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Clinical Trial Results:
An Open-Label, Multicenter, Extension Study of AG-348 in Adult Subjects With Pyruvate Kinase Deficiency Previously Enrolled in AG-348 Studies

Summary
EudraCT number	2018-003459-39
Trial protocol	DK GB ES FR IE NL DE IT
Global end of trial date	03 Jul 2024

Results information
Results version number	v1(current)
This version publication date	18 Jul 2025
First version publication date	18 Jul 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

AG348-C-011

ISRCTN number

US NCT number

NCT03853798

WHO universal trial number (UTN)

Sponsor organisation name

Agios Pharmaceuticals, Inc.

Sponsor organisation address

88 Sidney Street, Cambridge, United States, MA 02139-4169

Public contact

Director, Scientific Communications, Agios Pharmaceuticals, Inc., +1 844633 2332, medinfo@agios.com

Scientific contact

Director, Scientific Communications, Agios Pharmaceuticals, Inc., +1 844633 2332, medinfo@agios.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

03 Jul 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

03 Jul 2024

Was the trial ended prematurely?

Main objective of the trial

This is an open-label, multicentre, extension study to evaluate the long-term safety, tolerability, and efficacy of treatment with mitapivat in subjects who were previously enrolled in Study AG348-C-006 or Study AG348-C-007.

Protection of trial subjects

Each subject was required to sign an informed consent form (ICF) to participate in the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

04 Mar 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 26

Country: Number of subjects enrolled

Netherlands: 4

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

United Kingdom: 5

Country: Number of subjects enrolled

Denmark: 11

Country: Number of subjects enrolled

France: 11

Country: Number of subjects enrolled

Germany: 5

Country: Number of subjects enrolled

Ireland: 1

Country: Number of subjects enrolled

Italy: 6

Country: Number of subjects enrolled

Switzerland: 1

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

Japan: 6

Country: Number of subjects enrolled

Korea, Republic of: 2

Country: Number of subjects enrolled

Thailand: 2

Country: Number of subjects enrolled

Brazil: 1

Country: Number of subjects enrolled

Türkiye: 1

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were enrolled at 42 investigative sites in Denmark, France, Italy, Spain, Germany, United Kingdom, Netherlands, Ireland, Switzerland, United States, Canada, Japan, Korea, Thailand, Brazil and Turkey from 21 March 2019 t 03 July 2024.

Screening details

A total of 90 subjects who had completed StudyAG348-C-006 (NCT03548220) or AG348-C-007 (NCT03559699), were enrolled in this extension study to receive mitapivat treatment. Subjects were assigned to Cohorts 1, 2 or 3 depending on the previous treatment received in the antecedent studies.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1

Arm description

Subjects who received placebo in Study AG348-C-006 and met the eligibility criteria of this extension study were enrolled to receive mitapivat 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 subject was determined at Week 12, and subjects then received that optimized dose for a period of 12 weeks (Weeks 13-24) as a fixed dose and from Week 25 to Week 193, until study withdrawal, or the study was closed.

Arm type

Experimental

Investigational medicinal product name

Mitapivat

Investigational medicinal product code

AG-348

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received mitapivat 5 mg, 20 mg, or 50 mg tablets, orally, BID, for up to 193 weeks or until study withdrawal, or the study was closed.

Cohort 2

Arm description

Subjects who received mitapivat at a dose of 5 mg, 20 mg, or 50 mg, BID, in the fixed dose period of Study AG348-C-006 and met the eligibility criteria of this extension study continued to receive the same mitapivat dose up to Week 193 or until study withdrawal, or the study was closed.

Arm type

Experimental

Investigational medicinal product name

Mitapivat

Investigational medicinal product code

AG-348

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received mitapivat 5 mg, 20 mg or 50 mg tablets, orally, BID, for up to 193 weeks or until study withdrawal, or the study was closed.

Cohort 3

Arm description

Subjects who received mitapivat at a dose of 5 mg, 20 mg, or 50 mg, BID, in the fixed dose period of Study AG348-C-007 and met the eligibility criteria of this extension study continued to receive the same mitapivat up to Week 193 or until study withdrawal, or the study was closed.

Arm type

Experimental

Investigational medicinal product name

Mitapivat

Investigational medicinal product code

AG-348

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received mitapivat 5 mg, 20 mg, or 50 mg tablets, orally, BID, for up to 193 weeks or until study withdrawal, or the study was closed.

Number of subjects in period 1	Cohort 1	Cohort 2	Cohort 3
Started	38	35	17
Completed	25	27	11
Not completed	13	8	6
Physician decision	1	-	1
Adverse Event	2	-	-
Death	-	1	-
Withdrawal by Subject	5	5	4
Approved Drug Available for Indication	1	1	-
Reason Unscpecified	2	1	-
Lack of efficacy	2	-	1

Baseline characteristics

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Reporting group title

Cohort 1

Reporting group description

Reporting group title

Cohort 2

Reporting group description

Reporting group title

Cohort 3

Reporting group description

Reporting group values	Cohort 1	Cohort 2	Cohort 3	Total
Number of subjects	38	35	17	90
Age categorical
Units: Subjects
In utero				0
Preterm newborn infants (gestational age < 37 wks)				0
Newborns (0-27 days)				0
Infants and toddlers (28 days-23 months)				0
Children (2-11 years)				0
Adolescents (12-17 years)				0
Adults (18-64 years)				0
From 65-84 years				0
85 years and over				0
Age continuous
Units: years
arithmetic mean (standard deviation)	38.0 ( 15.95 )	36.9 ( 15.77 )	36.9 ( 15.09 )	-
Gender categorical
Units: Subjects
Female	23	20	12	55
Male	15	15	5	35
Ethnicity
Units: Subjects
Hispanic or Latino	1	2	0	3
Not Hispanic or Latino	33	23	12	68
Unknown or Not Reported	4	10	5	19
Race/Ethnicity
Units: Subjects
White	31	23	13	67
Asian	3	5	2	10
Native Hawaiian or Other Pacific Islander	0	1	0	1
Other	1	0	0	1
Not reported	3	6	2	11

End points

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Reporting group title

Cohort 1

Reporting group description

Reporting group title

Cohort 2

Reporting group description

Reporting group title

Cohort 3

Reporting group description

Subject analysis set title

MItapivat: 5 mg

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received mitapivat in study AG348-C-003 and AG348-C-007 and who received both mitapivat and placebo in study AG348-C-006 were enrolled to receive mitapivat 5 mg, orally, BID until sequential step of dose increase to 20 mg BID, until withdrawal, or the study was closed. The safety analysis set was defined as all subjects who received at least 1 dose of study drug. The safety exposure-response (E-R) analysis was based on pooled data, consisting of all subjects from Study AG348-C-003 (SAS-003, only core part), Study AG348-C-006 (SAS-006), Study AG348 C-007 (SAS-007), and Study AG348-C-011 (SAS-011, Cohort 1), as well as the placebo-treated subjects from Study AG348-C-006.

Subject analysis set title

MItapivat: 20 mg

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received mitapivat in study AG348-C-003 and AG348-C-007 and who received both mitapivat and placebo in study AG348-C-006 were enrolled to receive mitapivat starting dose of 5 mg BID with sequential step of dose increase to 20 mg BID. Subjects received 20 mg, orally, BID until sequential step of dose increase to 50 mg BID, study withdrawal, or the study was closed. The safety analysis set was defined as all subjects who received at least 1 dose of study drug. The safety E-R analysis was based on pooled data, consisting of all subjects from Study AG348-C-003 (SAS-003, only core part), Study AG348-C-006 (SAS-006), Study AG348 C-007 (SAS-007), and Study AG348-C-011 (SAS-011, Cohort 1), as well as the placebo-treated subjects from Study AG348-C-006.

Subject analysis set title

MItapivat: 50 mg

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received mitapivat in study AG348-C-003 and AG348-C-007 and who received both mitapivat and placebo in study AG348-C-006 were enrolled to receive mitapivat starting dose of 5 mg BID with sequential steps of dose increases to 20 mg BID and from 20 mg BID to 50 mg BID. Subjects received 50 mg, orally, BID until study withdrawal, or the study was closed. The safety analysis set was defined as all subjects who received at least 1 dose of study drug. The safety E-R analysis was based on pooled data, consisting of all subjects from Study AG348-C-003 (SAS-003, only core part), Study AG348-C-006 (SAS-006), Study AG348 C-007 (SAS-007), and Study AG348-C-011 (SAS-011, Cohort 1), as well as the placebo-treated subjects from Study AG348-C-006.

Primary: All Cohorts: Number of Subjects With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3

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End point title

All Cohorts: Number of Subjects With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 ^[1]

End point description

TEAEs are adverse events (AEs) with initial onset date during on-treatment period/worsening from baseline & includes both serious & non-serious TEAEs. Severity of AEs was evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03):grade 1:mild;grade 2:moderate;grade 3:severe or medically significant but not immediately life-threatening;grade 4:life threatening or disabling;grade 5:death related to AE. Safety analysis set included all subjects who received at least 1 dose of study drug.

End point type

Primary

End point timeframe

Up to 197 weeks

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was performed for this end point.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	38	35	17
Units: count of subjects
Subjects with TEAEs	37	33	15
Subjects with Serious TEAEs	11	8	4
Subjects with TEAEs related to study drug	22	14	4
Subjects with any TEAE of Grade ≥3	18	10	5

No statistical analyses for this end point

Primary: All Cohorts: Number of Subjects With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation

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End point title

All Cohorts: Number of Subjects With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation ^[2]

End point description

A clinical AE is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study drug. TEAE is defined as any AE that increased in severity or newly developed during the treatment-emergent period. The safety analysis set included all subjects who received at least 1 dose of study treatment.

End point type

Primary

End point timeframe

Up to 197 weeks

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was performed for this end point.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	38	35	17
Units: count of subjects
Subjects with TEAEs Leading to Dose Reduction	2	2	1
Subjects with TEAEs Leading to Interruption	3	4	0
Subjects with TEAEs Leading to Discontinuation	2	1	0

No statistical analyses for this end point

Primary: All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Laboratory Parameters Reported as TEAEs

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End point title

All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Laboratory Parameters Reported as TEAEs ^[3]

End point description

Clinical laboratory assessments including hematology, clinical chemistry, triglycerides, urate, coagulation, urinalysis, and liver function tests were performed in the study. Number of subjects with clinically significant abnormalities graded ≥3 in laboratory parameters were reported as TEAEs. Clinically significant treatment-emergent laboratory abnormalities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE. Clinical significance was determined based on the judgment of the Investigator. The safety analysis set included all subjects who received at least 1 dose of study treatment.

End point type

Primary

End point timeframe

Up to 197 weeks

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was performed for this end point.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	38	35	17
Units: count of subjects
Anaemia	3	1	0
Haemolysis	1	2	0
Alanine aminotransferase increased	0	0	1
Aspartate aminotransferase increased	2	1	1
Blood bilirubin increased	0	0	1
Blood triglycerides increased	1	0	0
Hypertriglyceridaemia	1	0	0

No statistical analyses for this end point

Primary: All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs

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End point title

All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs ^[4]

End point description

Vital signs and physical examinations including height, weight, body mass index (BMI), systolic blood pressure, diastolic blood pressure, pulse rate, temperature were assessed. Number of subjects who experienced clinically significant abnormalities in vital signs and physical examinations as TEAEs were reported. Clinical significance was determined based on the judgment of the Investigator. The safety analysis set included all subjects who received at least 1 dose of study treatment.

End point type

Primary

End point timeframe

Up to 197 weeks

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was performed for this end point.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	38	35	17
Units: count of subjects
Weight decreased	0	1	1
Hot flush	2	0	2
Hypotension	1	0	0
Hypertension	1	2	0

No statistical analyses for this end point

Primary: All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters Reported as TEAEs

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End point title

All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters Reported as TEAEs ^[5]

End point description

The following ECG parameters including RR, PR, heart rate-corrected QT interval using the Fridericia's formula [QRS], QT, and QTc were assessed during the study. Number of subjects with clinically significant abnormalities in ECG parameters as TEAEs were reported. Clinical significance was determined based on the judgment of the Investigator. The safety analysis set included all subjects who received at least 1 dose of study treatment.

End point type

Primary

End point timeframe

Up to 197 weeks

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analysis was not planned for this end point.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	38	35	17
Units: count of subjects	0	1	0

No statistical analyses for this end point

Primary: All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Bone Mineral Density (BMD)

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End point title

All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Bone Mineral Density (BMD) ^[6]

End point description

BMD was measured by DXA scans during the study. Number of subjects with clinically significant bone abnormalities ((i.e., grade 2 bone density decreased) were reported. Clinical significance was determined based on the judgment of the Investigator. The safety analysis set included all subjects who received at least 1 dose of study treatment.

End point type

Primary

End point timeframe

Up to 197 weeks

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was performed for this end point.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	38	35	17
Units: count of subjects	0	1	0

No statistical analyses for this end point

Primary: All Cohorts: Change From Baseline in Adjusted Spine T-score

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End point title

All Cohorts: Change From Baseline in Adjusted Spine T-score ^[7]

End point description

T-score of adjusted spine were assessed by DXA scans. The T-score is the number of standard deviations that bone density is above or below the average. A score of ≥ -1 indicates normal bone density; score between < -1 and > -2.5 indicates a sign of osteopenia (bone density below normal), and score of ≤ -2.5 indicates a sign of osteoporosis. The baseline was the last assessment before start of study treatment (mitapivat). The safety analysis set included all subjects who received at least 1 dose of study treatment. Here, number of subjects analysed indicates the number of subjects who were evaluable for this end point, and "n" indicates number of subjects who were evaluable for this end point at the specified time points.

End point type

Primary

End point timeframe

Baseline, Week 192

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive analysis has been reported for this end point.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	38	34	17
Units: score on a scale
arithmetic mean (standard deviation)
Baseline (n = 38, 34, 17)	-1.143 ( 1.0926 )	-1.808 ( 1.1589 )	-1.161 ( 1.0469 )
Week 192 (n = 24, 20, 8)	0.046 ( 0.4874 )	0.234 ( 0.4383 )	0.416 ( 1.1090 )

No statistical analyses for this end point

Primary: All Cohorts: Change From Baseline in Adjusted Spine Z-score

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End point title

All Cohorts: Change From Baseline in Adjusted Spine Z-score ^[8]

End point description

The Z-score of adjusted spine was assessed by DXA scans. The Z-score is a statistical measure to describe whether a value was above or below the standard. A Z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard. The baseline was the last assessment before start of study treatment (mitapivat). The safety analysis set included all subjects who received at least 1 dose of study treatment. Here, number of subjects analysed indicates the number of subjects who were evaluable for this end point, and "n" indicates number of subjects who were evaluable for this end point at the specified time points.

End point type

Primary

End point timeframe

Baseline, Week 192

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive analysis has been reported for this end point.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	38	34	17
Units: Z-score
arithmetic mean (standard deviation)
Baseline (n = 38, 34, 17)	-0.804 ( 1.2529 )	-1.536 ( 1.2469 )	-0.848 ( 1.0420 )
Week 192 (n = 24, 20, 8)	0.152 ( 0.4585 )	0.332 ( 0.4002 )	0.530 ( 1.2409 )

No statistical analyses for this end point

Primary: All Cohorts: Change From Baseline in Femoral Total T-score

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End point title

All Cohorts: Change From Baseline in Femoral Total T-score ^[9]

End point description

T-score of femoral total were assessed by DXA scans. The T-score is the number of standard deviations that bone density is above or below the average. A score of ≥ -1 indicates normal bone density; score between < -1 and > -2.5 indicates a sign of osteopenia (bone density below normal), and score of ≤ -2.5 indicates a sign of osteoporosis. The baseline was the last assessment before start of study treatment (mitapivat). The safety analysis set included all subjects who received at least 1 dose of study treatment. Here, number of subjects analysed indicates the number of subjects who were evaluable for this end point, and "n" indicates number of subjects who were evaluable for this end point at the specified time points.

End point type

Primary

End point timeframe

Baseline, Week 192

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive analysis has been reported for this end point.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	38	34	17
Units: score on a scale
arithmetic mean (standard deviation)
Baseline (n = 38, 34, 17)	-0.834 ( 1.1182 )	-1.139 ( 1.0995 )	-0.813 ( 0.6748 )
Week 192 (n = 24, 20, 8)	-0.020 ( 0.2612 )	0.047 ( 0.3893 )	0.114 ( 0.5050 )

No statistical analyses for this end point

Primary: All Cohorts: Change From Baseline in Femoral Total Z-score

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End point title

All Cohorts: Change From Baseline in Femoral Total Z-score ^[10]

End point description

The Z-score of femoral total was assessed by DXA scans. The Z-score is a statistical measure to describe whether a value was above or below the standard. A Z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard. The baseline was the last assessment before start of study treatment (mitapivat). The safety analysis set included all subjects who received at least 1 dose of study treatment. Here, number of subjects analysed indicates the number of subjects who were evaluable for this end point, and "n" indicates number of subjects who were evaluable for this end point at the specified time points.

End point type

Primary

End point timeframe

Baseline, Week 192

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive analysis has been reported for this end point.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	38	34	17
Units: Z-score
arithmetic mean (standard deviation)
Baseline (n = 38, 34, 17)	-0.548 ( 1.1574 )	-0.916 ( 1.0657 )	-0.529 ( 0.7137 )
Week 192 (n = 24, 20, 8)	0.054 ( 0.2468 )	0.126 ( 0.3631 )	0.214 ( 0.5099 )

No statistical analyses for this end point

Secondary: Cohort 1: Percentage of Subjects Who Achieved a Hemoglobin (Hb) Response

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End point title

Cohort 1: Percentage of Subjects Who Achieved a Hemoglobin (Hb) Response ^[11]

End point description

The Hb response was defined as a ≥1.5 grams per deciliter (g/dL) (0.93 millimoles per liter [mmol/L]) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments, excluding those within 2 months (61 days) of transfusion. The baseline value for cohort 1 subjects was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment is available. Full analysis set (FAS) included all subjects who received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Baseline up to Week 24

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As pre-specified in the protocol, data for this end point was planned to be reported for Cohort 1 only based on FAS.

End point values	Cohort 1
Number of subjects analysed	38
Units: percentage of subjects
number (not applicable)	39.5

No statistical analyses for this end point

Secondary: Cohort 1: Average Change From Baseline in Hb Concentration at Weeks 16, 20, and 24

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End point title

Cohort 1: Average Change From Baseline in Hb Concentration at Weeks 16, 20, and 24 ^[12]

End point description

The baseline value for subjects was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment is available. The mean of average change from baseline in Hb concentration across Weeks 16, 20 and 24 is reported. FAS included all subjects who received at least 1 dose of study treatment. Here, number of subjects analysed indicates the number of subjects who were evaluable for this end point.

End point type

Secondary

End point timeframe

Baseline, Weeks 16, 20, and 24

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As pre-specified in the protocol, data for this endpoint was planned to be reported for Cohort 1 only based on FAS.

End point values	Cohort 1
Number of subjects analysed	36
Units: grams per litre
arithmetic mean (standard deviation)	16.45 ( 15.634 )

No statistical analyses for this end point

Secondary: Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to 8-hours Post-dose (AUC0-8) of Mitapivat

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End point title

Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to 8-hours Post-dose (AUC0-8) of Mitapivat ^[13]

End point description

Pharmacokinetics (PK) analysis population included all subjects who were enrolled and received at least 1 dose of study treatment (mitapivat) with at least 1 non-zero plasma concentration of mitapivat at the Week 12 visit. Here, number of subjects analyzed indicates the number of subjects who received 50 mg BID mitapivat in Cohort 1 and were evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As pre-specified in the protocol, data for this endpoint was planned to be reported for Cohort 1 only.

End point values	Cohort 1
Number of subjects analysed	23
Units: hournanograms/millilitre (hrng/mL)
geometric mean (geometric coefficient of variation)	3016 ( 27.5 )

No statistical analyses for this end point

Secondary: Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Mitapivat

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End point title

Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Mitapivat ^[14]

End point description

PK analysis population included all subjects who were enrolled and received at least 1 dose of study treatment (mitapivat) with at least 1 non-zero plasma concentration of mitapivat at the Week 12 visit. Here, number of subjects analyzed indicates the number of subjects who received 50 mg BID mitapivat in Cohort 1 and were evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As pre-specified in the protocol, data for this endpoint was planned to be reported for Cohort 1 only.

End point values	Cohort 1
Number of subjects analysed	28
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)	2990 ( 26.3 )

No statistical analyses for this end point

Secondary: Cohort 1: Maximum Observed Plasma Concentration (Cmax) of Mitapivat

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End point title

Cohort 1: Maximum Observed Plasma Concentration (Cmax) of Mitapivat ^[15]

End point description

PK analysis population included all subjects who were enrolled and received at least 1 dose of study treatment (mitapivat) with at least 1 non-zero plasma concentration of mitapivat at the Week 12 visit. Here, number of subjects analysed indicates the number of subjects who received 50 mg BID mitapivat in Cohort 1 and were evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As pre-specified in the protocol, data for this endpoint was planned to be reported for Cohort 1 only.

End point values	Cohort 1
Number of subjects analysed	30
Units: nanograms/millilitre (ng/mL)
geometric mean (geometric coefficient of variation)	1018 ( 22.5 )

No statistical analyses for this end point

Secondary: Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat

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End point title

Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat ^[16]

End point description

PK analysis population included all subjects who were enrolled and received at least 1 dose of study treatment (mitapivat) with at least 1 non-zero plasma concentration of mitapivat at the Week 12 visit. Here, number of subjects analysed indicates the number of subjects who received 50 mg BID mitapivat in Cohort 1 and were evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As pre-specified in the protocol, data for this endpoint was planned to be reported for Cohort 1 only.

End point values	Cohort 1
Number of subjects analysed	30
Units: hours
median (full range (min-max))	1.00 (0.45 to 4.3)

No statistical analyses for this end point

Secondary: Cohort 1: Plasma Concentration (Ctrough) at the End of a Dosing Interval of Mitapivat

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End point title

Cohort 1: Plasma Concentration (Ctrough) at the End of a Dosing Interval of Mitapivat ^[17]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As pre-specified in the protocol, data for this endpoint was planned to be reported for Cohort 1 only.

End point values	Cohort 1
Number of subjects analysed	28
Units: ng/mL
geometric mean (geometric coefficient of variation)	62.8 ( 72.7 )

No statistical analyses for this end point

Secondary: Cohort 1: Exposure-response (E-R) Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters

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End point title

Cohort 1: Exposure-response (E-R) Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters

End point description

Statistically significant E-R relationships were identified for safety parameters including all grade insomnia and all grade hot flush and were reported in terms of percent probability based on E-R model. The safety E-R analysis was based on pooled data, consisting of all 155 subjects from Study AG348-C-003 (SAS-003, only core part): 52 subjects , Study AG348-C-006 (SAS-006): 40 subjects , Study AG348 C-007 (SAS-007): 27 subjects , and Study AG348-C-011 (SAS-011, Cohort 1): 36 subjects , as well as the placebo-treated subjects from Study AG348-C-006. As pre-specified in the protocol, data for this end point was planned to be reported for Cohort 1 only. Subjects analysed is the number of subjects who were evaluable for this end point.

End point type

Secondary

End point timeframe

First dose to up to 24 weeks

End point values	MItapivat: 5 mg	MItapivat: 20 mg	MItapivat: 50 mg
Number of subjects analysed	155	155	155
Units: percent probability
arithmetic mean (confidence interval 95%)
Hot Flush	3.37 (1.22 to 7.35)	4.03 (1.61 to 8.36)	5.5 (2.48 to 10.5)
Insomnia	19.9 (13.3 to 28.0)	22.1 (15.5 to 29.9)	26.0 (19.3 to 33.9)

No statistical analyses for this end point

Secondary: Cohorts 1 and 2: Change From Baseline in Hb Concentration

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End point title

Cohorts 1 and 2: Change From Baseline in Hb Concentration ^[18]

End point description

The baseline value for cohort 1 subjects was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment was available. The baseline value for cohort 2 was from Study AG348-C-006. FAS included all subjects who received at least 1 dose of study treatment. Here, number of subjects analysed indicates the number of subjects who were evaluable for this end point.

End point type

Secondary

End point timeframe

Baseline, Week 192

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As pre-specified in the statistical analysis plan (SAP), data for this endpoint was planned to be reported for Cohort 1 and 2 only based on FAS.

End point values	Cohort 1	Cohort 2
Number of subjects analysed	22	23
Units: grams per litre
arithmetic mean (standard deviation)	22.39 ( 21.211 )	21.32 ( 20.721 )

No statistical analyses for this end point

Secondary: Cohorts 1 and 2: Change From Baseline in Indirect Bilirubin

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End point title

Cohorts 1 and 2: Change From Baseline in Indirect Bilirubin ^[19]

End point description

The baseline value for cohort 1 subjects was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment is available. The baseline value for cohort 2 was from Study AG348-C-006. FAS included all subjects who received at least 1 dose of study treatment. Here, number of subjects analysed indicates the number of subjects who were evaluable for this end point.

End point type

Secondary

End point timeframe

Baseline, Week 192

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As pre-specified in the SAP, data for this endpoint was planned to be reported for Cohort 1 and 2 only based on FAS.

End point values	Cohort 1	Cohort 2
Number of subjects analysed	22	21
Units: micromoles per litre (μmol/L)
arithmetic mean (standard deviation)	-57.50 ( 54.542 )	-36.73 ( 35.511 )

No statistical analyses for this end point

Secondary: Cohorts 1 and 2: Change From Baseline in Lactate Dehydrogenase (LDH)

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End point title

Cohorts 1 and 2: Change From Baseline in Lactate Dehydrogenase (LDH) ^[20]

End point description

End point type

Secondary

End point timeframe

Baseline, Week 192

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As pre-specified in the SAP, data for this endpoint was planned to be reported for Cohort 1 and 2 only based on FAS.

End point values	Cohort 1	Cohort 2
Number of subjects analysed	24	22
Units: Units per Litre (U/L)
arithmetic mean (standard deviation)	-46.10 ( 75.310 )	-130.80 ( 275.424 )

No statistical analyses for this end point

Secondary: Cohorts 1 and 2: Change From Baseline in Haptoglobin Levels

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End point title

Cohorts 1 and 2: Change From Baseline in Haptoglobin Levels ^[21]

End point description

The baseline value for cohort 1 subjects was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment is available. The baseline value for cohort 2 was from Study AG348-C-006. FAS included all subjects who received at least 1 dose of study treatment. Here, number of subjects analysed indicates the number of subjects who were evaluable for this end point.

End point type

Secondary

End point timeframe

Baseline, Week 192

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As pre-specified in the SAP, data for this endpoint was planned to be reported for Cohort 1 and 2 only based on FAS.

End point values	Cohort 1	Cohort 2
Number of subjects analysed	24	25
Units: grams per litre
arithmetic mean (standard deviation)	0.254 ( 0.4340 )	0.250 ( 0.4689 )

No statistical analyses for this end point

Secondary: Cohorts 1 and 2: Change From Baseline in Reticulocytes/Erythrocytes Ratio

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End point title

Cohorts 1 and 2: Change From Baseline in Reticulocytes/Erythrocytes Ratio ^[22]

End point description

The baseline value for cohort 1 subjects was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment is available. The baseline value for cohort 2 was from Study AG348-C-006. FAS included all subjects who received at least 1 dose of study treatment. Here, number of subjects analysed indicates the number of subjects who were evaluable for this end point.

End point type

Secondary

End point timeframe

Baseline, Week 192

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As pre-specified in the SAP, data for this endpoint was planned to be reported for Cohort 1 and 2 only based on FAS.

End point values	Cohort 1	Cohort 2
Number of subjects analysed	22	20
Units: Reticulocytes/Erythrocytes Ratio
arithmetic mean (standard deviation)	-0.1696 ( 0.16243 )	-0.1565 ( 0.14631 )

No statistical analyses for this end point

Secondary: Cohort 3: Change From Baseline in Number of Transfusion Episodes

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End point title

Cohort 3: Change From Baseline in Number of Transfusion Episodes ^[23]

End point description

Number of transfusions at baseline was determined based on the transfusion data during the 52 weeks before informed consent for Cohort 3. Number of on-study transfusions was based on transfusions collected up to the end of the fixed dose period and standardized to 52 weeks. The change from baseline in number of transfusions was summarized for Cohort 3. FAS included all subjects who received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Baseline, Week 192

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per planned analysis, data for this end point was reported for Cohort 3 only based on FAS.

End point values	Cohort 3
Number of subjects analysed	17
Units: number of transfusion episodes
arithmetic mean (standard deviation)	4.14 ( 5.487 )

No statistical analyses for this end point

Secondary: Cohort 3: Change from Baseline in Number of Red Blood Cell (RBC) Units Transfused

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End point title

Cohort 3: Change from Baseline in Number of Red Blood Cell (RBC) Units Transfused ^[24]

End point description

Annualized total number of RBC units transfused (units/52-week) during the study, including data up to end of study (EOS), was the total number of RBC units transfused during the entire study*52 / [(date of EOS – date of start of study treatment + 1)/7]. Number of RBC units were determined based on the transfusion data during the 52 weeks before informed consent of the antecedent study for Cohort 3. Number of on-study RBC units was based on transfusion data collected up to the end of the fixed dose period and standardized to 52 weeks. FAS included all subjects who received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Baseline, Week 192

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As pre-specified in the SAP, analysis of number of RBC units transfused at baseline was planned for Cohort 3 only.

End point values	Cohort 3
Number of subjects analysed	17
Units: number of RBC units transfused
arithmetic mean (standard deviation)	7.25 ( 7.915 )

No statistical analyses for this end point

Secondary: All Cohorts: Change From Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD)

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End point title

All Cohorts: Change From Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD)

End point description

PKDD is a 7-item PRO measure of core signs & symptoms associated with PK deficiency in adults. Subjects rate their experience with symptoms of PK deficiency on present day. Symptoms include tiredness, jaundice, bone pain, shortness of breath, & energy level. Score ranges from 25 to 76, with higher scores indicating more severe symptoms & higher disease burden. Change from baseline in weekly mean scores was summarized. Negative change from baseline indicates lower disease burden. Baseline of weekly mean score was defined as average of daily scores collected within 7 days before start of study treatment (mitapivat). For Cohort 1, last measurement before start of study treatment in AG348-C-011 was used as baseline; if baseline was missing, baseline value from AG348-c-006 was used. For Cohorts 2 & 3, baseline values from 006 & 007, respectively, were used. FAS included all subjects who received at least 1 dose of study treatment. Subjects analysed:number of subjects evaluable for endpoint

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	27	24	10
Units: score on a scale
arithmetic mean (standard deviation)	-3.75 ( 5.805 )	-6.09 ( 7.617 )	-5.04 ( 12.273 )

No statistical analyses for this end point

Secondary: All Cohorts: Change From Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA)

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End point title

All Cohorts: Change From Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA)

End point description

PKDIA is a 12-item PRO measure of common impacts of PK deficiency on activities of daily living. Subjects rated how PK deficiency has impacted aspects of daily living in past 7 days, including impacts on relationships & leisure and social, mental, and physical activities. Score ranges from 30 to 76, with higher scores indicating higher disease burden. Negative change from baseline indicates lower disease burden. Baseline was defined as the last complete assessment (with no missing item in response) before start of study treatment. For Cohort 1, the last measurement before the start of study treatment in AG348-C-011 was used as the baseline; if baseline was missing, the baseline value from AG348-C-006 was used. For Cohort 2 and Cohort 3, the baseline values from 006 and 007, respectively, were used. FAS included all subjects who received at least 1 dose of study treatment. Subjects analysed indicates the number of subjects evaluable for this end point.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	31	28	14
Units: score on a scale
arithmetic mean (standard deviation)	-3.9 ( 7.38 )	-6.6 ( 8.75 )	-5.4 ( 12.83 )

No statistical analyses for this end point

Secondary: Cohort 1: Time of Last Quantifiable Concentration (Tlast) of Mitapivat

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End point title

Cohort 1: Time of Last Quantifiable Concentration (Tlast) of Mitapivat ^[25]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As pre-specified in the protocol, data for this endpoint was planned to be reported for Cohort 1 only.

End point values	Cohort 1
Number of subjects analysed	28
Units: hours
median (full range (min-max))	7.61 (3.57 to 8.53)

No statistical analyses for this end point

Secondary: Cohort 1: E-R Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters

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End point title

Cohort 1: E-R Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters

End point description

Statistically significant E-R relationships were identified for safety parameters including all grade male sex hormones including estrone, total testosterone and free testosterone and were reported in terms of percent change based on E-R model. Safety analysis set was used. The safety E-R analysis was based on pooled data, consisting of 68 subjects from Study AG348-C-003 (only core part): 32 subjects, Study AG348-C-006: 15 subjects, Study AG348 C-007: 7subjects and Study AG348-C-011 (Cohort 1): 14 subjects, as well as the placebo-treated subjects from Study AG348-C-006. As pre-specified in the protocol, data for this end point was planned to be reported for Cohort 1 only. Subjects analysed is the number of subjects who were evaluable for this end point. Here, "n" is number of subjects with data available for analysis for the specified category.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	MItapivat: 5 mg	MItapivat: 20 mg	MItapivat: 50 mg
Number of subjects analysed	68	68	68
Units: percent change
arithmetic mean (confidence interval 95%)
Total Testosterone	0.877 (0.41 to 1.43)	3.18 (1.49 to 5.4)	7.59 (3.29 to 13.7)
Free Testosterone	6.01 (1.66 to 13.2)	14.1 (4 to 27.5)	26.0 (7.14 to 55.1)
Estrone (n=67)	-31.5 (-51 to -21.1)	-56.5 (-67.3 to -48.4)	-68.2 (-74.5 to -62.6)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 197 weeks

Adverse event reporting additional description

The safety analysis set included all subjects who received at least 1 dose of study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.0

Reporting group title

Cohort 1

Reporting group description

Subjects who received placebo in Study AG348-C-006 and met the eligibility criteria of this extension study were enrolled to receive mitapivat 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 subject was determined at Week 12, and subjects then received that optimized dose for a period of 12 weeks (Weeks 13-24) as a fixed dose and from Week 25 to Week 193, until study withdrawal, or the study was closed.

Reporting group title

Cohort 2

Reporting group description

Reporting group title

Cohort 3

Reporting group description

Subjects who received mitapivat at a dose of 5 mg, 20 mg, or 50 mg, BID, in the fixed dose period of Study AG348-C-007 and met the eligibility criteria of this extension study continued to receive the same mitapivat dose up to Week 193 or until study withdrawal, or the study was closed.

Serious adverse events	Cohort 1	Cohort 2	Cohort 3
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 38 (28.95%)	8 / 35 (22.86%)	4 / 17 (23.53%)
number of deaths (all causes)	0	1	0
number of deaths resulting from adverse events	0	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hodgkin's disease
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatocellular carcinoma
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastatic malignant melanoma
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningioma
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Tibia fracture
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Accident
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Femur fracture
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Vascular stenosis
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	1 / 38 (2.63%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Carotid artery aneurysm
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intracranial aneurysm
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Haemolysis
subjects affected / exposed	1 / 38 (2.63%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis chronic
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Sepsis
subjects affected / exposed	3 / 38 (7.89%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 38 (2.63%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Varicella zoster virus infection
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Cohort 1	Cohort 2	Cohort 3
Total subjects affected by non serious adverse events
subjects affected / exposed	36 / 38 (94.74%)	31 / 35 (88.57%)	15 / 17 (88.24%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Back pain
subjects affected / exposed	5 / 38 (13.16%)	3 / 35 (8.57%)	2 / 17 (11.76%)
occurrences all number	6	4	3
Meningioma
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Superficial spreading melanoma stage unspecified
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Vascular disorders
Hot flush
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	2 / 17 (11.76%)
occurrences all number	3	0	2
Hypertension
subjects affected / exposed	1 / 38 (2.63%)	2 / 35 (5.71%)	0 / 17 (0.00%)
occurrences all number	2	2	0
Arteriosclerosis
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	0	1
Haematoma
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Vertigo positional
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	11 / 38 (28.95%)	8 / 35 (22.86%)	4 / 17 (23.53%)
occurrences all number	16	10	6
Pyrexia
subjects affected / exposed	10 / 38 (26.32%)	9 / 35 (25.71%)	3 / 17 (17.65%)
occurrences all number	16	15	4
Influenza like illness
subjects affected / exposed	4 / 38 (10.53%)	2 / 35 (5.71%)	2 / 17 (11.76%)
occurrences all number	4	2	4
Oedema peripheral
subjects affected / exposed	3 / 38 (7.89%)	1 / 35 (2.86%)	2 / 17 (11.76%)
occurrences all number	3	1	2
Asthenia
subjects affected / exposed	2 / 38 (5.26%)	3 / 35 (8.57%)	0 / 17 (0.00%)
occurrences all number	2	5	0
Injection site pain
subjects affected / exposed	2 / 38 (5.26%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences all number	3	1	0
Chest pain
subjects affected / exposed	0 / 38 (0.00%)	2 / 35 (5.71%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Face oedema
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Inflammation
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Peripheral swelling
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Immune system disorders
Seasonal allergy
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	2 / 38 (5.26%)	2 / 35 (5.71%)	0 / 17 (0.00%)
occurrences all number	2	2	0
Menstruation irregular
subjects affected / exposed	0 / 38 (0.00%)	2 / 35 (5.71%)	2 / 17 (11.76%)
occurrences all number	0	2	2
Intermenstrual bleeding
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	0	2
Bartholin's cyst
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Breast cyst
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Perineal cyst
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Uterine polyp
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 38 (10.53%)	5 / 35 (14.29%)	4 / 17 (23.53%)
occurrences all number	4	5	5
Oropharyngeal pain
subjects affected / exposed	5 / 38 (13.16%)	2 / 35 (5.71%)	2 / 17 (11.76%)
occurrences all number	12	2	2
Dyspnoea
subjects affected / exposed	5 / 38 (13.16%)	3 / 35 (8.57%)	0 / 17 (0.00%)
occurrences all number	5	3	0
Asthma
subjects affected / exposed	1 / 38 (2.63%)	1 / 35 (2.86%)	2 / 17 (11.76%)
occurrences all number	1	1	2
Rhinitis allergic
subjects affected / exposed	3 / 38 (7.89%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences all number	9	1	0
Rhinorrhoea
subjects affected / exposed	2 / 38 (5.26%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences all number	2	1	0
Pulmonary mass
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Psychiatric disorders
Middle insomnia
subjects affected / exposed	8 / 38 (21.05%)	2 / 35 (5.71%)	1 / 17 (5.88%)
occurrences all number	19	2	1
Initial insomnia
subjects affected / exposed	10 / 38 (26.32%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	12	0	0
Depression
subjects affected / exposed	2 / 38 (5.26%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	2	1	1
Anxiety
subjects affected / exposed	2 / 38 (5.26%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences all number	2	1	0
Panic attack
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Sleep disorder
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	0	1
Stress
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	8 / 38 (21.05%)	5 / 35 (14.29%)	3 / 17 (17.65%)
occurrences all number	8	5	5
Aspartate aminotransferase increased
subjects affected / exposed	6 / 38 (15.79%)	3 / 35 (8.57%)	4 / 17 (23.53%)
occurrences all number	6	4	6
Vitamin D decreased
subjects affected / exposed	1 / 38 (2.63%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	1	1	1
Blood bilirubin increased
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	0	1	1
High density lipoprotein increased
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	0	1	1
Weight decreased
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	0	1	3
Haemoglobin increased
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Liver iron concentration increased
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	3 / 38 (7.89%)	3 / 35 (8.57%)	1 / 17 (5.88%)
occurrences all number	3	4	1
Immunisation reaction
subjects affected / exposed	3 / 38 (7.89%)	3 / 35 (8.57%)	0 / 17 (0.00%)
occurrences all number	6	3	0
Contusion
subjects affected / exposed	3 / 38 (7.89%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences all number	4	1	0
Bone contusion
subjects affected / exposed	0 / 38 (0.00%)	2 / 35 (5.71%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Foot fracture
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Ankle fracture
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Fibula fracture
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Lip injury
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Lipohaemarthrosis
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Tibia fracture
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Cardiac disorders
Palpitations
subjects affected / exposed	1 / 38 (2.63%)	2 / 35 (5.71%)	0 / 17 (0.00%)
occurrences all number	1	2	0
Sinus bradycardia
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Hypertensive heart disease
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Nervous system disorders
Headache
subjects affected / exposed	21 / 38 (55.26%)	8 / 35 (22.86%)	4 / 17 (23.53%)
occurrences all number	50	11	4
Dizziness
subjects affected / exposed	3 / 38 (7.89%)	2 / 35 (5.71%)	1 / 17 (5.88%)
occurrences all number	3	6	1
Anosmia
subjects affected / exposed	1 / 38 (2.63%)	2 / 35 (5.71%)	2 / 17 (11.76%)
occurrences all number	1	2	2
Migraine
subjects affected / exposed	3 / 38 (7.89%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	3	1	1
Ageusia
subjects affected / exposed	0 / 38 (0.00%)	2 / 35 (5.71%)	2 / 17 (11.76%)
occurrences all number	0	2	2
Neuropathy peripheral
subjects affected / exposed	2 / 38 (5.26%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences all number	2	2	0
Paraesthesia
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Carotid artery aneurysm
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Cerebrovascular accident
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Intracranial aneurysm
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 38 (13.16%)	2 / 35 (5.71%)	1 / 17 (5.88%)
occurrences all number	8	3	1
Haemolysis
subjects affected / exposed	2 / 38 (5.26%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	2	1	1
Lymphadenopathy
subjects affected / exposed	3 / 38 (7.89%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	5	0	0
Blood loss anaemia
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Thrombocytosis
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	3 / 38 (7.89%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	3	0	0
Tinnitus
subjects affected / exposed	3 / 38 (7.89%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	10	0	0
Deafness unilateral
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Eye disorders
Cataract
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	0	1	2
Vision blurred
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Lacrimation increased
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Meibomian gland dysfunction
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Gastrointestinal disorders
Diarrhea
subjects affected / exposed	6 / 38 (15.79%)	5 / 35 (14.29%)	2 / 17 (11.76%)
occurrences all number	7	5	3
Nausea
subjects affected / exposed	6 / 38 (15.79%)	3 / 35 (8.57%)	3 / 17 (17.65%)
occurrences all number	6	4	3
Vomiting
subjects affected / exposed	2 / 38 (5.26%)	1 / 35 (2.86%)	4 / 17 (23.53%)
occurrences all number	2	1	8
Abdominal pain
subjects affected / exposed	1 / 38 (2.63%)	3 / 35 (8.57%)	2 / 17 (11.76%)
occurrences all number	1	4	2
Dyspepsia
subjects affected / exposed	0 / 38 (0.00%)	5 / 35 (14.29%)	1 / 17 (5.88%)
occurrences all number	0	6	1
Constipation
subjects affected / exposed	2 / 38 (5.26%)	2 / 35 (5.71%)	0 / 17 (0.00%)
occurrences all number	2	2	0
Abdominal pain upper
subjects affected / exposed	3 / 38 (7.89%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	3	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	2	0	2
Toothache
subjects affected / exposed	2 / 38 (5.26%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences all number	2	1	0
Hepatobiliary disorders
Jaundice
subjects affected / exposed	1 / 38 (2.63%)	2 / 35 (5.71%)	0 / 17 (0.00%)
occurrences all number	1	4	0
Hepatic steatosis
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	0	1	1
Hyperbilirubinaemia
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	0	1	1
Biliary colic
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	2
Hepatic pain
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	2	0	1
Alopecia
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Erythema
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Hair growth abnormal
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Skin hypertrophy
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Renal and urinary disorders
Dysuria
subjects affected / exposed	2 / 38 (5.26%)	3 / 35 (8.57%)	0 / 17 (0.00%)
occurrences all number	2	3	0
Nephrolithiasis
subjects affected / exposed	0 / 38 (0.00%)	2 / 35 (5.71%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Polyuria
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Proteinuria
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Renal cyst
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	9 / 38 (23.68%)	7 / 35 (20.00%)	3 / 17 (17.65%)
occurrences all number	9	12	5
Pain in extremity
subjects affected / exposed	5 / 38 (13.16%)	3 / 35 (8.57%)	1 / 17 (5.88%)
occurrences all number	7	4	1
Osteoporosis
subjects affected / exposed	4 / 38 (10.53%)	4 / 35 (11.43%)	0 / 17 (0.00%)
occurrences all number	4	4	0
Myalgia
subjects affected / exposed	2 / 38 (5.26%)	1 / 35 (2.86%)	3 / 17 (17.65%)
occurrences all number	2	1	3
Muscle spasms
subjects affected / exposed	3 / 38 (7.89%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	3	2	1
Osteopenia
subjects affected / exposed	0 / 38 (0.00%)	5 / 35 (14.29%)	0 / 17 (0.00%)
occurrences all number	0	6	0
Joint effusion
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	2 / 17 (11.76%)
occurrences all number	2	0	2
Bone pain
subjects affected / exposed	1 / 38 (2.63%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	1	1	1
Joint swelling
subjects affected / exposed	1 / 38 (2.63%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	1	1	1
Arthritis
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	0	5	1
Neck pain
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Osteoarthritis
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	0	1
Synovial cyst
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	0	2
Gouty arthritis
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Muscular weakness
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Infections and infestations
COVID-19
subjects affected / exposed	12 / 38 (31.58%)	16 / 35 (45.71%)	6 / 17 (35.29%)
occurrences all number	15	20	8
Nasopharyngitis
subjects affected / exposed	6 / 38 (15.79%)	6 / 35 (17.14%)	3 / 17 (17.65%)
occurrences all number	8	8	3
Upper respiratory tract infection
subjects affected / exposed	9 / 38 (23.68%)	4 / 35 (11.43%)	1 / 17 (5.88%)
occurrences all number	20	4	2
Sinusitis
subjects affected / exposed	5 / 38 (13.16%)	1 / 35 (2.86%)	4 / 17 (23.53%)
occurrences all number	14	3	4
Influenza
subjects affected / exposed	2 / 38 (5.26%)	4 / 35 (11.43%)	2 / 17 (11.76%)
occurrences all number	2	4	2
Urinary tract infection
subjects affected / exposed	2 / 38 (5.26%)	3 / 35 (8.57%)	3 / 17 (17.65%)
occurrences all number	2	4	3
Gastroenteritis
subjects affected / exposed	2 / 38 (5.26%)	4 / 35 (11.43%)	0 / 17 (0.00%)
occurrences all number	2	5	0
Suspected COVID-19
subjects affected / exposed	4 / 38 (10.53%)	0 / 35 (0.00%)	2 / 17 (11.76%)
occurrences all number	13	0	2
Respiratory tract infection
subjects affected / exposed	4 / 38 (10.53%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	10	0	0
Hordeolum
subjects affected / exposed	3 / 38 (7.89%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	3	0	0
Oral herpes
subjects affected / exposed	1 / 38 (2.63%)	2 / 35 (5.71%)	0 / 17 (0.00%)
occurrences all number	1	2	0
Pharyngitis
subjects affected / exposed	3 / 38 (7.89%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	3	0	0
Respiratory tract infection viral
subjects affected / exposed	2 / 38 (5.26%)	1 / 35 (2.86%)	0 / 17 (0.00%)
occurrences all number	2	1	0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 38 (2.63%)	0 / 35 (0.00%)	2 / 17 (11.76%)
occurrences all number	2	0	3
Acarodermatitis
subjects affected / exposed	0 / 38 (0.00%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	0	1	1
Bronchitis
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Rhinitis
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	8	0	0
Vulvovaginal mycotic infection
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Conjunctivitis viral
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Ear lobe infection
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Enterovirus infection
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Escherichia urinary tract infection
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Eye infection
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Helminthic infection
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Implant site infection
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Infective tenosynovitis
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Pharyngitis streptococcal
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Viral infection
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Viral sinusitis
subjects affected / exposed	0 / 38 (0.00%)	0 / 35 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Metabolism and nutrition disorders
Vitamin D deficiency
subjects affected / exposed	2 / 38 (5.26%)	4 / 35 (11.43%)	4 / 17 (23.53%)
occurrences all number	2	4	4
Iron overload
subjects affected / exposed	2 / 38 (5.26%)	2 / 35 (5.71%)	0 / 17 (0.00%)
occurrences all number	2	2	0
Decreased appetite
subjects affected / exposed	1 / 38 (2.63%)	1 / 35 (2.86%)	1 / 17 (5.88%)
occurrences all number	1	1	1
Type 2 diabetes mellitus
subjects affected / exposed	2 / 38 (5.26%)	0 / 35 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0

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Were there any global substantial amendments to the protocol? Yes

03 Oct 2019

The following changes were made as per Amendment 2: Revised the text explaining an allowance for a lapse between signing the ICF/screening and the start of study treatment to specify that this was allowed only for subjects in Cohort 1 (i.e., subjects who were previously receiving placebo). Additionally, the text was revised to clarify that it is anticipated that no lapse will occur between the last visit of the antecedent study and signing the ICF/screening of this extension study for all cohorts. For subjects in Cohort 1, text was added to ensure that investigators assess subjects for clinical benefit after the fixed-dose period before proceeding into the continued treatment period. Revised text to include additional reasons a subject may not continue the mitapivat dose regimen they were receiving at the end of their fixed-dose period (either on the antecedent study [Cohorts 2 and 3] or in this extension study [Cohort 1]). Revised the dose titration language for subjects in Cohort 1 to allow dosing decisions to be based on results from local laboratories at the Week 4 and Week 8 Visits. Increased the sample size based on the increase in Study 007. Increased the length of contraception period for males exposed to study treatment to cover 1 complete spermatogenesis cycle. Removed the option for a rapid dose taper and simplified the recommended gradual dose taper. Revised the requirements for clinical laboratory results. Added text to specify that the requirements for pregnancy reporting are for female subjects and consented female partners of male subjects.

26 Aug 2020

The following changes were made as per Amendment 3: Management of concomitant therapy was updated per the mitapivat Investigator’s Brochure: a. Digoxin and strong inhibitors of P-gp were removed from the list of therapies that are prohibited. Accordingly, receipt of digoxin or strong inhibitors of P-gp was removed from the exclusion criteria. b. Moderate inducers of CYP3A4 were added to the list of therapies that require careful monitoring. c. Deferoxamine, deferasirox, and deferiprone, which are iron chelators, were added to the list of therapies that require careful monitoring. d. Sensitive substrates of CYP2B6 were removed from the list of therapies requiring careful monitoring. Guidance on allowed modifications to study conduct during declared public health emergencies and natural disasters was added for situations during which adherence to protocol-specified procedures is impeded, such as the COVID-19 pandemic. Modified Exclusion Criterion #5 to exclude subjects who were currently receiving medications that are strong inducers of CYP3A4 that had not been stopped for a duration of at least 28 days or a time frame equivalent to 5 half-lives (whichever was longer) before start of study drug. Previously, the duration to stop receiving medications that are strong inducers of CYP3A4 was at least 5 days or a time frame equivalent to 5 half-lives (whichever was longer) before start of study drug. Telemedicine visits and direct-to-subject shipment of study drug were implemented (every other visit starting at Week 109).

19 Jul 2022

The following changes were made as per Amendment 4: Transaminase increase was removed as an AESI per updated mitapivat Investigator’s Brochure, in which transaminase increase is no longer classified as a risk or ADR of treatment with mitapivat. Added guidance for managing subjects who transition to receiving treatment with mitapivat outside of Study AG348-C-011, as subjects may choose to obtain mitapivat from other available sources (eg, commercial). Removed or reduced frequency of following assessments to reduce subject burden and/or because more frequent monitoring of these assessments is no longer warranted based on established safety profile of mitapivat. Schedule of assessments was modified on or after Week 37 and was not modified through Week 24 (last scheduled visit before Week 37) because all subjects enrolled in study have discontinued before or completed Week 24 visit. a. Removed electrocardiogram assessments from Week 37 through End of Study, which are no longer warranted based on established safety profile of mitapivat. b. Removed PE assessments from Week 37 through Week 145 because frequent PE assessments are no longer warranted based on established safety profile of mitapivat. c. Removed menstrual cycle eDiary assessments from Week 37 through End of Study to reduce subject burden. Identified risk, changes in sex hormones, can be monitored adequately with laboratory assessments. Assessments of reproductive potential from Week 37 through End of Study have been added to support analyses of changes in sex hormones. d. Reduced frequency of lipid assessments from Week 37 through End of Study to be performed annually and removed requirement for lipid tests to be performed after a fast because hypertriglyceridemia is no longer considered an important potential risk (now considered a nonimportant potential risk) or ADR of treatment with mitapivat and can be monitored adequately with annual assessments.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: An Open-Label, Multicenter, Extension Study of AG-348 in Adult Subjects With Pyruvate Kinase Deficiency Previously Enrolled in AG-348 Studies

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: All Cohorts: Number of Subjects With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3

Primary: All Cohorts: Number of Subjects With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3

Primary: All Cohorts: Number of Subjects With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation

Primary: All Cohorts: Number of Subjects With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation

Primary: All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Laboratory Parameters Reported as TEAEs

Primary: All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Laboratory Parameters Reported as TEAEs

Primary: All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs

Primary: All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs

Primary: All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters Reported as TEAEs

Primary: All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters Reported as TEAEs

Primary: All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Bone Mineral Density (BMD)

Primary: All Cohorts: Number of Subjects With Clinically Significant Abnormalities in Bone Mineral Density (BMD)

Primary: All Cohorts: Change From Baseline in Adjusted Spine T-score

Primary: All Cohorts: Change From Baseline in Adjusted Spine T-score

Primary: All Cohorts: Change From Baseline in Adjusted Spine Z-score

Primary: All Cohorts: Change From Baseline in Adjusted Spine Z-score

Primary: All Cohorts: Change From Baseline in Femoral Total T-score

Primary: All Cohorts: Change From Baseline in Femoral Total T-score

Primary: All Cohorts: Change From Baseline in Femoral Total Z-score

Primary: All Cohorts: Change From Baseline in Femoral Total Z-score

Secondary: Cohort 1: Percentage of Subjects Who Achieved a Hemoglobin (Hb) Response

Secondary: Cohort 1: Percentage of Subjects Who Achieved a Hemoglobin (Hb) Response

Secondary: Cohort 1: Average Change From Baseline in Hb Concentration at Weeks 16, 20, and 24

Secondary: Cohort 1: Average Change From Baseline in Hb Concentration at Weeks 16, 20, and 24

Secondary: Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to 8-hours Post-dose (AUC0-8) of Mitapivat

Secondary: Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to 8-hours Post-dose (AUC0-8) of Mitapivat

Secondary: Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Mitapivat

Secondary: Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Mitapivat

Secondary: Cohort 1: Maximum Observed Plasma Concentration (Cmax) of Mitapivat

Secondary: Cohort 1: Maximum Observed Plasma Concentration (Cmax) of Mitapivat

Secondary: Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat

Secondary: Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat

Secondary: Cohort 1: Plasma Concentration (Ctrough) at the End of a Dosing Interval of Mitapivat

Secondary: Cohort 1: Plasma Concentration (Ctrough) at the End of a Dosing Interval of Mitapivat

Secondary: Cohort 1: Exposure-response (E-R) Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters

Secondary: Cohort 1: Exposure-response (E-R) Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters

Secondary: Cohorts 1 and 2: Change From Baseline in Hb Concentration

Secondary: Cohorts 1 and 2: Change From Baseline in Hb Concentration

Secondary: Cohorts 1 and 2: Change From Baseline in Indirect Bilirubin

Secondary: Cohorts 1 and 2: Change From Baseline in Indirect Bilirubin

Secondary: Cohorts 1 and 2: Change From Baseline in Lactate Dehydrogenase (LDH)

Secondary: Cohorts 1 and 2: Change From Baseline in Lactate Dehydrogenase (LDH)

Secondary: Cohorts 1 and 2: Change From Baseline in Haptoglobin Levels

Secondary: Cohorts 1 and 2: Change From Baseline in Haptoglobin Levels

Secondary: Cohorts 1 and 2: Change From Baseline in Reticulocytes/Erythrocytes Ratio

Secondary: Cohorts 1 and 2: Change From Baseline in Reticulocytes/Erythrocytes Ratio

Secondary: Cohort 3: Change From Baseline in Number of Transfusion Episodes

Secondary: Cohort 3: Change From Baseline in Number of Transfusion Episodes

Secondary: Cohort 3: Change from Baseline in Number of Red Blood Cell (RBC) Units Transfused

Secondary: Cohort 3: Change from Baseline in Number of Red Blood Cell (RBC) Units Transfused

Secondary: All Cohorts: Change From Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD)

Secondary: All Cohorts: Change From Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD)

Secondary: All Cohorts: Change From Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA)

Secondary: All Cohorts: Change From Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA)

Secondary: Cohort 1: Time of Last Quantifiable Concentration (Tlast) of Mitapivat

Secondary: Cohort 1: Time of Last Quantifiable Concentration (Tlast) of Mitapivat

Secondary: Cohort 1: E-R Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters

Secondary: Cohort 1: E-R Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
An Open-Label, Multicenter, Extension Study of AG-348 in Adult Subjects With Pyruvate Kinase Deficiency Previously Enrolled in AG-348 Studies