Trial Outcomes & Findings for A Study of AG-348 in Adult Participants With Pyruvate Kinase (PK) Deficiency (NCT NCT02476916)

NCT ID: NCT02476916

Last Updated: 2025-05-02

Results Overview

An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug-related.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 52 participants
• Primary outcome timeframe: Up to Week 24
• Results posted on: 2025-05-02

Participant Flow

Participants were recruited in the core period of the study at 14 investigative sites in the 6 countries from 13 July 2015 to 14 July 2017 (data cut-off date). The core period is completed, and results of this period are reported. The extension period is ongoing.

A total of 52 participants were enrolled in the Core Period of the study. Out of 52 participants, 9 discontinued during the core period, and 43 completed the core period. Out of these 43, 36 entered the extension period, and 7 did not enter the extension period and were followed up to 4 weeks after their last dose of AG-348 in the core study.

Participant milestones

Measure	AG-348 50 mg BID Participants with Pyruvate Kinase (PK) deficiency received AG-348, 50 milligrams (mg), as initial dose, twice daily (BID) for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent adverse events (AEs) and hemoglobin (Hb) levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Core Period STARTED	27	25
Core Period COMPLETED	21	22
Core Period NOT COMPLETED	6	3
Extension Period STARTED	18	18
Extension Period COMPLETED	0	0
Extension Period NOT COMPLETED	18	18

Reasons for withdrawal

Measure	AG-348 50 mg BID Participants with Pyruvate Kinase (PK) deficiency received AG-348, 50 milligrams (mg), as initial dose, twice daily (BID) for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent adverse events (AEs) and hemoglobin (Hb) levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Core Period Adverse Event	2	2
Core Period Investigator decision	1	1
Core Period Withdrawal by Subject	3	0
Extension Period Prematurely Discontinued Treatment	6	1
Extension Period On Treatment	12	17

Baseline Characteristics

A Study of AG-348 in Adult Participants With Pyruvate Kinase (PK) Deficiency

Baseline characteristics by cohort

Measure	AG-348 50 mg BID n=27 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	Total n=52 Participants Total of all reporting groups
Age, Continuous	30.7 years STANDARD_DEVIATION 11.26 • n=5 Participants	37.7 years STANDARD_DEVIATION 12.03 • n=7 Participants	34.1 years STANDARD_DEVIATION 12.05 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	11 Participants n=7 Participants	20 Participants n=5 Participants
Sex: Female, Male Male	18 Participants n=5 Participants	14 Participants n=7 Participants	32 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	24 Participants n=5 Participants	23 Participants n=7 Participants	47 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	22 Participants n=5 Participants	21 Participants n=7 Participants	43 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to Week 24

Population: The Safety Analysis Set included all participants who had received at least one dose of study drug.

An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug-related.

Outcome measures

Measure	AG-348 50 mg BID n=27 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Percentage of Participants Experiencing at Least One Adverse Event (AEs) in the Core Period	96.3 percentage of participants	100.0 percentage of participants

SECONDARY outcome

Timeframe: Up to approximately 8.5 years

An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug-related.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: The Efficacy Analysis Set included all participants who enrolled and received any study treatment for at least 3 weeks. Number analyzed is the number of participants with evaluable data at the given time-point.

Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased Hb values indicate improvement.

Outcome measures

Measure	AG-348 50 mg BID n=27 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Change From Baseline in Hemoglobin (Hb) Value at Week 24 Baseline	9.243 grams per deciliter (g/dL) Standard Deviation 1.4757	8.636 grams per deciliter (g/dL) Standard Deviation 1.1664
Change From Baseline in Hemoglobin (Hb) Value at Week 24 Change at Week 24	1.205 grams per deciliter (g/dL) Standard Deviation 1.4181	1.611 grams per deciliter (g/dL) Standard Deviation 1.7058

SECONDARY outcome

Timeframe: Up to approximately 8.5 years

Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Increased Hb values indicate improvement.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.

Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased hematocrit values indicate improvement.

Outcome measures

Measure	AG-348 50 mg BID n=27 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Change From Baseline in Hematocrit at Week 24 Baseline	0.289 volume per volume (V/V) Standard Deviation 0.0470	0.268 volume per volume (V/V) Standard Deviation 0.0367
Change From Baseline in Hematocrit at Week 24 Change at Week 24	0.033 volume per volume (V/V) Standard Deviation 0.0414	0.045 volume per volume (V/V) Standard Deviation 0.0499

SECONDARY outcome

Timeframe: Up to approximately 8.5 years

Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Increased hematocrit values indicate improvement.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.

Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased reticulocyte count values indicate improvement.

Outcome measures

Measure	AG-348 50 mg BID n=27 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Change From Baseline in Reticulocyte Count at Week 24 Baseline	493.248 cells * 10^9/liter Standard Deviation 234.2242	549.436 cells * 10^9/liter Standard Deviation 291.5301
Change From Baseline in Reticulocyte Count at Week 24 Change at Week 24	-99.248 cells * 10^9/liter Standard Deviation 309.9473	-46.222 cells * 10^9/liter Standard Deviation 351.9823

SECONDARY outcome

Timeframe: Up to approximately 8.5 years

Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased reticulocyte count values indicate improvement.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.

Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased haptoglobin values indicate improvement.

Outcome measures

Measure	AG-348 50 mg BID n=27 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Change From Baseline in Haptoglobin at Week 24 Baseline	0.246 gram per liter (g/L) Standard Deviation 0.1474	0.240 gram per liter (g/L) Standard Deviation 0.2082
Change From Baseline in Haptoglobin at Week 24 Change at Week 24	0.128 gram per liter (g/L) Standard Deviation 0.2845	0.139 gram per liter (g/L) Standard Deviation 0.2726

SECONDARY outcome

Timeframe: Up to approximately 8.5 years

Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Increased haptoglobin values indicate improvement.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.

Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased carbon monoxide values indicate improvement.

Outcome measures

Measure	AG-348 50 mg BID n=27 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Change From Baseline in Carbon Monoxide at Week 24 Baseline	5.263 percentage Hb bound to carbon monoxide Standard Deviation 1.7270	6.200 percentage Hb bound to carbon monoxide Standard Deviation 2.3079
Change From Baseline in Carbon Monoxide at Week 24 Change at Week 24	-1.063 percentage Hb bound to carbon monoxide Standard Deviation 2.2940	-1.706 percentage Hb bound to carbon monoxide Standard Deviation 3.2742

SECONDARY outcome

Timeframe: Up to approximately 8.5 years

Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased carbon monoxide values indicate improvement.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.

Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased LDH values indicate improvement.

Outcome measures

Measure	AG-348 50 mg BID n=27 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 Baseline	282.074 units per liter (U/L) Standard Deviation 188.3558	254.840 units per liter (U/L) Standard Deviation 122.3587
Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 Change at Week 24	-26.292 units per liter (U/L) Standard Deviation 145.3151	-8.913 units per liter (U/L) Standard Deviation 139.8509

SECONDARY outcome

Timeframe: Up to approximately 8.5 years

Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased LDH values indicate improvement.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.

Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased total bilirubin values indicate improvement.

Outcome measures

Measure	AG-348 50 mg BID n=27 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Change From Baseline in Total Bilirubin at Week 24 Baseline	5.152 milligrams per deciliter (mg/dL) Standard Deviation 2.3407	5.608 milligrams per deciliter (mg/dL) Standard Deviation 3.4625
Change From Baseline in Total Bilirubin at Week 24 Change at Week 24	-1.921 milligrams per deciliter (mg/dL) Standard Deviation 1.9465	-3.017 milligrams per deciliter (mg/dL) Standard Deviation 2.5848

SECONDARY outcome

Timeframe: Up to approximately 8.5 years

Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased total bilirubin values indicate improvement.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.

Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased indirect bilirubin values indicate improvement.

Outcome measures

Measure	AG-348 50 mg BID n=27 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Change From Baseline in Indirect Bilirubin at Week 24 Baseline	4.752 mg/dL Standard Deviation 2.3629	5.208 mg/dL Standard Deviation 3.4272
Change From Baseline in Indirect Bilirubin at Week 24 Change at Week 24	-1.967 mg/dL Standard Deviation 1.8318	-3.195 mg/dL Standard Deviation 2.5537

SECONDARY outcome

Timeframe: Up to approximately 8.5 years

Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased indirect bilirubin values indicate improvement.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.

Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased EPO values indicate improvement.

Outcome measures

Measure	AG-348 50 mg BID n=27 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Change From Baseline in Erythropoietin (EPO) at Week 24 Baseline	85.448 international units per liter (IU/L) Standard Deviation 159.4090	60.900 international units per liter (IU/L) Standard Deviation 19.5188
Change From Baseline in Erythropoietin (EPO) at Week 24 Change at Week 24	-7.738 international units per liter (IU/L) Standard Deviation 33.1934	-13.675 international units per liter (IU/L) Standard Deviation 26.5065

SECONDARY outcome

Timeframe: Up to approximately 8.5 years

Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased EPO values indicate improvement.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.

Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased hepcidin values indicate improvement.

Outcome measures

Measure	AG-348 50 mg BID n=27 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Change From Baseline in Hepcidin at Week 24 Baseline	3.392 nanomoles per liter (nmol/L) Standard Deviation 3.4013	4.988 nanomoles per liter (nmol/L) Standard Deviation 4.0416
Change From Baseline in Hepcidin at Week 24 Change at Week 24	0.095 nanomoles per liter (nmol/L) Standard Deviation 1.4795	-2.310 nanomoles per liter (nmol/L) Standard Deviation 2.5061

SECONDARY outcome

Timeframe: Up to approximately 8.5 years

Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased hepcidin values indicate improvement.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.

Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased ferritin values indicate improvement.

Outcome measures

Measure	AG-348 50 mg BID n=27 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Change From Baseline in Ferritin at Week 24 Baseline	860.852 ng/mL Standard Deviation 682.6346	859.680 ng/mL Standard Deviation 490.2734
Change From Baseline in Ferritin at Week 24 Change at Week 24	68.875 ng/mL Standard Deviation 388.1866	-37.870 ng/mL Standard Deviation 308.0896

SECONDARY outcome

Timeframe: Up to approximately 8.5 years

Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased ferritin values indicate improvement.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.

Transferrin saturation is the ratio of serum iron to iron-binding capacity. Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased transferrin saturation values indicate improvement.

Outcome measures

Measure	AG-348 50 mg BID n=27 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Change From Baseline in Transferrin Saturation at Week 24 Baseline	50.143 percentage of saturation Standard Deviation 23.7388	64.292 percentage of saturation Standard Deviation 22.0779
Change From Baseline in Transferrin Saturation at Week 24 Change at Week 24	-3.625 percentage of saturation Standard Deviation 16.1777	-5.750 percentage of saturation Standard Deviation 19.8968

SECONDARY outcome

Timeframe: Up to approximately 8.5 years

Transferrin saturation is the ratio of serum iron to iron-binding capacity. Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased transferrin saturation values indicate improvement.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15

Population: The Pharmacokinetic Analysis Set included all participants from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess pharmacokinetic parameters. Number analyzed is the number of participants with evaluable data at the given time-point.

Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.

Outcome measures

Measure	AG-348 50 mg BID n=5 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=7 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 Day 1: AG-348	3287 nanograms*hours per milliliter(hr*ng/mL) Geometric Coefficient of Variation 20.9	27930 nanograms*hours per milliliter(hr*ng/mL) Geometric Coefficient of Variation 38.1
Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 Day 15: AG-348	3609 nanograms*hours per milliliter(hr*ng/mL) Geometric Coefficient of Variation 38.2	11610 nanograms*hours per milliliter(hr*ng/mL) Geometric Coefficient of Variation 11.3
Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 Day 1: AGI-8702	235.6 nanograms*hours per milliliter(hr*ng/mL) Geometric Coefficient of Variation 32.6	2637 nanograms*hours per milliliter(hr*ng/mL) Geometric Coefficient of Variation 34.9
Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 Day 15: AGI-8702	425.8 nanograms*hours per milliliter(hr*ng/mL) Geometric Coefficient of Variation 21.8	2235 nanograms*hours per milliliter(hr*ng/mL) Geometric Coefficient of Variation 19.4

SECONDARY outcome

Timeframe: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15

Population: The Pharmacokinetic Analysis Set included all participants from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess pharmacokinetic parameters. Number analyzed is the number of participants with evaluable data at the given time-point.

Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.

Outcome measures

Measure	AG-348 50 mg BID n=5 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=7 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 Day 1: AG-348	870.0 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 9.2	7606 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 41.8
Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 Day 15: AG-348	943.4 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 30.7	5259 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 35.6
Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 Day 1: AGI-8702	41.03 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 43.6	414.7 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 35.6
Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 Day 15: AGI-8702	71.94 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 22.0	533.7 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 25.6

SECONDARY outcome

Timeframe: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15

Population: The Pharmacokinetic Analysis Set included all participants from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess pharmacokinetic parameters. Number analyzed is the number of participants with evaluable data at the given time-point.

Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.

Outcome measures

Measure	AG-348 50 mg BID n=5 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=7 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 Day 1: AG-348	1.92 hour (hr) Interval 0.97 to 2.03	1.97 hour (hr) Interval 1.0 to 2.08
Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 Day 15: AG-348	1.00 hour (hr) Interval 0.97 to 1.9	1.00 hour (hr) Interval 0.42 to 2.0
Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 Day 1: AGI-8702	2.00 hour (hr) Interval 1.92 to 2.03	1.97 hour (hr) Interval 1.0 to 2.13
Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 Day 15: AGI-8702	2.00 hour (hr) Interval 1.95 to 4.0	1.00 hour (hr) Interval 0.93 to 4.0

SECONDARY outcome

Timeframe: pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15

Population: The Pharmacokinetic Analysis Set included all participants from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess pharmacokinetic parameters. Number analyzed is the number of participants with evaluable data at the given time-point.

Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.

Outcome measures

Measure	AG-348 50 mg BID n=5 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=7 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Apparent Clearance at Steady-State (Clss/F) for AG-348 and Its Metabolite AGI-8702 Day 15: AG-348	12.27 liter per hour (L/hr) Geometric Coefficient of Variation 40.3	25.31 liter per hour (L/hr) Geometric Coefficient of Variation 11.7
Apparent Clearance at Steady-State (Clss/F) for AG-348 and Its Metabolite AGI-8702 Day 15: AGI-8702	91.50 liter per hour (L/hr) Geometric Coefficient of Variation 31.0	128.2 liter per hour (L/hr) Geometric Coefficient of Variation 18.8

SECONDARY outcome

Timeframe: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15

Population: The Pharmacodynamic (PD) Analysis Set included all participants from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess PD parameters. Number analyzed is the number of participants with evaluable data at the given time-point.

Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline.

Outcome measures

Measure	AG-348 50 mg BID n=5 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=7 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP) Change at Day 1	16.50 µg/mL Standard Deviation 11.790	20.67 µg/mL Standard Deviation 6.8896
Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP) Change at Day 15	1.500 µg/mL Standard Deviation 31.032	45.50 µg/mL Standard Deviation 60.995

SECONDARY outcome

Timeframe: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15

Population: The PD Analysis Set included all participants from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess PD parameters. Number analyzed is the number of participants with evaluable data at the given time-point.

Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline.

Outcome measures

Measure	AG-348 50 mg BID n=5 Participants Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=7 Participants Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for 2,3 - Diphosphoglycerate (2,3-DPG) Change at Day 1	42.25 microgram per milliliter (µg/mL) Standard Deviation 38.836	59.57 microgram per milliliter (µg/mL) Standard Deviation 58.569
Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for 2,3 - Diphosphoglycerate (2,3-DPG) Change at Day 15	-65.50 microgram per milliliter (µg/mL) Standard Deviation 69.745	8.200 microgram per milliliter (µg/mL) Standard Deviation 195.13

Adverse Events

AG-348 50 mg BID

Serious events: 5 serious events

Other events: 26 other events

Deaths: 0 deaths

AG-348 300 mg BID

Serious events: 3 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Measure	AG-348 50 mg BID n=27 participants at risk Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 participants at risk Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Infections and infestations Pharyngitis	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	4.0% 1/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Infections and infestations Influenza	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	0.00% 0/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Blood and lymphatic system disorders Haemolytic anaemia	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	4.0% 1/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Blood and lymphatic system disorders Haemolysis	0.00% 0/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	4.0% 1/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Hepatobiliary disorders Cholelithiasis	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	0.00% 0/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Metabolism and nutrition disorders Hypertriglyceridaemia	0.00% 0/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	4.0% 1/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Osteoporosis	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	0.00% 0/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.

Other adverse events

Measure	AG-348 50 mg BID n=27 participants at risk Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.	AG-348 300 mg BID n=25 participants at risk Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348.
Nervous system disorders Dysgeusia	0.00% 0/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	12.0% 3/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	14.8% 4/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	16.0% 4/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	11.1% 3/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	16.0% 4/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Gastrointestinal disorders Nausea	37.0% 10/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	40.0% 10/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Gastrointestinal disorders Vomiting	7.4% 2/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	20.0% 5/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Gastrointestinal disorders Diarrhoea	11.1% 3/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	12.0% 3/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Gastrointestinal disorders Dyspepsia	7.4% 2/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	8.0% 2/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Gastrointestinal disorders Abdominal pain	0.00% 0/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	12.0% 3/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	12.0% 3/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Nervous system disorders Headache	33.3% 9/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	56.0% 14/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Nervous system disorders Dizziness	18.5% 5/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	8.0% 2/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Nasal congestion	11.1% 3/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	8.0% 2/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	12.0% 3/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Epistaxis	7.4% 2/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	4.0% 1/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Infections and infestations Viral upper respiratory tract infection	25.9% 7/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	8.0% 2/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Infections and infestations Influenza	22.2% 6/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	4.0% 1/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Infections and infestations Gastroenteritis	11.1% 3/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	4.0% 1/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Infections and infestations Sinusitis	7.4% 2/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	4.0% 1/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Infections and infestations Upper respiratory tract infection	7.4% 2/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	4.0% 1/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Psychiatric disorders Insomnia	18.5% 5/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	64.0% 16/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	18.5% 5/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	12.0% 3/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Back pain	14.8% 4/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	12.0% 3/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	7.4% 2/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	8.0% 2/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	8.0% 2/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	8.0% 2/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
General disorders Fatigue	14.8% 4/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	16.0% 4/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
General disorders Pyrexia	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	20.0% 5/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
General disorders Chest discomfort	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	16.0% 4/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
General disorders Asthenia	11.1% 3/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	4.0% 1/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
General disorders Non-cardiac chest pain	0.00% 0/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	12.0% 3/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Skin and subcutaneous tissue disorders Night sweats	0.00% 0/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	16.0% 4/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Skin and subcutaneous tissue disorders Rash	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	12.0% 3/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Skin and subcutaneous tissue disorders Pruritus generalised	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	8.0% 2/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Skin and subcutaneous tissue disorders Skin ulcer	0.00% 0/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	12.0% 3/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Vascular disorders Hot flush	7.4% 2/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	28.0% 7/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Vascular disorders Flushing	7.4% 2/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	8.0% 2/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Reproductive system and breast disorders Dysmenorrhoea	11.1% 3/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	16.0% 4/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Metabolism and nutrition disorders Hypertriglyceridaemia	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	16.0% 4/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Metabolism and nutrition disorders Decreased appetite	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	8.0% 2/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.
Cardiac disorders Palpitations	3.7% 1/27 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.	8.0% 2/25 • Up to Week 24 The Safety Analysis Set included all participants who had received at least one dose of study drug.

Additional Information

Medical Affairs

Agios Pharmaceuticals, Inc.

Phone: 833-228-8474

Email: medinfo@agios.com

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