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/39 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	0.00% 0/2 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	33.3% 1/3 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	0.00% 0/35 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.
Gastrointestinal disorders Obstructive pancreatitis	2.6% 1/39 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	0.00% 0/2 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	0.00% 0/3 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.	0.00% 0/35 • From time of signing of informed consent form to end of study, including follow-up (up to Day 197) The placebo arm includes AEs that occurred in participants who received at least 1 dose of AG-348 matching placebo during the study. As pre-specified in SAP, AEs that occurred in AG-348 arms for participants who received AG-348 treatment during the study are reported based on the fixed dose treatment received. The safety analysis set included all participants who received at least 1 dose of study treatment.

Other adverse events

Additional Information

Medical Affairs

Agios Pharmaceuticals, Inc.

Phone: 833-228-8474

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The information obtained from the clinical study will be used towards the development of AG-348 and may be disclosed to regulatory authority(ies), other Investigators, corporate partners, or consultants as required
Publication restrictions are in place

Restriction type: OTHER