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

• Sponsor: Agios Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03548220
• Collaborator: (none)
• Enrollment: 80
• Locations: 46
• Arms: 4
• Actual Duration (Months): 26
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Study AG348-C-006 evaluated the efficacy and safety of orally administered AG-348 as compared with placebo in participants with pyruvate kinase (PK) deficiency, who were not regularly receiving blood transfusions. Participants were randomized 1:1 to receive either AG-348 or a matching placebo.

Condition or Disease	Intervention/Treatment	Phase
Pyruvate Kinase Deficiency; Anemia, Hemolytic	Drug: Placebo; Drug: AG-348	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Subjects With Pyruvate Kinase Deficiency
• Actual Study Start Date: Aug 9, 2018
• Actual Primary Completion Date: Oct 9, 2020
• Actual Study Completion Date: Oct 9, 2020

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: Placebo; Placebo matching AG-348 tablets, administered to maintain the blind.
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.	Drug: AG-348; AG-348 tablets.
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.	Drug: AG-348; AG-348 tablets.
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.	Drug: AG-348; AG-348 tablets.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR) [Baseline, Weeks 16, 20, 24]

   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).

Secondary Outcome Measures

1. Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24 [Baseline, Weeks 16, 20, 24]

   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).

2. Maximum Change From Baseline in Hb Concentration [Baseline, up to Week 24]

   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).

3. Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More [Baseline, up to Week 24]

   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).

4. Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24 [Baseline, Weeks 16, 20, 24]

   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).

5. Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24 [Baseline, Weeks 16, 20, 24]

   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).

6. Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24 [Baseline, Weeks 16, 20, 24]

   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).

7. Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24 [Baseline, Weeks 16, 20, 24]

   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).

8. Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24 [Baseline, Week 24]

   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).

9. Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24 [Baseline, Week 24]

   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).

10. Percentage of Participants With Adverse Events [From signing of informed consent form to the end of study, including follow-up (up to Day 197)]

    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.

11. Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12 [Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)]

12. Maximum Plasma Concentration (Cmax) for AG-348 [Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)]

13. Time to Cmax (Tmax) for AG-348 [Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)]

14. Time to Last Measurable Concentration (Tlast) for AG-348 [Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)]

15. Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters [From first dose of mitapivat to the end of study, including follow-up (up to Day 197)]

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

16. Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters [Baseline, Week 24]

    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.

Other Outcome Measures

1. Percentage of Participants With Adverse Events of Special Interest (AESI) [Through 4 weeks after last dose (approximately Week 31)]

   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. An AESI can be serious or non-serious.

2. Change From Baseline in Bone Mineral Density Z-Score at Week 24 [Baseline, Week 24]

3. Change From Baseline in Bone Mineral Density T-Score at Week 24 [Baseline, Week 24]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Informed consent;

• Male or female, aged 18 years or older;

• Documented clinical laboratory confirmation of pyruvate kinase (PK) deficiency, defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation;

• Hemoglobin (Hb) concentration less than or equal to 10.0 grams per deciliter (g/dL) regardless of gender (average of at least 2 Hb measurements [separated by a minimum of 7 days] during the Screening Period)

• Considered not regularly transfused, defined as having had no more than 4 transfusion episodes in the 12-month period up to the first day of study treatment and no transfusions in the 3 months prior to the first day of study treatment;

• Received at least 0.8 mg oral folic acid daily for at least 21 days prior to the first dose of study treatment, to be continued daily during study participation.

• Adequate organ function;

• Women of reproductive potential, have a negative serum pregnancy test;

• For women of reproductive potential as well as men with partners who are women of reproductive potential, be abstinent as part of their usual lifestyle, or agree to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of giving informed consent, during the study, and for 28 days following the last dose of study treatment for women and 90 days for men following the last dose of study treatment;

• Willing to comply with all study procedures for the duration of the study;

Exclusion Criteria:

• Homozygous for the R479H mutation or have 2 non-missense mutations, without the presence of another missense mutation, in the PKLR gene;

• Significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound the interpretation of the study data;

• Splenectomy scheduled during the study treatment period or have undergone splenectomy within 12 months prior to signing informed consent;

• Currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Prior and subsequent participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted however, concurrent participation is not; participants enrolling in this current study will be expected to temporarily suspend participation in the NHS or Registry;

• Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study treatment;

• Prior treatment with a pyruvate kinase activator;

• Prior bone marrow or stem cell transplant;

• Currently pregnant or breastfeeding;

• History of major surgery within 6 months of signing informed consent;

• Currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to the first dose of study treatment;

• Currently receiving hematopoietic stimulating agents that have not been stopped for a duration of at least 28 days prior to the first dose of study treatment;

• History of allergy to sulfonamides if characterized by acute hemolytic anemia, drug induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis, or other serious clinical manifestations;

• History of allergy to AG-348 or its excipients;

• Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
2	Emory University	Atlanta	Georgia	United States	30322
3	Indiana Hemophilia and Thrombosis Center	Indianapolis	Indiana	United States	46260
4	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
5	The Children's Hospital Corporation d/b/a Boston's Children Hospital	Boston	Massachusetts	United States	02115
6	Wayne State University School of Medicine, Children's Hospital of Michigan	Detroit	Michigan	United States	48304
7	Duke University	Durham	North Carolina	United States	27705
8	East Carolina University	Greenville	North Carolina	United States	27858
9	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
10	Houston Methodist Research Institute	Houston	Texas	United States	77030
11	Primary Children's Hospital Univ. of Utah	Salt Lake City	Utah	United States	84112
12	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
13	Hospital Central da Faculdade de Medicina USP Cidade Universitaria	São Paulo		Brazil
14	McMaster University - Health Sciences Centre	Hamilton		Canada	L8S 4LB
15	Toronto General Hospital, University Health Network	Toronto		Canada	M5G 2C4
16	Institute of Hematology and Blood Transfusion	Prague		Czechia
17	University of Copenhagen, Herlev Hospital	Herlev		Denmark	2730
18	CHU Amiens Picardie	Amiens		France	80054
19	Hopital Saint-Andre	Bordeaux		France
20	Hôpital Henri-Mondor	Créteil		France	94010
21	Hôpital de la Timone	Marseille, Cedex 5		France	13385
22	Institut Claudius Regaud	Toulouse		France
23	Charite University Medicine	Berlin		Germany
24	Universitätsklinikum Würzburg	Würzburg		Germany	97080
25	Ospedale Galliera	Genova		Italy	16128
26	Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico	Milano		Italy	20122
27	AOU Policlinico, Università della Campania "Luigi Vanvitelli"	Napoli		Italy	80138
28	Tohoku University Hospital	Sendai-City	Miyagi	Japan
29	Kyoto Katsura Hospital	Kyoto		Japan
30	Agios Investigative Site	Mie		Japan
31	Osaka City General Hospital	Osaka		Japan	534-0021
32	Kansai Medical University, Department of Pediatrics, Hirakata Hospital	Osaka		Japan
33	Toho University Omori Medical Center	Tokyo		Japan
34	Yeungnam University Hospital	Daegu 705-703		Korea, Republic of	42415
35	Universitair Medisch Centrum Utrecht	Utrecht		Netherlands	3584
36	Hospital U. Vall d'Hebron Servicio de Hematología Clínica	Barcelona		Spain	08035
37	Hospital Clinico Universitario Virgen de la Arricaxa	El Palmar		Spain	30120
38	Hospital Universitario La Paz	Madrid		Spain	28046
39	Centre Hospitalier Universitaire Vaudois (CHUV)	Lausanne		Switzerland	1011
40	Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj	Bangkok		Thailand	10700
41	Hacettepe University	Ankara		Turkey
42	Addenbrooke's Hospital	Cambridge		United Kingdom	94609
43	The Royal Liverpool and Broadgreen University	Liverpool		United Kingdom	L7 8XP
44	Imperial College Healthcare NHS Trust, Hammersmith Hospital	London		United Kingdom	W12 0NN
45	University College London	London		United Kingdom	W12 0NN
46	Manchester Royal Infirmary	Manchester		United Kingdom	M13 9WL

Sponsors and Collaborators

• Agios Pharmaceuticals, Inc.

Investigators

• Study Chair: Medical Affairs, Agios Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Study Protocol - Aug 14, 2019
• Statistical Analysis Plan - Jun 30, 2020

More Information

Publications

None provided.

• Responsible Party: Agios Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03548220
• Other Study ID Numbers: AG348-C-006
• First Posted: Jun 7, 2018
• Last Update Posted: May 24, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Anemia, Hemolytic, Congenital Nonspherocytic; Anemia, Hemolytic; Pyruvate Metabolism, Inborn Errors

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	Placebo Comparator: Placebo	Experimental: AG-348 5 mg	Experimental: AG-348, 20 mg	Experimental: AG-348, 50 mg
Arm/Group Description	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.	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.	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.	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.
Period Title: Overall Study
STARTED	40	2	3	35
COMPLETED	39	2	3	35
NOT COMPLETED	1	0	0	0

Baseline Characteristics

Arm/Group Title	Placebo Comparator: Placebo	Experimental: AG-348, 5 mg	Experimental: AG-348, 20 mg	Experimental: AG-348, 50 mg	Total
Arm/Group Description	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.	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.	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.	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 of all reporting groups
Overall Participants	40	2	3	35	80
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.2 (15.92)	21.5 (4.95)	48.0 (26.21)	35.8 (14.07)	36.6 (15.47)
Sex: Female, Male (Count of Participants)
Female	24 60%	0 0%	2 66.7%	22 62.9%	48 60%
Male	16 40%	2 100%	1 33.3%	13 37.1%	32 40%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2.5%	0 0%	0 0%	2 5.7%	3 3.8%
Not Hispanic or Latino	34 85%	1 50%	2 66.7%	25 71.4%	62 77.5%
Unknown or Not Reported	5 12.5%	1 50%	1 33.3%	8 22.9%	15 18.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	3 7.5%	0 0%	0 0%	5 14.3%	8 10%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	1 2.9%	1 1.3%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%
White	32 80%	2 100%	3 100%	23 65.7%	60 75%
More than one race	1 2.5%	0 0%	0 0%	0 0%	1 1.3%
Unknown or Not Reported	4 10%	0 0%	0 0%	6 17.1%	10 12.5%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR)
Description	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).
Time Frame	Baseline, Weeks 16, 20, 24

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants who were randomized.

Arm/Group Title	Placebo Comparator: Placebo	Experimental: AG-348
Arm/Group Description	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.	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.
Measure Participants	40	40
Number [percentage of participants]	0 0%	40.0 2000%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Comparator: Placebo, Experimental: AG-348
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	2-sided p-value
	Method	Exact Cochran-Mantel-Haenszel
	Comments

2. Secondary Outcome

Title	Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24
Description	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).
Time Frame	Baseline, Weeks 16, 20, 24

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants who were randomized.

Arm/Group Title	Placebo Comparator: Placebo	Experimental: AG-348
Arm/Group Description	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.	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.
Measure Participants	40	40
Least Squares Mean (Standard Error) [grams per liter (g/L)]	-1.48 (2.082)	16.73 (2.075)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Comparator: Placebo, Experimental: AG-348
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	18.21
	Confidence Interval	(2-Sided) 95%; 12.41 to 24.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	Standard error = 2.913

3. Secondary Outcome

Title	Maximum Change From Baseline in Hb Concentration
Description	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).
Time Frame	Baseline, up to Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo Comparator: Placebo	Experimental: AG-348
Arm/Group Description	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.	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.
Measure Participants	39	39
Mean (Standard Deviation) [g/L]	4.76 (4.217)	23.94 (21.367)

4. Secondary Outcome

Title	Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More
Description	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).
Time Frame	Baseline, up to Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo Comparator: Placebo	Experimental: AG-348
Arm/Group Description	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.	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.
Measure Participants	0	17
Mean (Standard Deviation) [weeks]	7.66 (4.050)

5. Secondary Outcome

Title	Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24
Description	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).
Time Frame	Baseline, Weeks 16, 20, 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo Comparator: Placebo	Experimental: AG-348
Arm/Group Description	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.	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.
Measure Participants	39	37
Least Squares Mean (Standard Error) [micromoles per liter (μmol/L)]	5.10 (4.061)	-21.16 (4.228)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Comparator: Placebo, Experimental: AG-348
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-26.26
	Confidence Interval	(2-Sided) 95%; -37.82 to -14.70
	Parameter Dispersion	Type: Value:
	Estimation Comments	Standard error = 5.788

6. Secondary Outcome

Title	Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24
Description	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).
Time Frame	Baseline, Weeks 16, 20, 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo Comparator: Placebo	Experimental: AG-348
Arm/Group Description	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.	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.
Measure Participants	40	39
Least Squares Mean (Standard Error) [units per litre (U/L)]	-21.18 (16.040)	-91.99 (16.222)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Comparator: Placebo, Experimental: AG-348
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0027
	Comments
	Method	Mixed-effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-70.81
	Confidence Interval	(2-Sided) 95%; -115.88 to -25.74
	Parameter Dispersion	Type: Value:
	Estimation Comments	Standard error = 22.488

7. Secondary Outcome

Title	Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24
Description	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).
Time Frame	Baseline, Weeks 16, 20, 24

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants who were randomized.

Arm/Group Title	Placebo Comparator: Placebo	Experimental: AG-348
Arm/Group Description	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.	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.
Measure Participants	40	40
Least Squares Mean (Standard Error) [g/L]	0.012 (0.0412)	0.169 (0.0408)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Comparator: Placebo, Experimental: AG-348
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0079
	Comments
	Method	Mixed-effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.158
	Confidence Interval	(2-Sided) 95%; 0.043 to 0.273
	Parameter Dispersion	Type: Value:
	Estimation Comments	Standard error = 0.0578

8. Secondary Outcome

Title	Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24
Description	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).
Time Frame	Baseline, Weeks 16, 20, 24

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants who were randomized.

Arm/Group Title	Placebo Comparator: Placebo	Experimental: AG-348
Arm/Group Description	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.	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.
Measure Participants	40	40
Least Squares Mean (Standard Error) [Reticulocyte percentages]	0.0038 (0.01390)	-0.0973 (0.01401)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Comparator: Placebo, Experimental: AG-348
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1011
	Confidence Interval	(2-Sided) 95%; -0.1391 to -0.0632
	Parameter Dispersion	Type: Value:
	Estimation Comments	Standard error = 0.01904

9. Secondary Outcome

Title	Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24
Description	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).
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo Comparator: Placebo	Experimental: AG-348
Arm/Group Description	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.	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.
Measure Participants	36	37
Least Squares Mean (Standard Error) [score on a scale]	-2.05 (0.976)	-5.16 (0.955)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Comparator: Placebo, Experimental: AG-348
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0247
	Comments
	Method	Mixed-effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.11
	Confidence Interval	(2-Sided) 95%; -5.80 to -0.41
	Parameter Dispersion	Type: Value:
	Estimation Comments	Standard error = 1.352

10. Secondary Outcome

Title	Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24
Description	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).
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo Comparator: Placebo	Experimental: AG-348
Arm/Group Description	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.	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.
Measure Participants	39	39
Least Squares Mean (Standard Error) [score on a scale]	-1.39 (1.157)	-4.65 (1.123)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Comparator: Placebo, Experimental: AG-348
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0421
	Comments
	Method	Mixed-effect Model Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.25
	Confidence Interval	(2-Sided) 95%; -6.39 to -0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Standard error = 1.574

11. Secondary Outcome

Title	Percentage of Participants With Adverse Events
Description	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.
Time Frame	From signing of informed consent form to the end of study, including follow-up (up to Day 197)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo Comparator: Placebo	Experimental: AG-348 5 mg	Experimental: AG-348 20 mg	Experimental: AG-348 50 mg
Arm/Group Description	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.	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	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.	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.
Measure Participants	39	2	3	35
Number [percentage of participants]	89.7 224.3%	50.0 2500%	100 3333.3%	88.6 253.1%

12. Secondary Outcome

Title	Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12
Time Frame	Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	AG-348, 5mg	AG-348, 20 mg	AG-348, 50mg
Arm/Group Description	Participants received 5mg AG-348 tablets BID at Week 12.	Participants received 20mg AG-348 tablets BID at Week 12.	Participants received 50mg AG-348 tablets BID at Week 12.
Measure Participants	2	3	24
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	565.9 (NA)	1481.2 (26.9)	2973.3 (35.6)

13. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) for AG-348
Time Frame	Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	AG-348, 5mg	AG-348, 20 mg	AG-348, 50mg
Arm/Group Description	Participants received 5mg AG-348 tablets BID at Week 12.	Participants received 20mg AG-348 tablets BID at Week 12.	Participants received 50mg AG-348 tablets BID at Week 12.
Measure Participants	2	3	26
Geometric Mean (Geometric Coefficient of Variation) [Nanograms per milliliter (ng/mL)]	156.9 (NA)	373.1 (13.6)	1033 (31.2)

14. Secondary Outcome

Title	Time to Cmax (Tmax) for AG-348
Time Frame	Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	AG-348, 5mg	AG-348, 20mg	AG-348, 50mg
Arm/Group Description	Participants received 5mg AG-348 tablets BID at Week 12.	Participants received 20mg AG-348 tablets BID at Week 12.	Participants received 50mg AG-348 tablets BID at Week 12.
Measure Participants	2	3	26
Median (Full Range) [hours (h)]	0.75	1.02	0.50

15. Secondary Outcome

Title	Time to Last Measurable Concentration (Tlast) for AG-348
Time Frame	Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	AG-348, 5mg	AG-348, 20mg	AG-346, 50mg
Arm/Group Description	Participants received 5mg AG-348 tablets BID at Week 12.	Participants received 20mg AG-348 tablets BID at Week 12.	Participants received 50mg AG-348 tablets BID at Week 12.
Measure Participants	2	3	24
Geometric Mean (Geometric Coefficient of Variation) [hours (h)]	7.787 (NA)	7.809 (4.2)	7.162 (28.0)

16. Secondary Outcome

Title	Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
Description	Predicted probability of experiencing all grade hot flush at the doses of 5, 20, and 50 mg mitapivat BID based on exposure-response model.
Time Frame	From first dose of mitapivat to the end of study, including follow-up (up to Day 197)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Experimental: AG-348 5 mg	Experimental: AG-348 20 mg	Experimental: AG-348 50 mg
Arm/Group Description	Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, participants continued to receive the same dose as determined by the investigator based on safety and efficacy up to Week 12, followed by the same optimized dose of 5 mg BID, for a period of 12 weeks as a fixed-dose.	Participants received AG-348 tablets, starting dose of 5 mg BID for 4 weeks, the dose was uptitrated to 20 mg BID, administered orally, up to Week 12 as an optimized dose as determined by the investigator based on safety and efficacy, followed by the same optimized dose of 20 mg BID further for a period of 12 weeks as a fixed-dose.	Participants received AG-348 tablets, starting dose of 5 mg BID for 4 weeks, the dose was uptitrated to 20 mg BID, administered orally, up to Week 8 followed by dose up titration to 50 mg BID up to Week 12 as an optimized dose, followed by the same optimized dose of 50 mg BID, as determined by the investigator based on safety and efficacy, further for a period of 12 weeks as a fixed-dose.
Measure Participants	2	3	150
Mean (95% Confidence Interval) [Percent probability]	3.37	4.03	5.5

17. Other Pre-specified Outcome

Title	Percentage of Participants With Adverse Events of Special Interest (AESI)
Description	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. An AESI can be serious or non-serious.
Time Frame	Through 4 weeks after last dose (approximately Week 31)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Other Pre-specified Outcome

Title	Change From Baseline in Bone Mineral Density Z-Score at Week 24
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

19. Other Pre-specified Outcome

Title	Change From Baseline in Bone Mineral Density T-Score at Week 24
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

20. Secondary Outcome

Title	Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Experimental: AG-348 5 mg	Experimental: AG-348 20 mg	Experimental: AG-348 50 mg
Arm/Group Description	Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, participants continued to receive the same dose as determined by the investigator based on safety and efficacy up to Week 12, followed by the same optimized dose of 5 mg BID, for a period of 12 weeks as a fixed-dose.	Participants received AG-348 tablets, starting dose of 5 mg BID for 4 weeks, the dose was uptitrated to 20 mg BID, administered orally, up to Week 12 as an optimized dose as determined by the investigator based on safety and efficacy, followed by the same optimized dose of 20 mg BID further for a period of 12 weeks as a fixed-dose.	Participants received AG-348 tablets, starting dose of 5 mg BID for 4 weeks, the dose was uptitrated to 20 mg BID, administered orally, up to Week 8 followed by dose up titration to 50 mg BID up to Week 12 as an optimized dose, followed by the same optimized dose of 50 mg BID, as determined by the investigator based on safety and efficacy, further for a period of 12 weeks as a fixed-dose.
Measure Participants	2	3	63
Total Testosterone	0.877	3.18	7.59
Free Testosterone	6.01	14.1	26
Estrone	-31.5	-56.5	-68.2

Adverse Events

Time Frame	From time of signing of informed consent form to end of study, including follow-up (up to Day 197)
Adverse Event Reporting Description	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.
Arm/Group Title	Placebo Comparator: Placebo		Experimental: AG-348, 5 mg		Experimental: AG-348, 20 mg		Experimental: AG-348, 50 mg
Arm/Group Description	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.		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.		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.		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.
All Cause Mortality
	Placebo Comparator: Placebo		Experimental: AG-348, 5 mg		Experimental: AG-348, 20 mg		Experimental: AG-348, 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/39 (0%)		0/2 (0%)		0/3 (0%)		0/35 (0%)
Serious Adverse Events
	Placebo Comparator: Placebo		Experimental: AG-348, 5 mg		Experimental: AG-348, 20 mg		Experimental: AG-348, 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/39 (5.1%)		0/2 (0%)		1/3 (33.3%)		3/35 (8.6%)
Cardiac disorders
Atrial fibrillation	0/39 (0%)		0/2 (0%)		0/3 (0%)		1/35 (2.9%)
Gastrointestinal disorders
Obstructive pancreatitis	1/39 (2.6%)		0/2 (0%)		0/3 (0%)		0/35 (0%)
Infections and infestations
Gastroenteritis	0/39 (0%)		0/2 (0%)		0/3 (0%)		1/35 (2.9%)
Metapneumovirus infection	1/39 (2.6%)		0/2 (0%)		0/3 (0%)		0/35 (0%)
Injury, poisoning and procedural complications
Rib fracture	0/39 (0%)		0/2 (0%)		0/3 (0%)		1/35 (2.9%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	0/39 (0%)		0/2 (0%)		1/3 (33.3%)		0/35 (0%)
Other (Not Including Serious) Adverse Events
	Placebo Comparator: Placebo		Experimental: AG-348, 5 mg		Experimental: AG-348, 20 mg		Experimental: AG-348, 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/39 (89.7%)		1/2 (50%)		3/3 (100%)		31/35 (88.6%)
Blood and lymphatic system disorders
Anaemia	2/39 (5.1%)		0/2 (0%)		0/3 (0%)		0/35 (0%)
Gastrointestinal disorders
Nausea	9/39 (23.1%)		0/2 (0%)		2/3 (66.7%)		5/35 (14.3%)
Diarrhoea	7/39 (17.9%)		0/2 (0%)		2/3 (66.7%)		2/35 (5.7%)
Abdominal pain	2/39 (5.1%)		0/2 (0%)		0/3 (0%)		4/35 (11.4%)
Abdominal distension	0/39 (0%)		0/2 (0%)		0/3 (0%)		2/35 (5.7%)
Constipation	0/39 (0%)		0/2 (0%)		0/3 (0%)		2/35 (5.7%)
Dyspepsia	2/39 (5.1%)		0/2 (0%)		1/3 (33.3%)		0/35 (0%)
Abdominal pain upper	3/39 (7.7%)		0/2 (0%)		0/3 (0%)		0/35 (0%)
General disorders
Fatigue	4/39 (10.3%)		0/2 (0%)		1/3 (33.3%)		4/35 (11.4%)
Influenza like illness	0/39 (0%)		0/2 (0%)		0/3 (0%)		2/35 (5.7%)
Pyrexia	2/39 (5.1%)		0/2 (0%)		0/3 (0%)		0/35 (0%)
Infections and infestations
Nasopharyngitis	6/39 (15.4%)		0/2 (0%)		2/3 (66.7%)		3/35 (8.6%)
Gastroenteritis	0/39 (0%)		1/2 (50%)		0/3 (0%)		2/35 (5.7%)
Urinary tract infection	3/39 (7.7%)		0/2 (0%)		0/3 (0%)		1/35 (2.9%)
Upper respiratory tract infection	4/39 (10.3%)		0/2 (0%)		0/3 (0%)		0/35 (0%)
Oral herpes	2/39 (5.1%)		0/2 (0%)		0/3 (0%)		0/35 (0%)
Injury, poisoning and procedural complications
Contusion	1/39 (2.6%)		0/2 (0%)		0/3 (0%)		2/35 (5.7%)
Investigations
Alanine aminotransferase increased	6/39 (15.4%)		0/2 (0%)		0/3 (0%)		1/35 (2.9%)
Aspartate aminotransferase increased	3/39 (7.7%)		0/2 (0%)		0/3 (0%)		1/35 (2.9%)
Metabolism and nutrition disorders
Hypertriglyceridaemia	0/39 (0%)		0/2 (0%)		0/3 (0%)		3/35 (8.6%)
Musculoskeletal and connective tissue disorders
Back pain	3/39 (7.7%)		0/2 (0%)		0/3 (0%)		5/35 (14.3%)
Arthralgia	2/39 (5.1%)		0/2 (0%)		2/3 (66.7%)		2/35 (5.7%)
Pain in extremity	3/39 (7.7%)		0/2 (0%)		0/3 (0%)		2/35 (5.7%)
Neck pain	2/39 (5.1%)		0/2 (0%)		0/3 (0%)		0/35 (0%)
Nervous system disorders
Headache	13/39 (33.3%)		0/2 (0%)		1/3 (33.3%)		5/35 (14.3%)
Dizziness	3/39 (7.7%)		0/2 (0%)		0/3 (0%)		4/35 (11.4%)
Presyncope	1/39 (2.6%)		0/2 (0%)		0/3 (0%)		2/35 (5.7%)
Paraesthesia	0/39 (0%)		0/2 (0%)		0/3 (0%)		2/35 (5.7%)
Psychiatric disorders
Middle insomnia	3/39 (7.7%)		0/2 (0%)		0/3 (0%)		3/35 (8.6%)
Insomnia	0/39 (0%)		0/2 (0%)		0/3 (0%)		2/35 (5.7%)
Initial insomnia	4/39 (10.3%)		0/2 (0%)		0/3 (0%)		1/35 (2.9%)
Stress	2/39 (5.1%)		0/2 (0%)		0/3 (0%)		0/35 (0%)
Reproductive system and breast disorders
Breast discomfort	0/39 (0%)		0/2 (0%)		0/3 (0%)		2/35 (5.7%)
Dysmenorrhoea	3/39 (7.7%)		0/2 (0%)		0/3 (0%)		1/35 (2.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	4/39 (10.3%)		0/2 (0%)		1/3 (33.3%)		2/35 (5.7%)
Cough	2/39 (5.1%)		0/2 (0%)		0/3 (0%)		3/35 (8.6%)
Oropharyngeal pain	2/39 (5.1%)		0/2 (0%)		0/3 (0%)		3/35 (8.6%)
Nasal congestion	3/39 (7.7%)		0/2 (0%)		0/3 (0%)		2/35 (5.7%)
Rhinitis allergic	3/39 (7.7%)		0/2 (0%)		0/3 (0%)		1/35 (2.9%)
Epistaxis	2/39 (5.1%)		0/2 (0%)		0/3 (0%)		1/35 (2.9%)
Skin and subcutaneous tissue disorders
Dry skin	1/39 (2.6%)		0/2 (0%)		0/3 (0%)		2/35 (5.7%)
Rash	3/39 (7.7%)		0/2 (0%)		0/3 (0%)		0/35 (0%)
Dermatitis acneiform	2/39 (5.1%)		0/2 (0%)		0/3 (0%)		0/35 (0%)
Vascular disorders
Hot flush	0/39 (0%)		0/2 (0%)		0/3 (0%)		3/35 (8.6%)
Hypertension	0/39 (0%)		0/2 (0%)		1/3 (33.3%)		1/35 (2.9%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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