An Open-Label, Multicenter, Extension Study of AG-348 in Adult Subjects With Pyruvate Kinase Deficiency Previously Enrolled in AG-348 Studies
Phase: PHASE3
Conditions: Pyruvate Kinase Deficiency
Sponsor: Agios Pharmaceuticals, Inc.

    Official Title:  AN OPEN-LABEL, MULTICENTER, EXTENSION STUDY OF AG-348 IN ADULT  
                           SUBJECTS WITH PYRUVATE KINASE DEFICIENCY PREVIOUSLY ENROLLED IN 
                           AG-348 STUDIES
             NCT ID:  NCT03853798
Document Date: Study Protocol Version 4.0: 19 July 2022                          
                           

Study AG348-C-011 
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Agios Pharmaceuticals, Inc. 
CLINICAL STUDY PROTOCOL 
AG348-C-011 
AN OPEN-LABEL, MULTICENTER, EXTENSION STUDY OF 
AG-348 IN ADULT SUBJECTS WITH PYRUVATE KINASE 
DEFICIENCY PREVIOUSLY ENROLLED IN AG-348 STUDIES 
Study Sponsor 
Agios Pharmaceuticals, Inc. 
88 Sidney Street  
Cambridge, MA 02139-4169 
USA 
Phone: 617-649-8600 
Fax: 617-649-8618 
Medical Director 
Associate Medical Director, Clinical Development 
Agios Pharmaceuticals, Inc. 
EudraCT Number 
2018-003459-39 
NCT Number 
NCT03853798 
Document Version (Date) 
Original Protocol, Version 1.0 (06 September 2018) 
Amendment 1, Version 1.1 (29 January 2019) (Denmark) 
Amendment 1, Version 1.2 (03 May 2019) (Japan) 
Amendment 2, Version 2.0 (03 October 2019) 
Amendment 2, Version 2.1 (15 November 2019) (Japan) 
Amendment 2, Version 2.2 (26 November 2019) (Denmark) 
Amendment 3, Version 3.0 (26 August 2020) 
Amendment 3, Version 3.1 (14 October 2020) (Japan) 
Amendment 3, Version 3.2 (09 December 2020) (Denmark) 
Amendment 3, Version 3.3 (10 December 2020) (Germany) 
Amendment 3, Version 3.4 (20 September 2021) (Denmark) 
Amendment 4, Version 4.0 (19 July 2022) 
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AGIOS PROTOCOL APPROVAL 
 
I hereby approve this clinical study protocol on behalf of Agios Pharmaceuticals, Inc. and attest 
that it complies with all applicable regulations and guidelines. 
 
Approved by: 
 
 
 
 
Associate Medical Director, Clinical Development 
Agios Pharmaceuticals, Inc. 
 
Print/Sign/Date (dd mmm yyyy) 
 
 
 
 
Senior Director, Biostatistics 
Agios Pharmaceuticals, Inc. 
 
Print/Sign/Date (dd mmm yyyy) 
 
DocuSign Envelope ID: D512C073-B0E4-4E47-9DBA-434237DF8353
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INVESTIGATOR’S AGREEMENT 
I understand that all documentation provided to me by Agios Pharmaceuticals, Inc. (Agios/the 
Sponsor) or its designated representative(s) concerning this study that has not been published 
previously will be kept in strict confidence. This documentation includes the study protocol, 
Investigator’s Brochure, case report forms, and other scientific data. 
This study will not commence without the prior written approval of a properly constituted 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC). No changes will be 
made to the study protocol without the prior written approval of Agios and the IRB/IEC, except 
where necessary to eliminate an immediate hazard to the subject. 
I have read, understood, and agree to conduct this study as outlined in the protocol and in 
accordance with the guidelines and all applicable government regulations. 
 
 
 
 
Investigator Name (printed)  
Investigator Signature 
 
Date 
(DD MMM YYYY) 
 
 
 
 
Investigational site or name of institution and location (printed) 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Agios Pharmaceuticals, Inc. 
Name of Investigational Product: 
AG-348 
Study Title:  
An Open-Label, Multicenter, Extension Study of AG-348 in Adult Subjects with Pyruvate Kinase 
Deficiency Previously Enrolled in AG-348 Studies 
Study Center(s):  
This multicenter study will be conducted in multiple countries at sites participating in 
Studies AG348-C-006 and/or AG348-C-007. 
Phase of Development:  
3 
Objectives:  
Primary: 
• 
To evaluate the long-term safety and tolerability of AG-348 
Secondary: 
• 
To evaluate the long-term efficacy of AG-348 
• 
To evaluate the efficacy of AG-348 in increasing hemoglobin (Hb) concentrations in subjects 
who previously received placebo in Study AG348-C-006 (Cohort 1 only)  
• 
To determine the effect of AG-348 on health-related quality of life (HRQoL) using patient 
reported outcomes (PROs) 
• 
To evaluate the pharmacokinetics of AG-348 after oral administration (Cohort 1 only) 
• 
To evaluate the relationship between AG-348 pharmacokinetics and safety parameters 
(Cohort 1 only) 
Study Endpoints:  
The baseline value is defined as the most recent measurement(s) before the first dose of AG-348, 
considering both the antecedent study and this extension study, unless otherwise specified.  
The following endpoints will be analyzed: 
Primary: 
• 
Type, incidence, severity, and relationship to study drug of treatment-emergent adverse events 
(TEAEs); serious adverse events (SAEs); adverse events of special interest (AESIs); and 
TEAEs leading to dose reduction, treatment interruption, and treatment discontinuation 
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• 
Changes from baseline in clinical laboratory tests (ie, serum chemistry, liver function tests 
[LFTs], hematology, lipids, sex steroids, coagulation, urinalysis), physical examination (PE) 
findings, bone mineral density T- and Z-scores (total hip, femoral neck, and lumbar spine), 
vital signs, and 12-lead electrocardiogram (ECG) data 
Secondary: 
• 
Cohort 1 only: 
– 
Proportion of subjects achieving a hemoglobin (Hb) response, defined as a ≥1.5 g/dL (0.93 
mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more 
scheduled assessments at Weeks 16, 20, and 24 
– 
Average change from baseline in Hb concentration at Weeks 16, 20, and 24  
– 
Pharmacokinetic endpoints, including plasma concentrations over time and 
pharmacokinetic parameters of AG-348 (eg, area under the plasma concentration × time 
curve, maximum [peak] concentration, others as applicable) 
– 
Exposure-response relationship between safety parameters and AG-348 concentration and 
relevant AG-348 pharmacokinetic parameters 
• 
All cohorts: 
– 
Change from baseline in Hb concentration  
– 
Change from baseline in markers of hemolysis: bilirubin, lactate dehydrogenase (LDH), 
and haptoglobin levels 
– 
Change from baseline in markers of erythropoietic activity: reticulocyte percentages  
– 
Change from baseline in the number of transfusion events  
– 
Change from baseline in the number of red blood cell (RBC) units transfused  
– 
Change from baseline in HRQoL PRO scores: Pyruvate Kinase Deficiency Diary (PKDD) 
and Pyruvate Kinase Deficiency Impact Assessment (PKDIA) 
Methodology: 
Overview: 
This is a multicenter, open-label, extension study to evaluate the long-term safety, tolerability, and 
efficacy of treatment with AG-348 in subjects who were previously enrolled in Study AG348-C-006 or 
Study AG348-C-007.  
All subjects enrolled in this extension study, including those who received placebo in Study AG348-C-
006, will receive AG-348 during participation in this extension study. 
Subjects will be assigned to 1 of the following 3 cohorts, depending on the antecedent study and the 
previous treatment received in the antecedent study: 
• 
Cohort 1: Subjects who received placebo in Study AG348-C-006 
• 
Cohort 2: Subjects who received AG-348 in Study AG348-C-006 
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• 
Cohort 3: Subjects who received AG-348 in Study AG348-C-007 
 
Cohort 1:  
Cohort 1 will consist of subjects who received placebo in Study AG348-C-006 and meet the eligibility 
criteria of this extension study. The first visit of this extension study should coincide with the last visit 
of Study AG348-C-006. After completion of all scheduled assessments at the subject’s last visit of 
Study AG348-C-006 and before the start of study drug in this extension study, the subject, 
Investigator, and site personnel will be unblinded to the Study AG348-C-006 treatment allocation of 
the subject, and the Investigator will determine whether the subject meets all eligibility criteria of this 
extension study. 
The first visit of this extension study should consist of subject consent, screening, confirmation of 
eligibility, and the start of study drug. If a subject in Cohort 1 cannot start study drug on the first visit 
of this extension study, discussion with and approval by the Medical Monitor, or designee, will be 
required for participation in this extension study, and to determine the timing and requirements for the 
start of study drug and assessments to be performed. 
Subjects in Cohort 1 will participate in a 12-week Dose Optimization Period followed by a 12-week 
Fixed Dose Period. The goal of the Dose Optimization Period is to maximize a subject’s increase in Hb 
while maintaining an acceptable safety profile. After the Dose Optimization Period, each subject will 
remain on his/her individually optimized dose and enter the Fixed Dose Period. 
After completion of the Fixed Dose Period, subjects who, in the opinion of the Investigator, have 
demonstrated clinical benefit from AG-348 treatment will continue AG-348 treatment in the Continued 
Treatment Period.  
Cohort 2:  
Cohort 2 will consist of subjects who received AG-348 in Study AG348-C-006 and meet the eligibility 
criteria of this extension study. The first visit of this extension study should coincide with the last visit 
of Study AG348-C-006. After completion of all scheduled assessments at the subject’s last visit of 
Study AG348-C-006 and before the start of study drug in this extension study, the subject, 
Investigator, and site personnel will be unblinded to the Study AG348-C-006 treatment allocation of 
the subject, and the Investigator will determine whether the subject meets all eligibility criteria of this 
extension study.  
In Cohort 2, the first visit of this extension study will consist of subject consent, screening, 
confirmation of eligibility, and the start of study drug on this extension study. Importantly, there will 
be no planned dosing interruption between the last dose of blinded AG-348 in Study AG348-C-006 
and the first dose of open-label AG-348 in this extension study due to the potential for withdrawal 
hemolysis (an identified risk of AG-348). Specifically, the first dose of open-label AG-348 in this 
extension study will be administered approximately 12 hours (ie, 12 hours ± 2 hours) after the last dose 
in Study AG348-C-006. Subjects will continue the AG-348 dose regimen they were receiving at the 
last visit of Study AG348-C-006 (unless a dose modification is required for reasons related to safety, 
the subject’s dose optimization, or other reasons after discussion with and approval by the Medical 
Monitor or designee). 
Cohort 3: 
Cohort 3 will consist of subjects who received AG-348 in Study AG348-C-007 and meet the eligibility 
criteria of this extension study. The first visit of this extension study should coincide with the last visit 
of Study AG348-C-007. After completion of all scheduled assessments at the subject’s last visit of 
Study AG348-C-007 and before the start of study drug in this extension study, the Investigator will 
determine whether the subject meets all eligibility criteria of this extension study.  
In Cohort 3, the first visit of this extension study will consist of subject consent, screening, 
confirmation of eligibility, and the start of study drug on this extension study. Importantly, there will 
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be no planned dosing interruption between the last dose of AG-348 in Study AG348-C-007 and the 
first dose of AG-348 in this extension study due to the potential for withdrawal hemolysis (an 
identified risk of AG-348). Specifically, the first dose of AG-348 in this extension study will be 
administered approximately 12 hours (ie, 12 hours ± 2 hours) after the last dose in Study 
AG348-C-007. Subjects will continue the AG-348 dose regimen they were receiving at the last visit of 
Study AG348-C-007 (unless a dose modification is required for reasons related to safety, the subject’s 
dose optimization, or other reasons after discussion with and approval by the Medical Monitor or 
designee). 
Study Schema: 
A study schema is provided below. 
 
Abbreviations: d=day; SCRN=Screening. 
a Eligible subjects in Cohort 1 will initiate treatment with AG-348 in this extension study. Therefore, these 
subjects will participate in a 12-week Dose Optimization Period followed by a 12-week Fixed Dose Period 
during the first 24 weeks of this extension study. 
b Subjects who are in Cohort 2 or 3 will continue AG-348 treatment. 
c Dosing between Week 24 and Week 25 is continuous. 
d All subjects who permanently discontinue AG-348 at any time will attend a Safety Follow-up Visit 28 days 
(±4 days) after the last dose of AG-348 (including the time required to dose taper). 
All cohorts discontinuation and follow-up: 
All subjects who interrupt or discontinue AG-348 at any time should undergo the recommended dose 
taper, unless an emergency situation justifies discontinuing or interrupting the study drug abruptly. 
Whether the dose taper is performed or not, subjects discontinuing or interrupting AG-348 should be 
monitored for signs of hemolysis and worsening of anemia. All subjects who permanently discontinue 
AG-348 at any time will attend a Safety Follow-up Visit 28 days (±4 days) after the last dose of 
AG-348 (including the time required to dose taper). 
Subjects with AEs will continue to be followed until resolution of the AE to baseline (ie, baseline of 
the study during which AE onset occurred), the AE is considered stable within the context of the study, 
the subject is lost to follow-up, or until 28 days after the last dose of AG-348. All SAEs will be 
followed until final outcome of the SAE is known or the subject is lost to follow-up. 
Number of Subjects Planned:  
Approximately 96, with up to 116, subjects are potentially eligible to be enrolled in this extension 
study: approximately 76 subjects from Study AG348-C-006 and approximately 20, with up to 40, 
subjects from Study AG348-C-007, if eligible. 
 
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Eligibility Criteria:  
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for inclusion in this extension study: 
1. Have provided signed written informed consent prior to participating in this extension study.  
2. Have completed the antecedent AG-348 study through the Part 2 Week 24 Visit of 
Study AG348-C-006 or AG348-C-007. 
3. Cohorts 2 and 3: Have demonstrated clinical benefit from AG-348 treatment in the antecedent 
study, in the opinion of the Investigator. 
4. For women of reproductive potential*: 
a. In Cohort 1, have a negative local serum (human chorionic gonadotropin [hCG]) 
pregnancy test during screening of this extension study.  
b. In Cohort 2 or 3, have a negative local urine pregnancy test during screening of this 
extension study. 
* Women of reproductive potential are defined as sexually mature women who have not 
undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion; or who have not been 
naturally postmenopausal (ie, who have not menstruated at all for at least the preceding 
12 months prior to screening of this extension study and have an elevated follicle-stimulating 
hormone [FSH] level indicative of menopause during screening of this extension study or at 
screening of the antecedent study). If the result from FSH testing conducted during 
screening of this extension study is not available on the same day, the woman must have a 
negative local serum (hCG) or urine pregnancy test during screening and follow 
contraception requirements (Inclusion Criterion #5) until an elevated FSH result 
indicative of menopause is confirmed. 
5. For women of reproductive potential as well as men with partners who are women of 
reproductive potential, be abstinent as part of their usual lifestyle, or agree to use 2 forms of 
contraception, 1 of which must be considered highly effective, from the time of giving 
informed consent, during the study, and for 28 days following the last dose of study drug for 
women and 90 days following the last dose of study drug for men. A highly effective form of 
contraception is defined as combined (estrogen and progestin containing) hormonal 
contraceptives (oral, intravaginal, or transdermal) known to be associated with inhibition of 
ovulation; progestin-only hormonal contraceptives (oral, injectable, or implantable) known to 
be associated with inhibition of ovulation; intrauterine device; intrauterine hormone releasing 
system; bilateral tube occlusion; or vasectomized partner. The second form of contraception 
can include an acceptable barrier method, which includes male or female condoms with or 
without spermicide, and cervical cap, diaphragm, or sponge with spermicide. Women of 
reproductive potential using hormonal contraception as a highly effective form of 
contraception must also utilize an acceptable barrier method while enrolled in the study and for 
at least 28 days after their last dose of study drug. 
6. Be willing and able to comply with study visits and procedures. 
Exclusion Criteria 
Subjects who meet any of the following criteria will not be enrolled in this extension study: 
1. Have a significant medical condition (including clinically significant laboratory abnormality) 
that developed during his/her antecedent AG-348 study that confers an unacceptable risk to 
participating in this extension study, that could confound the interpretation of the study data, 
and/or that compromises the ability of the subject to complete study visits and procedures.  
2. Are currently pregnant or breastfeeding. 
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3. Have a splenectomy scheduled during the study treatment period. 
4. Meet the withdrawal criteria of his/her antecedent AG-348 study during screening of this 
extension study. 
Withdrawal criteria of the antecedent AG-348 studies are as follows: 
• 
Withdrawal of consent 
• 
Development of an intercurrent medical condition that precludes further participation 
in the study 
• 
Subject requires use of a prohibited concomitant medication 
• 
Investigator decision 
• 
Persistent nonadherence to protocol requirements 
• 
Pregnancy 
• 
Lost to follow-up 
5. Are currently receiving medications that are strong inhibitors of CYP3A4 that have not been 
stopped for a duration of at least 5 days or a time frame equivalent to 5 half-lives (whichever is 
longer) before start of study drug; or strong inducers of CYP3A4 that have not been stopped 
for a duration of at least 28 days or a time frame equivalent to 5 half-lives (whichever is 
longer) before start of study drug on this extension study. 
6. Have received anabolic steroids, including testosterone preparations, within 28 days prior to 
start of study drug on this extension study. 
7. Have received hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony 
stimulating factors, thrombopoietins) within 28 days prior to start of study drug on this 
extension study. 
8. Have exposure to any investigational drug other than AG-348, device, or procedure within 
3 months prior to start of study drug on this extension study. 
Investigational Product, Dosage, and Mode of Administration:  
AG-348 will be administered orally as tablets of different sizes for the 5, 20, and 50 mg dose levels. 
Doses of AG-348 may be taken with or without food. Tablets should be swallowed whole with water 
and not crushed, chewed, or dissolved in water. The dose regimen will be 5, 20, or 50 mg twice daily 
(BID), with each dose administered approximately 12 hours (ie, 12 hours ± 2 hours) apart, unless a 
dose taper is required at any time during this extension study, in which case the frequency of 
administration will be once daily (QD) or once every other day (QOD) during different steps of the 
taper. At any time during this extension study, the Investigator can reduce the subject’s dose or 
interrupt dosing for reasons related to safety. 
For subjects in Cohort 1, the initial dose will be 5 mg BID with the potential for 2 sequential dose level 
increases (from 5 mg BID to 20 mg BID and from 20 mg BID to 50 mg BID), which may occur at the 
Week 4 and/or Week 8 Visits.  
Subjects in Cohorts 2 and 3 will continue the dose regimen they were receiving at their last visit of 
Study AG348-C-006 or AG348-C-007, respectively (unless otherwise noted). 
Duration of Treatment and End of Study: 
Subjects may continue AG-348 treatment for up to a maximum of 192 weeks in this extension study 
(not including the time required for completion of the recommended dose taper) until they meet study 
withdrawal criteria or the study is closed. 
This extension study will end when all subjects have discontinued or completed the study, are lost to 
follow-up, or the Study Sponsor terminates the study. 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................6 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
Pyruvate Kinase Deficiency .......................................................................................23 
5.1.1. 
Epidemiology and Prevalence ....................................................................................23 
5.1.2. 
Biochemistry and Genetics .........................................................................................23 
5.1.3. 
Clinical Characteristics ...............................................................................................24 
5.2. 
Investigational Product (AG-348) ..............................................................................25 
5.2.1. 
Proposed Mechanism of Action of AG-348 ...............................................................25 
5.2.2. 
Summary of AG-348 Nonclinical Data With Potential Clinical Interest ...................25 
5.2.3. 
Summary of AG-348 Clinical Data ............................................................................26 
5.2.3.1. 
Summary of AG-348 Pharmacokinetics .....................................................................27 
5.2.3.2. 
Summary of AG-348 Pharmacodynamics ..................................................................27 
5.2.3.3. 
Summary of AG-348 Clinical Safety Data .................................................................28 
5.2.3.4. 
Summary of AG-348 Efficacy Data ...........................................................................28 
5.3. 
Study Rationale ...........................................................................................................28 
5.3.1. 
Purpose of the Study ...................................................................................................29 
5.3.2. 
Justification of the Study Design ................................................................................29 
5.3.3. 
Justification for Individual Dose Optimization for Subjects in Cohort 1 ...................29 
5.3.4. 
Rationale for the Doses Selected for the Individual Dose Optimization ....................30 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................32 
6.1. 
Study Objectives .........................................................................................................32 
6.1.1. 
Primary Objective .......................................................................................................32 
6.1.2. 
Secondary Objectives .................................................................................................32 
 
 
6.2. 
Study Endpoints ..........................................................................................................32 
6.2.1. 
Primary Endpoint ........................................................................................................33 
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6.2.2. 
Secondary Endpoints ..................................................................................................33 
 
 
7. 
STUDY DESIGN .......................................................................................................35 
7.1. 
Study Design Overview ..............................................................................................35 
7.1.1. 
Cohort 1 ......................................................................................................................36 
7.1.2. 
Cohort 2 ......................................................................................................................36 
7.1.3. 
Cohort 3 ......................................................................................................................37 
7.2. 
Study Description .......................................................................................................38 
7.2.1. 
Screening Period .........................................................................................................38 
7.2.2. 
Dose Optimization Period (Cohort 1 Only) ................................................................38 
7.2.3. 
Fixed Dose Period (Cohort 1 Only) ............................................................................39 
7.2.4. 
Continued Treatment Period .......................................................................................39 
7.2.5. 
Discontinuation and Safety Follow-up .......................................................................40 
7.3. 
Number of Subjects to be Enrolled .............................................................................40 
7.4. 
Modifications Allowed During Declared Public Health Emergencies and 
Natural Disasters .........................................................................................................40 
7.4.1. 
Allowable Modifications ............................................................................................40 
7.5. 
Criteria for Study Closure ...........................................................................................42 
8. 
STUDY POPULATION .............................................................................................43 
8.1. 
Inclusion Criteria ........................................................................................................43 
8.2. 
Exclusion Criteria .......................................................................................................44 
8.3. 
Subject Withdrawal Criteria .......................................................................................45 
8.3.1. 
Withdrawal From Study Drug ....................................................................................45 
8.3.2. 
Withdrawal From the Study ........................................................................................46 
8.3.3. 
Temporary Withdrawal From Study Drug for Pregnancy ..........................................46 
9. 
STUDY TREATMENTS............................................................................................47 
9.1. 
Description of Study Drug ..........................................................................................47 
9.1.1. 
Study Drug Packaging and Labeling ..........................................................................47 
9.1.2. 
Study Drug Storage .....................................................................................................47 
9.1.3. 
Study Drug Administration.........................................................................................47 
9.1.4. 
Study Drug Accountability .........................................................................................48 
9.1.5. 
Study Drug Handling and Disposal ............................................................................48 
9.2. 
Assignment of Subjects to Treatment .........................................................................48 
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10.7. 
Pharmacokinetic Assessments ....................................................................................70 
10.7.1. 
Blood Sample Collection ............................................................................................70 
10.7.2. 
Sample Analysis .........................................................................................................70 
 
 
10.9. 
Health-Related Quality of Life Assessments ..............................................................71 
10.10. 
Other Assessments ......................................................................................................72 
 
 
10.10.2. 
Other Laboratory Assessments ...................................................................................72 
11. 
ADVERSE EVENTS..................................................................................................73 
11.1. 
Reporting Period for Adverse Events and Serious Adverse Events ...........................73 
11.2. 
Definition of Adverse Events .....................................................................................73 
11.2.1. 
Adverse Event .............................................................................................................73 
11.2.2. 
Serious Adverse Event ................................................................................................74 
11.2.3. 
Adverse Events Occurring Secondary to Other Events ..............................................74 
11.2.4. 
Preexisting Medical Conditions ..................................................................................74 
11.2.5. 
Abnormal Laboratory Values .....................................................................................75 
11.2.6. 
Adverse Events of Special Interest .............................................................................75 
 
 
11.3. 
Procedures for Reporting Adverse Events, Adverse Events of Special 
Interest, and Serious Adverse Events .........................................................................76 
11.3.1. 
Intensity ......................................................................................................................77 
11.3.2. 
Relationship to Study Drug ........................................................................................77 
11.4. 
Pregnancy Reporting ..................................................................................................78 
12. 
STATISTICAL METHODS .......................................................................................79 
12.1. 
Analysis Sets ...............................................................................................................79 
12.2. 
Statistical Analysis ......................................................................................................79 
12.2.1. 
General Methods .........................................................................................................79 
12.2.2. 
Background Characteristics ........................................................................................79 
12.2.2.1. 
Subject Disposition .....................................................................................................80 
12.2.2.2. 
Demographics and Baseline Characteristics ...............................................................80 
12.2.2.3. 
Prior and Concomitant Medications and Procedures ..................................................80 
12.2.3. 
Study Drug Exposure and Compliance .......................................................................80 
12.2.3.1. 
Study Drug Exposure ..................................................................................................80 
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12.2.3.2. 
Study Drug Compliance .............................................................................................81 
12.3. 
Efficacy Analyses .......................................................................................................81 
12.3.1. 
Analysis for the Primary Endpoint .............................................................................81 
12.3.2. 
Analyses for the Secondary Endpoints .......................................................................81 
12.3.2.1. 
Hemoglobin-related Secondary Endpoints .................................................................81 
12.3.2.2. 
Change from Baseline in Markers of Hemolysis and Markers of 
Erythropoiesis .............................................................................................................81 
12.3.2.3. 
Number of Transfusion Events ...................................................................................81 
12.3.2.4. 
Patient Reported Outcome-related Endpoints ............................................................82 
12.4. 
Safety Analyses ..........................................................................................................82 
12.4.1. 
Adverse Events ...........................................................................................................82 
12.4.2. 
Laboratory Assessments .............................................................................................83 
12.4.3. 
Bone Mineral Density Findings ..................................................................................84 
12.4.4. 
Vital Signs ..................................................................................................................84 
12.4.5. 
Electrocardiogram Findings ........................................................................................84 
12.4.6. 
Physical Examination .................................................................................................84 
12.5. 
Pharmacokinetic/Pharmacodynamic Analyses ...........................................................84 
12.5.1. 
Pharmacokinetic Analyses ..........................................................................................84 
 
 
12.6. 
Sample Size and Power Considerations .....................................................................85 
13. 
ADMINISTRATIVE REQUIREMENTS ..................................................................86 
13.1. 
Good Clinical Practices ..............................................................................................86 
13.2. 
Ethical Considerations ................................................................................................86 
13.3. 
Subject Information and Informed Consent ...............................................................86 
13.4. 
Subject Confidentiality ...............................................................................................86 
13.5. 
Protocol Compliance ..................................................................................................87 
13.6. 
Data Management .......................................................................................................87 
13.7. 
Source Documentation and Electronic Case Report Form Completion .....................87 
13.8. 
Direct Access to Source Data .....................................................................................88 
13.9. 
Record Retention ........................................................................................................88 
13.10. 
Liability and Insurance ...............................................................................................88 
13.11. 
Publication of Study Findings and Use of Information ..............................................88 
14. 
LIST OF REFERENCES ............................................................................................89 
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15. 
APPENDICES ............................................................................................................91 
 
LIST OF TABLES 
Table 1: 
Study AG348-C-011 Investigational Product .............................................................47 
Table 2: 
Dose Modification for Adverse Events Considered Related to Study Drug 
, Study AG348-C-011 ......................................49 
Table 3: 
Recommended Dose Taper Regimen, Study AG348-C-011 ......................................51 
Table 4: 
Schedule of Assessments for Cohort 1 Only (Day 1-Week 24) .................................56 
Table 5: 
Schedule of Assessments for Cohorts 2 and 3 Only (Day 1-Week 24) ......................60 
Table 6: 
Schedule of Assessments for All Cohorts, Continued Treatment Period 
(W37D1-W193D1) .....................................................................................................64 
Table 7: 
95% Exact Confidence Intervals Assuming Different Observed Incidences of 
Adverse Events (N=116) ............................................................................................85 
 
LIST OF FIGURES 
Figure 1: 
Glycolysis in Red Blood Cells of Patients With Pyruvate Kinase Deficiency ...........24 
Figure 2: 
Overview of Design for Study AG348-C-011 ............................................................35 
Figure 3: 
Cohort 1 Dosing Schema for the First 24 Weeks, Study AG348-C-011 ....................38 
 
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4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation 
Definition 
2,3-DPG 
2,3-diphosphoglycerate 
ADP 
Adenosine diphosphate 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
AUC 
Area under the plasma concentration × time curve 
AUC0-12 
Area under the plasma concentration × time curve from 0 to 12 hours 
AUC0-last 
Area under the plasma concentration × time curve from time 0 to the time of the 
last measurable concentration 
BID 
Twice daily 
BP 
Blood pressure 
Cmax 
Maximum (peak) concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DXA 
Dual-energy X-ray absorptiometry 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EPO 
Erythropoietin 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
Hb 
Hemoglobin 
hCG 
Human chorionic gonadotropin 
HRQoL 
Health-related quality of life 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
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Abbreviation 
Definition 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LFTs 
Liver function tests 
 
 
MAD 
Multiple ascending dose study 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
NHS 
Natural history study 
PD 
Pharmacodynamics 
PE 
Physical examination 
PEP 
Phosphoenolpyruvate 
P-gp 
P-glycoprotein 
PK 
Pyruvate kinase 
PKDD 
Pyruvate Kinase Deficiency Diary 
PKDIA 
Pyruvate Kinase Deficiency Impact Assessment 
PKL 
Liver-specific form of pyruvate kinase 
PKM 
Muscle-specific form of pyruvate kinase 
PKR 
RBC-specific form of pyruvate kinase 
PRO 
Patient-reported outcome 
PT 
Preferred Term 
QD 
Once daily 
QOD 
Every other day 
QTcB 
Heart rate-corrected QT interval by Bazett’s method 
QTcF 
Heart rate-corrected QT interval by Fridericia’s method 
RBC 
Red blood cell 
SAD 
Single ascending dose study 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety Analysis Set 
SD 
Standard deviation 
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Abbreviation 
Definition 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum (peak) concentration 
TT 
Transfusion trigger 
UGT 
Uridine 5ʹ-diphospho-glucuronosyltransferase 
ULN 
Upper limit of normal 
US 
United States 
WT 
Wild-type 
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5. 
INTRODUCTION 
5.1. 
Pyruvate Kinase Deficiency 
Pyruvate kinase deficiency (PK deficiency) is a glycolytic enzymopathy that results in life-long, 
nonspherocytic hemolytic anemia. It is an autosomal recessive disease with a variable clinical 
presentation, ranging from mild to life-threatening, which can be associated with severe, 
debilitating comorbidities.  
5.1.1. 
Epidemiology and Prevalence 
Epidemiological data for PK deficiency are scarce; however, the current estimated diagnosed 
prevalence of patients with PK deficiency in the US and EU5 (ie, France, Germany, Italy, Spain, 
the United Kingdom) is approximately 2,400 cases (Carey et al, 2000; de Medicis et al, 1992). 
As with many rare genetic diseases, true prevalence of PK deficiency is not well understood 
(Beutler and Gelbart, 2000). Most recent estimates have been cited at approximately 1:20,000-
1:485,000 (Beutler and Gelbart, 2000; Carey et al, 2000; Hirono A et al, 2014; Zanella et al, 
2007). 
5.1.2. 
Biochemistry and Genetics 
In normal cells, pyruvate kinase enzymatically catalyzes the metabolic conversion of 
phosphoenolpyruvate (PEP) and adenosine diphosphate (ADP) into pyruvate and adenosine 
triphosphate (ATP) as the final step in glycolysis. It is believed that PK deficiency leads to 
insufficient ATP production, resulting in red blood cell (RBC) hemolysis due to an impaired 
ability to maintain cellular membrane homeostasis (van Wijk and van Solinge, 2005). Indeed, 
PK deficiency has been reported to be associated with reduced RBC survival, as well as with 
impaired RBC maturation (Aizawa et al, 2003). 
Pyruvate kinase deficiency is the second most common of the glycolytic enzymopathies after 
glucose-6-phosphate dehydrogenase deficiency. Red blood cells from patients with 
PK deficiency are characterized by changes in metabolism associated with defective glycolysis, 
including a deficiency in ATP levels. Levels of 2,3-diphosphoglycerate (2,3-DPG), PEP, and 
other glycolytic intermediates upstream of the reaction catalyzed by the RBC-specific form of 
pyruvate kinase (PKR) have been reported to be elevated in patients with PK deficiency, 
reflecting the inhibition of glycolysis at the PKR step (Oski and Bowman, 1969) (see Figure 1). 
Red blood cells from patients with PK deficiency show less efficient utilization of glucose than 
the RBCs of normal healthy individuals (Tanaka et al, 1962). 
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Figure 1: 
Glycolysis in Red Blood Cells of Patients With Pyruvate Kinase Deficiency 
 
Abbreviations: 1,3-DPG=1,3-diphosphoglycerate; 2,3-DPG=2,3-diphosphoglycerate; 3-PG=3-phosphoglycerate; 
ADP=adenosine diphosphate; ATP=adenosine triphosphate; FBP=fructose 1,6-biphosphate; 
PEP=phosphoenolpyruvate; PKR=red blood cell-specific form of pyruvate kinase. 
Note: Not all steps in glycolysis are shown. 
Pyruvate kinase deficiency is an autosomal recessive disease (patients must have 2 mutated 
alleles, usually as compound heterozygotes), and most patients with PK deficiency present with 
unique combinations of poorly characterized or private mutations. In addition to genetic 
heterogeneity, PK deficiency exhibits considerable phenotypic variability. For example, the US 
Pennsylvanian Amish community represents a subgroup of PK deficient patients with a relatively 
homogeneous genetic background (eg, homozygous R479H mutation, restricted marriage pool) 
and uniform lifestyle. Yet, despite these similarities, there is still considerable phenotypic 
variation within this community in terms of disease severity (Grace et al, 2015). 
A non-drug study protocol to obtain critical information regarding the natural history of 
PK deficiency and the range and incidence of related symptoms, treatments, and complications—
known as the PK Deficiency Natural History Study (NHS) (NCT02053480, 2017)—has been 
developed by Boston Children’s Hospital (Boston, Massachusetts, US) and is funded and 
supported by Agios. This multicenter, global NHS is designed as a longitudinal cohort study with 
retrospective, baseline, and annual collection of data over a 2-year period. The study has thus far 
identified 123 mutations in 255 subjects (Bianchi et al, 2017). Fifty mutations, or approximately 
40% of the identified mutations, had not been previously described and were only identified as a 
consequence of the systematic genotyping effort for participants in this NHS. This highlights the 
evolving understanding of the genetic basis of PK deficiency. 
An attempt has been made to impose a system of classification onto this large collection of 
potential genotypes by dividing the genotypes into 2 classifications and 3 groups (Bianchi et al, 
2015). This classification shows that 79 of the 123 mutations (64.2%) were missense mutations, 
which are single nucleotide changes that result in amino acid substitutions in the PKR enzyme. 
The effects of these missense mutations can include a loss of catalytic efficiency and/or a loss of 
protein stability of the enzyme. Non-missense mutations include those that cause premature 
truncations of the enzyme, deletions or frameshifts, or mutations that affect splicing of the 
enzyme. Many of these non-missense mutations are predicted to be null alleles of PKR, resulting 
in a lack of functional protein expression (Bianchi et al, 2017). 
5.1.3. 
Clinical Characteristics 
The natural history of untreated PK deficiency is characterized by life-long hemolytic anemia 
and subsequent associated comorbidities, which can include a need for transfusions, 
susceptibility to infections after splenectomy, worsening anemia during pregnancy, and 
symptoms associated with chronic hemolytic anemia (Rider et al, 2011). Some patients with PK 
deficiency may present with severe hemolytic anemia in early infancy that requires immediate 
care. Unconjugated bilirubin is also often chronically elevated in patients with PK deficiency; 
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thus, pigmented gallstones are common in both children and adults with the disease. 
Additionally, iron overload is progressive and can ultimately lead to life-threatening symptoms. 
There are no generally agreed-upon definitions of “mild”, “moderate”, and “severe” disease, 
because multiple factors – such as the degree of anemia, the level of bilirubin and severity of 
jaundice, and complications (including iron overload, transfusion need, and subjective feelings of 
fatigue and low energy level) – must be taken into account before an evaluation can be made.  
There are no guidelines for transfusion management in patients with PK deficiency. Most adults 
with the disease have been splenectomized and require only sporadic or ad hoc transfusions, 
which are usually administered in the context of an acute hemolytic episode triggered by 
infection, trauma, or stress (Grace et al, 2018; Grace et al, 2016; Zanella et al, 2007; Zanella et 
al, 2005). These patients are considered “not regularly transfused.” Some adult patients who have 
not been splenectomized require regular transfusions. A minority of adult patients with PK 
deficiency still require regular transfusions after splenectomy. There is no clear definition of 
what constitutes a regularly transfused patient with PK deficiency; data from the PK Deficiency 
NHS point to a wide range of transfusion frequencies in adults with the disease. 
5.2. 
Investigational Product (AG-348) 
AG-348 (PYRUKYND) was approved by the US FDA on 17 February 2022 for the treatment of 
hemolytic anemia in adults with PK deficiency (PYRUKYND (mitapivat) USPI, 2022). 
5.2.1. 
Proposed Mechanism of Action of AG-348 
AG-348 is a potent, broad-spectrum activator of PKR, 1 of 4 pyruvate kinase isoenzymes 
expressed in human tissues from 2 separate genes. Both PKR and the liver-specific form of 
pyruvate kinase (PKL) are splice isoforms of the PKLR gene, while pyruvate kinase muscle 
isozyme (PKM)1 and PKM2 are both expressed from the PKM gene. AG-348 is an allosteric 
activator of the PKR, PKL, and PKM2 isoenzymes, with similar activity for each. AG-348 acts 
by directly binding to the PKR tetramer and allosterically enhancing its affinity for PEP. 
As described in Section 5.1.2, the activity of the glycolytic pathway is disrupted in patients with 
PK deficiency. This disruption results in significantly reduced RBC lifespan and manifests 
clinically as nonspherocytic hemolytic anemia. In patients with PK deficiency, RBCs and their 
progenitors are characterized by changes in metabolism associated with defective glycolysis, 
including a buildup of PEP and the intermediate 2,3-DPG, and lowered levels of ATP. It is 
hypothesized that AG-348 restores the ability of RBCs to convert PEP + ADP to pyruvate + ATP 
and thereby normalizes RBC metabolism in patients with PK deficiency. 
5.2.2. 
Summary of AG-348 Nonclinical Data With Potential Clinical Interest 
A series of exploratory pharmacology studies were conducted to characterize the ability of 
AG-348 to activate wild-type (WT) PKR and anemia-associated PKR mutants in vitro, ex vivo, 
and in vivo. 
Biochemical studies showed that AG-348 is a potent, broad-spectrum activator of recombinant 
PKR with low nanomolar potency against both WT and mutant enzymes. The effect of AG-348 
on PKR activity and a number of downstream pathway markers was evaluated in both human 
and murine RBCs and whole blood. AG-348 dose-response curves in human and murine RBCs 
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5.3.1. 
Purpose of the Study 
This study (Study AG348-C-011) is a multicenter, open-label extension study to evaluate the 
long-term safety, tolerability, and efficacy of treatment with AG-348 in subjects who were 
previously enrolled in Study AG348-C-006 or Study AG348-C-007. 
The natural history of untreated PK deficiency is characterized by life-long hemolytic anemia 
and subsequent associated comorbidities, which can include a need for transfusions, iron 
overload, susceptibility to infections after splenectomy, worsening anemia during pregnancy, and 
symptoms associated with chronic hemolytic anemia (Rider et al, 2011).  
Based on the pathophysiology of PK deficiency and the mechanism of action of AG-348, it is 
assumed that chronic, life-long treatment with AG-348 will be required to maintain clinical 
benefit. The long-term data collected during the course of this extension study will inform the 
long-term benefit/risk profile of chronic AG-348 treatment in this patient population. 
5.3.2. 
Justification of the Study Design 
This is a 3-cohort, multicenter, open-label extension study in which all subjects will receive 
treatment with AG-348. As this study will include subjects who received AG-348 in 1 of the 
2 pivotal trials (ie, AG348-C-006 or AG348-C-007) and subjects who previously received 
placebo in the AG348-C-006 study, this extension study will consist of 3 cohorts as follows:  
• Cohort 1: Subjects who received placebo in Study AG348-C-006  
• Cohort 2: Subjects who received AG-348 in Study AG348-C-006  
• Cohort 3: Subjects who received AG-348 in Study AG348-C-007  
Subjects who previously received placebo on Study AG348-C-006 (ie, Cohort 1), will have the 
chance to receive initial treatment with AG-348 in this study. As subjects in Cohort 1 will be 
initiating treatment with AG-348, they will follow the same dose scheme of Study AG348-C-006 
with a 12-week Dose Optimization Period to identify their individually optimized dose of 
AG-348 followed by a 12-week Fixed Dose Period before entering the long-term Continued 
Treatment Period.  
Subjects who received AG-348 on Studies AG348-C-006 or AG348-C-007 (ie, Cohort 2 and 
Cohort 3, respectively) will be able to continue receiving treatment with AG-348 during this 
extension study. Because withdrawal hemolysis is an identified risk of AG-348, it is critical that 
subjects in Cohorts 2 and 3, who were actively receiving treatment with AG-348, maintain 
treatment without dose interruption when transitioning to this extension study. Therefore, the last 
visit of the antecedent study should coincide with the first visit of this extension study to avoid 
interruption in study drug administration. 
5.3.3. 
Justification for Individual Dose Optimization for Subjects in Cohort 1 
This extension study will have an individual Dose Optimization Period for subjects in Cohort 1 
similar to the individual dose optimization performed in Study AG348-C-006.  
The reason for performing individual dose optimization is based on prior experience from the 
Phase 2 DRIVE-PK study (Study AG348-C-003). In Study AG348-C-003, subjects with PK 
deficiency were randomized to receive AG-348 at a dose of either 50 mg BID or 300 mg BID. 
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However several subjects required dose reductions during the study either due to excess increase 
in Hb or the occurrence of AEs, such as insomnia, headache, or nausea. Therefore, the actual 
doses that were evaluated in Study AG348-C-003 ranged from 5 mg once daily (QD) to 300 mg 
BID. In addition, an evaluation of the efficacy endpoint in Study AG348-C-003 showed that 
subjects responded to AG-348 across this wide range of doses (5 mg QD to 300 mg BID). Given 
these observations combined with the number of mutations that are known to occur in patients 
with PK deficiency, individual dose optimization is incorporated in Cohort 1, allowing each 
subject to gradually increase his or her dose of AG-348 in order to identify a dose that confers 
maximum benefit with minimum risk to that subject.  
Preliminary data from the DRIVE-PK study indicated that subjects with PK deficiency who 
respond to activation of the PKR protein typically do so within 2-3 weeks. Therefore, every 
4 weeks during Part 1, subjects in Cohort 1 are assessed for safety and efficacy (as defined by Hb 
increase) to determine if their dose should be increased, maintained at the current level, or 
decreased. After identification of an optimized dose, each subject is then maintained on AG-348 
at their optimized dose for a fixed period of time (Fixed Dose Period) to allow for efficacy 
evaluation.  
As in Study AG348-C-006, all subjects in Cohort 1 of this extension study (Study 
AG348-C-011) will start on an initial AG-348 dose of 5 mg BID with 2 potential sequential steps 
for dose level increases (ie, from 5 mg BID to 20 mg BID and from 20 mg BID to 50 mg BID), 
depending on safety and Hb change. Similar to Study AG348-C-006, subjects in Cohort 1 will be 
assessed every 4 weeks during Part 1 for safety and efficacy (as defined by Hb increase) to 
determine if their dose should be increased, maintained at the current level, or decreased. The 
rationale for the dose levels being used in the Dose Optimization Period for Cohort 1 (5 mg, 
20 mg, and 50 mg) is provided in Section 5.3.4.  
5.3.4. 
Rationale for the Doses Selected for the Individual Dose Optimization 
The dose levels being used in the Dose Optimization Period for Cohort 1 (5 mg, 20 mg, and 
50 mg) in this extension study are the same as those used in the antecedent studies 
(Study AG348-C-006 and Study AG348-C-007).  
To assist with dose selection, an exposure-response analysis was conducted using 
pharmacokinetic, efficacy, and safety data from the DRIVE-PK study. Briefly, a sequential 
population pharmacokinetic-efficacy model was developed using increase in Hb as the efficacy 
endpoint, while a binary logistic regression approach incorporating the safety endpoints of ALT, 
AST, total and free testosterone, estrone, estradiol, insomnia, and hot flush was used for the 
analysis of exposure-safety relationship. Insomnia was the only safety event that was found to be 
significant in the logistic regression analysis. 
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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Study Objectives 
6.1.1. 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety and tolerability of AG-348. 
6.1.2. 
Secondary Objectives 
Secondary objectives of the study are as follows: 
• To evaluate the long-term efficacy of AG-348 
• To evaluate the efficacy of AG-348 in increasing Hb concentrations in subjects who 
previously received placebo in Study AG348-C-006 (Cohort 1 only) 
• To determine the effect of AG-348 on health-related quality of life (HRQoL) using 
patient reported outcomes (PROs) 
• To evaluate the pharmacokinetics of AG-348 after oral administration (Cohort 1 only) 
• To evaluate the relationship between AG-348 pharmacokinetics and safety 
parameters (Cohort 1 only) 
6.2. 
Study Endpoints 
The baseline value is defined as the most recent measurement(s) before the first dose of AG-348, 
considering both the antecedent study and this extension study, unless otherwise specified in 
Section 12.2.1.  
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6.2.1. 
Primary Endpoint 
The primary endpoint is to assess the long-term safety and tolerability of AG-348 by: 
• Type, incidence, severity, and relationship to study drug of treatment-emergent 
adverse events (TEAEs); serious adverse events (SAEs); AESIs; and TEAEs leading 
to dose reduction, treatment interruption, and treatment discontinuation 
• Changes from baseline in clinical laboratory tests (ie, serum chemistry, liver function 
tests [LFTs], hematology, lipids, sex steroids, coagulation, urinalysis), physical 
examination (PE) findings, bone mineral density T- and Z-scores (total hip, femoral 
neck, and lumbar spine), vital signs, and 12-lead electrocardiogram (ECG) data 
6.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are as follows: 
• Cohort 1 only: 
− Proportion of subjects achieving a hemoglobin response, defined as a ≥1.5 g/dL 
(0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or 
more scheduled assessments at Weeks 16, 20, and 24 
− Average change from baseline in Hb concentration at Weeks 16, 20, and 24  
− Pharmacokinetic endpoints, including plasma concentrations over time and 
pharmacokinetic parameters of AG-348 (eg, AUC, Cmax, others as applicable) 
− Exposure-response relationship between safety parameters and AG-348 
concentration and relevant AG-348 pharmacokinetic parameters 
• All cohorts: 
− Change from baseline in Hb concentration  
− Change from baseline in markers of hemolysis: bilirubin, lactate dehydrogenase 
(LDH), and haptoglobin levels 
− Change from baseline in markers of erythropoietic activity: reticulocyte 
percentages  
− Change from baseline in the number of transfusion events  
− Change from baseline in the number of RBC units transfused  
− Change from baseline in HRQoL PRO scores: Pyruvate Kinase Deficiency Diary 
(PKDD) and Pyruvate Kinase Deficiency Impact Assessment (PKDIA) 
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7. 
STUDY DESIGN 
7.1. 
Study Design Overview 
This is a multicenter, open-label, extension study to evaluate the long-term safety, tolerability, 
and efficacy of treatment with AG-348 in subjects who were previously enrolled in 
Study AG348-C-006 or Study AG348-C-007.  
Subjects will be assigned to 1 of the following 3 cohorts, depending on the antecedent study and 
the previous treatment received in the antecedent study: 
• Cohort 1: Subjects who received placebo in Study AG348-C-006 (Section 7.1.1) 
• Cohort 2: Subjects who received AG-348 in Study AG348-C-006 (Section 7.1.2) 
• Cohort 3: Subjects who received AG-348 in Study AG348-C-007 (Section 7.1.3) 
All subjects enrolled in this extension study, including those who received placebo in 
Study AG348-C-006, will receive AG-348 during participation in this extension study. Subjects 
may continue AG-348 treatment for up to a maximum of 192 weeks in this extension study (not 
including the time required for completion of the recommended dose taper) until they meet study 
withdrawal criteria (Section 8.3) or the study is closed (Section 7.5). 
At any time during the study, the Investigator can discontinue, interrupt, or reduce the 
subject’s dose of study drug for reasons related to safety (as described in Section 9.3). 
An overview of the study design is provided in Figure 2. Details about screening, the Dose 
Optimization and Fixed Dose Periods (Cohort 1 only), the Continued Treatment Period, and 
Discontinuation and Safety Follow-up are described in Section 7.2. 
Figure 2: 
Overview of Design for Study AG348-C-011 
 
Abbreviations: d=day; SCRN=Screening. 
a Eligible subjects in Cohort 1 will initiate treatment with AG-348 in this extension study. Therefore, these subjects 
will participate in a 12-week Dose Optimization Period followed by a 12-week Fixed Dose Period during the first 
24 weeks of this extension study. 
b Subjects who are in Cohort 2 or 3 will continue AG-348 treatment. 
c Dosing between Week 24 and Week 25 is continuous. 
d All subjects who permanently discontinue AG-348 at any time will attend a Safety Follow-up Visit 28 days 
(±4 days) after the last dose of AG-348 (including the time required to dose taper). 
 
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7.1.1. 
Cohort 1 
Cohort 1 will consist of subjects who received placebo in Study AG348-C-006 and meet the 
eligibility criteria of this extension study. The first visit of this extension study should coincide 
with the last visit of Study AG348-C-006. After completion of all scheduled assessments at the 
subject’s last visit of Study AG348-C-006 and before the start of study drug in this extension 
study, the subject, Investigator, and site personnel will be unblinded to the Study AG348-C-006 
treatment allocation of the subject, and the Investigator will determine whether the subject meets 
all eligibility criteria of this extension study. 
The first visit of this extension study should consist of subject consent, screening, confirmation 
of eligibility, and the start of study drug. If a subject in Cohort 1 cannot start study drug on the 
first visit of this extension study, discussion with and approval by the Medical Monitor, or 
designee, will be required for participation in this extension study, and to determine the timing 
and requirements for the start of study drug and assessments to be performed. 
Subjects in Cohort 1 will participate in a 12-week Dose Optimization Period followed by a 
12-week Fixed Dose Period (see Section 7.2.2 and Section 7.2.3, respectively). The goal of the 
Dose Optimization Period is to maximize a subject’s increase in Hb while maintaining an 
acceptable safety profile. After the Dose Optimization Period, each subject will remain on 
his/her individually optimized dose and enter the Fixed Dose Period. A schedule of assessments 
is provided for the Dose Optimization Period and Fixed Dose Period for Cohort 1 in Table 4. 
After completion of the Fixed Dose Period, subjects who, in the opinion of the Investigator, have 
demonstrated clinical benefit from AG-348 treatment will continue AG-348 treatment in the 
Continued Treatment Period (see Section 7.2.4).  
7.1.2. 
Cohort 2  
Cohort 2 will consist of subjects who received AG-348 in Study AG348-C-006 and meet the 
eligibility criteria of this extension study. The first visit of this extension study should coincide 
with the last visit of Study AG348-C-006. After completion of all scheduled assessments at the 
subject’s last visit of Study AG348-C-006 and before the start of study drug in this extension 
study, the subject, Investigator, and site personnel will be unblinded to the Study AG348-C-006 
treatment allocation of the subject, and the Investigator will determine whether the subject meets 
all eligibility criteria of this extension study.  
In Cohort 2, the first visit of this extension study will consist of subject consent, screening, 
confirmation of eligibility, and the start of study drug on this extension study. Importantly, there 
will be no planned dosing interruption between the last dose of blinded AG-348 in Study 
AG348-C-006 and the first dose of open-label AG-348 in this extension study due to the 
potential for withdrawal hemolysis (an identified risk of AG-348). Specifically, the first dose of 
open-label AG-348 in this extension study will be administered approximately 12 hours (ie, 
12 hours ± 2 hours) after the last dose in Study AG348-C-006. Subjects will continue the 
AG-348 dose regimen they were receiving at the last visit of Study AG348-C-006 (unless a dose 
modification is required for reasons related to safety, the subject’s dose optimization, or other 
reasons after discussion with and approval by the Medical Monitor or designee).  
A schedule of assessments for the first 24 weeks of Cohort 2 is provided in Table 5. Additional 
details regarding the Continued Treatment Period are provided in Section 7.2.4. 
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7.1.3. 
Cohort 3 
Cohort 3 will consist of subjects who received AG-348 in Study AG348-C-007 and meet the 
eligibility criteria of this extension study. The first visit of this extension study should coincide 
with the last visit of Study AG348-C-007. After completion of all scheduled assessments at the 
subject’s last visit of Study AG348-C-007 and before the start of study drug in this extension 
study, the Investigator will determine whether the subject meets all eligibility criteria of this 
extension study.  
In Cohort 3, the first visit of this extension study will consist of subject consent, screening, 
confirmation of eligibility, and the start of study drug on this extension study. Importantly, there 
will be no planned dosing interruption between the last dose of AG-348 in Study AG348-C-007 
and the first dose of AG-348 in this extension study due to the potential for withdrawal 
hemolysis (an identified risk of AG-348). Specifically, the first dose of AG-348 in this extension 
study will be administered approximately 12 hours (ie, 12 hours ± 2 hours) after the last dose in 
Study AG348-C-007. Subjects will continue the AG-348 dose regimen they were receiving at the 
last visit of Study AG348-C-007 (unless a dose modification is required for reasons related to 
safety, the subject’s dose optimization, or other reasons after discussion with and approval by the 
Medical Monitor or designee).  
A schedule of assessments for the first 24 weeks of Cohort 3 is provided in Table 5. Additional 
details regarding the Continued Treatment Period are provided in Section 7.2.4. 
Subjects in Cohort 3 should continue to be transfused with their mean number of blood units 
when they reach their Individual transfusion trigger (TT). As defined in Study AG348-C-007, the 
Individual TT is: 
• The sum of the Hb values within 1 week before and closest to each transfusion (when 
available) for the transfusions in the 52-week period before informed consent (for 
Study AG348-C-007) divided by the number of such available Hb values during that 
period, calculated to the first decimal point if expressed in g/dL, or to the second 
decimal point if expressed in mmol/L.  
− A margin of ±0.5 g/dL (or ±0.31 mmol/L) will be attached to this value.  
• The mean number of blood units is the sum of the number of units transfused at each 
transfusion during the 52-week period before informed consent (for Study AG348-C-
007) divided by the number of transfusions during this period. Fractional numbers 
will be rounded to the closest integer. 
At the discretion of the Investigator, some subjects may need additional hematology assessments. 
Blood sampling for these additional assessments (unscheduled visits) should be analyzed by the 
central laboratory but may be conducted and analyzed by a local laboratory or physician’s office 
local to the subject, as feasible and allowed by Investigators and local regulations. All on-study 
transfusion data will be recorded as noted in Section 9.5.4. 
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7.2. 
Study Description 
7.2.1. 
Screening Period 
A subject’s screening during this extension study should coincide with his/her last visit of their 
antecedent study (ie, Study AG348-C-006 or Study AG348-C-007). Assessments that overlap 
between the last visit of the antecedent study and screening of this extension study only need to 
be performed once.  
All assessments for eligibility for this extension study must be completed before a subject can 
begin study drug in this extension study. 
7.2.2. 
Dose Optimization Period (Cohort 1 Only)  
The Dose Optimization and Fixed Dose Periods of Cohort 1 will replicate the Dose Optimization 
and Fixed Dose Periods of Study AG348-C-006 in terms of frequency of assessments (Table 4) 
and dosing schema (Figure 3).  
Figure 3: 
Cohort 1 Dosing Schema for the First 24 Weeks, Study AG348-C-011 
 
Abbreviations: BID=twice daily. 
 
Subjects in Cohort 1 will participate in a 12-week Dose Optimization Period followed by a 
12-week Fixed Dose Period. The Dose Optimization Period will begin with the first dose of 
AG-348 administered at the study site.  
The starting dose will be 5 mg BID, with 2 potential sequential steps for dose level increases 
(from 5 mg BID to 20 mg BID and from 20 mg BID to 50 mg BID; no increases beyond 50 mg 
BID will be allowed) at the Week 4 and/or Week 8 Visits. Subjects will be assessed for safety 
and efficacy (as defined by Hb increase) every 4 weeks during the Dose Optimization Period to 
determine if their dose should be increased, maintained at the current level, or decreased. At the 
Week 4 and Week 8 Visits, AG-348 dose should be increased to the next dose level if the subject 
has met both of the following criteria: 
• The subject is tolerating the study drug and  
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• The subject’s Hb concentrations on the day of the visit based on local laboratory 
results is lower than 2.5 g/dL (1.55 mmol/L) below the ULN as applies to men and 
women.  
Dose re-escalation or re-introduction should be avoided after the Week 8 Visit, but may be 
permitted after discussion with the Medical Monitor or designee. 
At the Week 12 Visit, if the subject has tolerated the study drug, then the subject will remain at 
his/her current dose level. If the Investigator deems it necessary to reduce the study drug dose for 
safety reasons, the subject’s dose may be reduced to 1 of the 2 available lower dose levels 
(ie, 5 mg BID, 20 mg BID). If the subject is already receiving 5 mg BID and/or cannot tolerate 
BID dosing, another regimen may be allowed after discussion with, and approval by, the Medical 
Monitor or designee. 
If questions arise about whether the dose level of a given subject should be increased, 
maintained, or decreased, the site is advised to contact the Medical Monitor, or designee, for 
discussion. 
A schedule of assessments is provided for the Dose Optimization Period in Table 4. 
7.2.3. 
Fixed Dose Period (Cohort 1 Only) 
The Fixed Dose Period is a 12-week period after the Week 12 Visit through Week 24.  
After the Dose Optimization Period, each subject will remain on his/her individually optimized 
dose and enter the Fixed Dose Period. For the purposes of dosing during the Fixed Dose Period, 
the dose the subject is being administered at the Week 12 Visit will be considered the subject’s 
optimized dose and will be the dose the subject receives during the Fixed Dose Period.  
Dose re-escalation or re-introduction should be avoided after the Week 8 Visit, but may be 
permitted, after discussion with the Medical Monitor or designee. 
A schedule of assessments is provided for the Fixed Dose Period in Table 4. 
7.2.4. 
Continued Treatment Period 
After the Week 24 Visit, subjects in Cohort 1 who, in the opinion of the Investigator, have 
demonstrated clinical benefit from AG-348 treatment will begin the Continued Treatment Period. 
During this period, they will continue the AG-348 dose regimen they were receiving at the 
Week 24 Visit (unless a dose modification is required for reasons related to safety, the subject’s 
dose optimization, or other reasons after discussion with and approval by the Medical Monitor or 
designee).  
Subjects in Cohorts 2 and 3 will continue treatment with AG-348 in this extension study as noted 
in Section 7.1. A schedule of assessments for the first 24 weeks of Cohorts 2 and 3 is provided in 
Table 5.  
A schedule of assessments for the Continued Treatment Period after Week 24 for all cohorts is 
provided in Table 6. 
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7.2.5. 
Discontinuation and Safety Follow-up 
All subjects who interrupt or discontinue AG-348 at any time should undergo the recommended 
dose taper (Section 9.3), unless an emergency situation justifies discontinuing or interrupting the 
study drug abruptly. Whether the dose taper is performed or not, subjects discontinuing or 
interrupting AG-348 should be monitored for signs of hemolysis and worsening of anemia.  
All subjects who permanently discontinue AG-348 at any time will attend a Safety Follow-up 
Visit 28 days (±4 days) after the last dose of AG-348 (including the time required to dose taper). 
Guidelines for the follow-up of subjects with any AE at the subject’s completion of the study are 
described in Section 11. 
7.3. 
Number of Subjects to be Enrolled 
Approximately 96, with up to 116, subjects are potentially eligible to be enrolled in this 
extension study: approximately 76 subjects from Study AG348-C-006 and approximately 20, 
with up to 40, subjects from Study AG348-C-007, if eligible. 
7.4. 
Modifications Allowed During Declared Public Health Emergencies 
and Natural Disasters 
In the event of a declared public health emergency or natural disaster that affects a geographic 
area (eg, state, province, country, region, continent) and impedes adherence to protocol-specified 
procedures, certain modifications (Section 7.4.1) are allowable, when consistent with applicable 
regulations and guidance, to ensure subject safety, maintain compliance with good clinical 
practice (GCP), and minimize risks to trial integrity; the protocol must be followed to the fullest 
extent possible. These modifications are allowable only for the duration of the declared public 
health emergency or natural disaster, including any renewals of the declaration. During this 
period, the need for all implemented modifications will be reassessed when warranted as the 
situation evolves. Examples of declared public health emergencies and disasters are: 
• The public health emergency related to coronavirus disease 2019 (COVID-19) 
declared by the US Secretary of Health and Human Services in 2020 
• The Australian Bushfires Disaster declared by the Australian Attorney-General in 
2020  
Documented approval from the Sponsor is required before these modifications can be 
implemented. 
7.4.1. 
Allowable Modifications 
The following modifications are allowed in the event of a public health emergency or natural 
disaster and must be reported as protocol deviations; refer to Section 10.1 for the timing of 
assessments: 
• Alternative distribution of study drug 
− A 3-month supply of AG-348 may be shipped to a local health care provider or 
pharmacy or, if necessary, directly to a subject. Delivery of a greater than 
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− The Investigator must document their review of the results of home health nursing 
visits. 
• Virtual informed consent/reconsent in lieu of in-person informed consent/reconsent 
− Consent to participate in this study may be completed virtually and documented in 
the relevant subject medical records because subjects are entering this study after 
participating in a previous study of the same study drug and study visits/ 
assessments in this study will be conducted at the same or a lower frequency than 
in the preceding study. 
− Reconsent (ie, consenting to an amended version of the protocol) may be 
completed virtually and documented in the relevant subject medical records. 
− The other allowable modifications described in this section may require consent 
from the subject because their implementation requires a variation from the 
specifications in the protocol to which the subject has consented (eg, consent for a 
home visit, consent to provide name and address to a third-party delivery service, 
consent to a new mode of completing study procedures and receiving study drug). 
In these instances, consent may be completed virtually and documented in the 
relevant subject medical records. 
7.5. 
Criteria for Study Closure 
This study may be terminated if, in the opinion of the Sponsor, there is sufficient reasonable 
cause. In the event of such action, written notification documenting the reason for study 
termination will be provided to each Investigator. 
Circumstances that may warrant termination include, but are not limited to the following: 
• Determination of unexpected, significant, or unacceptable risk to subjects  
• Plans to modify, suspend, or discontinue the development of AG-348 
• Decisions of competent authorities or Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) 
• Other administrative or business reasons 
Should the study be closed prematurely, all study materials must be returned to the Sponsor or 
the Sponsor’s designee. 
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8. 
STUDY POPULATION 
8.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for inclusion in this extension 
study: 
1. Have provided signed written informed consent prior to participating in this extension 
study.  
2. Have completed the antecedent AG-348 study through the Part 2 Week 24 Visit of Study 
AG348-C-006 or AG348-C-007. 
3. Cohorts 2 and 3: Have demonstrated clinical benefit from AG-348 treatment in the 
antecedent study, in the opinion of the Investigator.  
4. For women of reproductive potential*: 
a. In Cohort 1, have a negative local serum (human chorionic gonadotropin [hCG]) 
pregnancy test during screening of this extension study.  
b. In Cohort 2 or 3, have a negative local urine pregnancy test during screening of this 
extension study. 
* Women of reproductive potential are defined as sexually mature women who have not 
undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion; or who have not 
been naturally postmenopausal (ie, who have not menstruated at all for at least the 
preceding 12 months prior to screening of this extension study and have an elevated 
follicle-stimulating hormone [FSH] level indicative of menopause during screening of 
this extension study or at screening of the antecedent study). If the result from FSH 
testing conducted during screening of this extension study is not available on the same 
day, the woman must have a negative local serum (hCG) or urine pregnancy test during 
screening and follow contraception requirements (Inclusion Criterion #5) until an 
elevated FSH result indicative of menopause is confirmed. 
5. For women of reproductive potential as well as men with partners who are women of 
reproductive potential, be abstinent as part of their usual lifestyle, or agree to use 2 forms 
of contraception, 1 of which must be considered highly effective, from the time of giving 
informed consent, during the study, and for 28 days following the last dose of study drug 
for women and 90 days following the last dose of study drug for men. A highly effective 
form of contraception is defined as combined (estrogen and progestin containing) 
hormonal contraceptives (oral, intravaginal, or transdermal) known to be associated with 
inhibition of ovulation; progestin-only hormonal contraceptives (oral, injectable, or 
implantable) known to be associated with inhibition of ovulation; intrauterine device; 
intrauterine hormone releasing system; bilateral tube occlusion; or vasectomized partner. 
The second form of contraception can include an acceptable barrier method, which 
includes male or female condoms with or without spermicide, and cervical cap, 
diaphragm, or sponge with spermicide. Women of reproductive potential using hormonal 
contraception as a highly effective form of contraception must also utilize an acceptable 
barrier method while enrolled in the study and for at least 28 days after their last dose of 
study drug. 
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6. Be willing and able to comply with study visits and procedures. 
8.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will not be enrolled in this extension study: 
1. Have a significant medical condition (including clinically significant laboratory 
abnormality) that developed during his/her antecedent AG-348 study that confers an 
unacceptable risk to participating in this extension study, that could confound the 
interpretation of the study data, and/or that compromises the ability of the subject to 
complete study visits and procedures.  
2. Are currently pregnant or breastfeeding. 
3. Have a splenectomy scheduled during the study treatment period. 
4. Meet the withdrawal criteria of his/her antecedent AG-348 study during screening of this 
extension study. 
Withdrawal criteria of the antecedent AG-348 studies are as follows: 
• Withdrawal of consent 
• Development of an intercurrent medical condition that precludes further 
participation in the study 
• Subject requires use of a prohibited concomitant medication 
• Investigator decision 
• Persistent nonadherence to protocol requirements 
• Pregnancy 
• Lost to follow-up 
5. Are currently receiving medications that are strong inhibitors of CYP3A4 that have not 
been stopped for a duration of at least 5 days or a time frame equivalent to 5 half-lives 
(whichever is longer) before start of study drug; or strong inducers of CYP3A4 that have 
not been stopped for a duration of at least 28 days or a time frame equivalent to 
5 half-lives (whichever is longer) before start of study drug on this extension study. 
6. Have received anabolic steroids, including testosterone preparations, within 28 days prior 
to start of study drug on this extension study. 
7. Have received hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony 
stimulating factors, thrombopoietins) within 28 days prior to start of study drug on this 
extension study. 
8. Have exposure to any investigational drug other than AG-348, device, or procedure 
within 3 months prior to start of study drug on this extension study. 
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8.3. 
Subject Withdrawal Criteria 
Subjects have the right to withdraw from the study drug or the study at any time for any reason. 
A subject’s withdrawal from study drug or the study will not jeopardize the relationship with 
their health care providers or affect their future care. Should a subject decide to withdraw 
consent, all efforts will be made to complete and report the protocol-defined study observations 
up to the time of the subject’s withdrawal as completely as possible and to determine the reason 
for withdrawal. 
In the event a subject is withdrawn from the study drug or the study, the Medical Monitor, or 
designee, must be informed. When a subject withdraws from the study drug or withdraws from 
the study, the primary reason for treatment discontinuation and study discontinuation must be 
recorded in the appropriate section of the electronic case report form (eCRF). 
8.3.1. 
Withdrawal From Study Drug 
Subjects may be permanently withdrawn from study drug based on the judgment of the 
Investigator. Subjects who are withdrawn from study drug will be encouraged to return for the 
Follow-Up Visit, unless consent has been withdrawn. Subjects may be withdrawn from study 
drug under the following conditions: 
• Withdrawal by subject 
• Development of an intercurrent medical condition that precludes further participation 
in the study  
• Development of an AE that meets the criteria for discontinuation from study drug as 
depicted in Section 9.3  
• Subject requires use of a prohibited concomitant medication (Section 9.5.1) 
• Persistent nonadherence to protocol requirements  
• Lost to follow-up  
• Approved drug available for indication 
• Study termination 
• Investigator decision 
• Other 
The Investigator should routinely assess the benefit/risk of continuing AG-348 to determine 
whether staying on the study drug is in the best interest of the subject. If questions arise, the 
Investigator may contact the Medical Monitor or designee. 
Refer to Section 9.3 for details on discontinuing study drug. 
Refer to Section 11 for details regarding the follow-up of AEs ongoing at the time a subject 
discontinues study drug.  
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9. 
STUDY TREATMENTS 
9.1. 
Description of Study Drug 
Details on the study drug are provided in Table 1. 
Table 1: 
Study AG348-C-011 Investigational Product 
 
Investigational product 
Product name: 
AG-348 
Dosage form: 
Tablets 
Unit dose: 
5 mg, 20 mg, and 50 mg 
Route of administration: 
Oral 
Physical description: 
Blue film-coated tablet 
Please see the IB for further details regarding AG-348. AG-348 is provided for investigational 
use only (considered an investigational medicinal product [IMP]) and is to be used only within 
the context of this study. All study drug product will be supplied by the Sponsor. 
9.1.1. 
Study Drug Packaging and Labeling 
AG-348 will be supplied as 5, 20, or 50 mg tablets in 35-tablet bottles with child-resistant 
closures and will be labeled appropriately as IMP for this study. Packaging and labeling will be 
prepared to meet all regulatory requirements.  
This is an open-label study; there are no additional requirements regarding the physical aspect of 
blinding related to packaging and labeling.  
9.1.2. 
Study Drug Storage 
AG-348 tablets must be stored according to the respective package label. All study drug must be 
stored in a secure, limited-access location and may be dispensed only by the Investigator, 
member of the staff specifically authorized by the Investigator, or party designated to deliver 
study drug directly to subjects.  
9.1.3. 
Study Drug Administration 
AG-348 tablets are to be taken orally and swallowed whole with water. The tablets are not to be 
crushed, chewed, or dissolved in water. Doses of AG-348 may be taken with or without food. 
Subjects will take 1 tablet twice a day, approximately 12 hours (ie, 12 hours ± 2 hours) apart, for 
a total of 2 tablets each day (unless a dose modification is required for reasons related to safety). 
If a dose of study drug is not taken within 2 hours before or 2 hours after the scheduled dosing 
time, the dose should be skipped. If a dose of study drug is skipped, the next dose should then be 
taken approximately 24 hours from the previous dose.  
Subjects should be advised not to abruptly interrupt or discontinue dosing without first speaking 
with the treating Investigator except in case of medical emergency; abrupt interruption or 
discontinuation of AG-348 may result in withdrawal hemolysis. If a subject needs to interrupt or 
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Table 2: 
Dose Modification for Adverse Events Considered Related to Study Drug 
, Study AG348-C-011 
Related AE(s) 
severity 
Dose modification 
the event resolves to baseline1 or Grade 1 (whichever is lower). If the event 
persists, performing the recommended dose taper or stopping the study drug 
abruptly should be considered. 
If the decision is made to perform the recommended dose taper or stop the study 
drug abruptly, the below instructions should be followed for re-introduction or re-
escalation of the study drug, respectively.  
In all cases, re-introduction and re-escalation of study drug should be 
performed only after discussion with the Medical Monitor or designee.  
• 
Restarting study drug after dosing was stopped:  
– 
Once the event resolves to baseline1 or Grade 1 (whichever is lower) 
and the decision is made to restart treatment, the study drug should be 
re-introduced at the 5 mg BID dose level. If the event does not re-
occur after at least 4 weeks on 5 mg BID (with at least once weekly 
monitoring), the dose may be increased from 5 mg BID to 20 mg 
BID. If the event does not re-occur after at least 4 weeks on 20 mg 
BID (with at least once weekly monitoring), the dose may be 
increased from 20 mg BID to 50 mg BID. In both cases, dose 
escalation should follow the guidance in Section 7.2.2.  
• 
Events resolving during the recommended dose taper (ie, the subject is 
still on study drug):  
– 
If during the dose taper, the event resolves to baseline1 or Grade 1 
(whichever is lower), the study drug should be maintained at the dose 
at which the event resolved for at least 4 weeks (with at least once 
weekly monitoring). If the event does not re-occur after at least 
4 weeks, then consider increasing the dose to the next highest BID 
dose (5 mg BID, 20 mg BID, or 50 mg BID) with at least once 
weekly monitoring. If the event does not re-occur after at least 4 
weeks (with at least once weekly monitoring), and the subject is not 
already receiving 50 mg BID, consider increasing the dose to the next 
BID dose level. In both cases, dose escalation should follow the 
guidance in Section 7.2.2. 
• 
Re-occurrence of the AE: 
– 
If the AE re-occurs at any point during the above scenarios, the 
subject should undergo the recommended dose taper or stop 
treatment abruptly, if necessitated by the risk of the AE. If the subject 
undergoes the recommended dose taper and the AE resolves during 
the taper, study drug should be maintained at the next lowest BID 
dose below the dose at which the AE resolved. If the subject cannot 
tolerate BID dosing, another regimen may be allowed after discussion 
with, and approval by, the Medical Monitor or designee. If the AE 
does not resolve to baseline1 or Grade 1 (whichever is lower) after the 
dose is decreased, a further decrease in the dose should be 
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Table 2: 
Dose Modification for Adverse Events Considered Related to Study Drug 
, Study AG348-C-011 
Related AE(s) 
severity 
Dose modification 
considered. If the AE still does not resolve, study drug should be 
permanently discontinued. 
Grade 4 
After careful consideration of the relative risk of withdrawal hemolysis when 
stopping study drug abruptly versus reducing the dose, the Investigator should 
determine which of the following options is appropriate: 
• 
Performing the recommended dose taper or 
• 
Stopping the study drug abruptly 
If the event resolves, and the Investigator believes that re-introducing study drug 
is justified, the Medical Monitor, or designee, should be consulted before any 
further study drug is administered. 
Abbreviations: BID=twice daily; Hb=hemoglobin. 
1 In the context of dose modification due to an AE, baseline is defined as the baseline of the study (antecedent or 
extension) during which AE onset occurred. If an AE worsens, baseline refers to the study during the initial 
onset of the AE.  
 
9.3.3. 
Study Drug Discontinuation or Interruption With Recommended Dose Taper 
Regimen 
All subjects who discontinue or interrupt study drug during the study should undergo the 
recommended dose taper regimen in Table 3. This regimen is based on the study drug dose 
administered to the subject at the start of the taper and occurs in 1 or 2 sequential steps. 
Subjects undergoing the recommended dose taper should be monitored as clinically indicated for 
signs of withdrawal hemolysis and worsening of anemia. If the recommended dose taper is 
performed to permanently discontinue study drug, subjects stop taking the study drug after the 
taper has been completed. 
Table 3: 
Recommended Dose Taper Regimen, Study AG348-C-011 
Starting dose  
(at the time of the dose taper) 
First step 
×7 days 
Second step 
×7 days 
5 mg BID 
5 mg QD 
--- 
20 mg BID 
20 mg QD 
5 mg QD 
50 mg BID 
50 mg QD 
20 mg QD  
Abbreviations: BID=twice daily; QD=once daily. 
 
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9.4. 
Duration of Subject Participation 
9.4.1. 
Treatment Duration 
Subjects may continue AG-348 treatment for up to a maximum of 192 weeks in this extension 
study (not including the time required for completion of the recommended dose taper) until they 
meet study withdrawal criteria (Section 8.3) or the study is closed (Section 7.5). 
9.4.2. 
End of Study 
The End of Study is defined as the point at which all subjects have discontinued or completed the 
study, are lost to follow-up, or the Study Sponsor terminates the study. 
9.4.3. 
Treatment Compliance 
Treatment compliance will be assessed by drug accountability (ie, number of tablets dispensed vs 
number returned). 
9.5. 
Concomitant Medications 
Concomitant medications are defined as those administered from the point of signing the 
informed consent form (ICF) on this extension study through the subject’s completion of the 
study. Prior medications will have already been collected as either a prior medication or 
concomitant medication in the respective antecedent study and, thus, will not be collected at the 
start of this extension study. All concomitant medications must be recorded in the appropriate 
section of the source documentation and eCRF along with any dosage information, dates of 
administration, mode of administration, and reason for use. For non-drug therapies, please refer 
to Section 9.5.4. 
9.5.1. 
Prohibited Medications 
Concomitant use of investigational drugs is not allowed while subjects are participating in this 
study. All subjects must discontinue any investigational drug (except for AG-348) no less than 
3 months before the start of study drug on this extension study. 
In vitro studies using human liver microsomes and recombinant CYP enzymes have shown that 
AG-348 is primarily metabolized by CYP3A4 and CYP3A5, with minor contributions from 
CYP2C9, CYP2C8, and CYP1A2. In addition, AG-348 has been shown to be a weak 
time-dependent CYP3A4/5 inhibitor and a potential inducer of CYP3A4 in vitro.  
Based on these results, below is a list of concomitant therapy to be avoided and concomitant 
therapy requiring careful monitoring. 
The following are prohibited at all times during participation in this study: 
• Strong inhibitors of CYP3A4 (listed in Appendix 5 of the AG-348 IB) 
Note: If a subject is taking any medication that is a strong inhibitor of CYP3A4 
before enrolling in the study, the medication must be discontinued at least 5 days or a 
time frame equivalent to 5 half-lives (whichever is longer) before the start of study 
drug on this extension study. 
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• Products known to inhibit CYP3A4, such as grapefruit or grapefruit juice 
• Strong inducers of CYP3A4 (listed in Appendix 5 of the AG-348 IB) 
Note: If a subject is taking any medication that is a strong inducer of CYP3A4 before 
enrolling in the study, the medication must be discontinued at least 28 days or a time 
frame equivalent to 5 half-lives (whichever is longer) before the start of study drug on 
this extension study. 
• Hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony stimulating 
factors, thrombopoietins) must be discontinued no less than 28 days before the start of 
study drug on this extension study. Vitamin B12 injections are permitted for subjects 
with a prior diagnosis of vitamin B12 deficiency syndromes. Subjects must be 
repleted to stability of the Hb and mean corpuscular volume before enrollment in this 
extension study. 
• Anabolic steroids, including testosterone preparations, administered for anemia must 
be discontinued no less than 28 days before the start of study drug on this extension 
study. 
9.5.2. 
Concomitant Therapy Requiring Careful Monitoring 
The medications that fall under the categories mentioned below should be replaced with 
alternative treatments. If this is not possible, subjects receiving these medications should be 
carefully monitored. A general monitoring guideline for Investigators whose patients take 
medications that fall under the categories mentioned below is as follows: Investigators must 
monitor subjects for lack of efficacy of the prescribed medication or for side effects arising from 
the medication. If either a lack of efficacy of the prescribed medication or side effects suspected 
to be related to the prescribed medication are noticed, then the Investigator should make 
appropriate modifications to the dose of the prescribed medication or find alternatives to the 
prescribed medication. 
• Corticosteroids (sensitive substrates of CYP3A4 and weak CYP3A4 inducers) 
• Sensitive substrates of CYP3A4 (listed in Appendix 5 of the AG-348 IB) 
• Moderate inhibitors of CYP3A4 (listed in Appendix 5 of the AG-348 IB) 
• Moderate inducers of CYP3A4 (listed in Appendix 5 of the AG-348 IB) 
• Proton-pump inhibitors and H2-receptor antagonists (listed in Appendix 5 of the 
AG-348 IB). Antacids, such as magnesium hydroxide and aluminum hydroxide, can 
be used with AG-348. 
• Deferoxamine, deferasirox, and deferiprone. AG-348, as a potential uridine 
5ʹ-diphospho-glucuronosyltransferase (UGT)1A1 inducer, has the potential to reduce 
the effectiveness of iron chelators metabolized by UGT1A1. As iron overload is a 
long-term complication of PK deficiency, any initiation, completion, or change of 
iron chelation therapy during this extension study should be recorded in the 
appropriate section of the source documentation and the eCRF. Information to be 
recorded includes type of chelation therapy, start date, stop date, and dose. 
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AG-348, being a potential CYP3A4 inducer, has the potential to reduce the effectiveness of oral 
contraceptives. Therefore, women using oral contraceptives must also utilize a barrier method 
while enrolled in the study and until at least 28 days after their last dose of study drug, as 
specified in Inclusion Criterion #5 (Section 8.1). 
9.5.3. 
Allowed Concomitant Medications 
Medications other than those specified above (Section 9.5.1) are permitted during the study. All 
intercurrent medical conditions will be treated at the discretion of the Investigator according to 
acceptable local standards of medical care. Subjects may receive analgesics, anti-emetics, 
anti-infectives, and antipyretics as medically indicated and consistent with the guidance in 
Section 9.5.1.  
The Sponsor has conducted a risk assessment for concomitant use of a COVID-19 vaccine with 
AG-348 with specific consideration for the trial population and determined that the COVID-19 
vaccine given to a trial subject is considered a simple concomitant medication with no interaction 
that requires advice on timing of the vaccine or other aspects that need to be mitigated. 
Subjects must continue taking at least 0.8 mg oral folic acid daily for the duration of the study.  
9.5.4. 
Concomitant Non-Drug Therapies 
Concomitant non-drug therapies are defined as those performed from the point of signing the 
ICF on this extension study through the subject’s completion of the study. As this is an extension 
study, prior non-drug therapies relevant for medical/surgical history will have been recorded 
with the antecedent study. Relevant concomitant non-drug therapies used to treat an AE should 
be collected from signing of ICF on this extension study until completion of the study.  
For each transfusion administered at any time during the study, the date of transfusion and 
number of RBC units transfused will be recorded from signing of ICF until completion of the 
study. 
9.6. 
Randomization and Blinding 
Not applicable, as this is an open-label study in which all subjects will be treated with AG-348.  
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10. 
ASSESSMENTS 
10.1. 
Schedule of Assessments 
The schedules of assessments for Cohort 1 (through Week 24), Cohorts 2 and 3 (through 
Week 24), and Cohorts 1, 2, and 3 (Week 37 Day 1 through Week 193 Day 1) are provided in 
Table 4, Table 5, and Table 6, respectively. 
Subjects may transition to receiving treatment with mitapivat (the international nonproprietary 
name of AG-348) outside of Study AG348-C-011 (eg, commercial) and may follow an altered 
schedule of assessments depending on whether they complete the study or prematurely 
discontinue, as described below: 
• Subjects who complete study (ie, complete the last scheduled visit) before 
transitioning: 
− Subjects who intend to complete the study and immediately transition to receiving 
treatment with mitapivat outside of Study AG348-C-011 without interruption of 
mitapivat dosing may have their End of Study visit at Week 193. These subjects 
would not be dispensed study drug on Week 193, not be required to undergo the 
final dose taper, and not attend the Safety Follow-up visit. 
• Subjects who prematurely discontinue study before transitioning: 
− Subjects who transition to receiving treatment with mitapivat outside of Study 
AG348-C-011 before their Week 193 visit will attend an End of Study visit that 
includes the same assessments that would have been performed on Week 193 and 
will be withdrawn from the study. These subjects will not be dispensed study drug 
at their End of Study visit and will not attend the Safety Follow-up visit. Subjects 
who intend to immediately transition to receiving treatment with mitapivat outside 
of Study AG348-C-011 without interruption of mitapivat dosing are not required 
to undergo the final dose taper. 
As summarized in Section 9.3, withdrawal hemolysis is an identified risk of mitapivat, and 
subjects should undergo dose taper if treatment with mitapivat is to be discontinued or 
interrupted. For subjects who transition to receive treatment with mitapivat outside of Study 
AG348-C-011, please refer to the dose management instructions (eg, package insert) to assess 
the need for subjects to undergo dose taper during the transition. 
 
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Table 4: 
Schedule of Assessments for Cohort 1 Only (Day 1-Week 24) 
Visit: 
SCRN/D11 
W2 
W4 
W6 
W8 
W102 
W12 
W16 
W20 
W243 
Safety Follow-up4 
Study Day: 
1 
15 
29 
43 
57 
71 
85 
113 
141 
169 
28 days after the 
last dose of AG-348 
Visit Window: 
0  
±3 D 
±3 D 
±3 D 
±3 D 
±3 D 
±3 D 
±3 D 
±3 D 
±3 D 
±4 D 
Procedures: 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
Demographics5 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination6 
X 
 
 
 
 
 
X 
 
 
X 
 
Vital signs7 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
12-lead ECG8 
X 
 
 
 
 
 
X 
 
 
X 
X 
DXA Scan 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs/AESIs9 
X 
Concomitant medications/non-drug therapies 
X 
On-study transfusion record10 
X 
Clinical Laboratory Evaluations: 
Hematology11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haptoglobin and LDH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry12 
X 
 
 
 
 
 
X 
 
 
X 
X 
LFTs13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation studies14 
X 
 
 
 
 
 
X 
 
 
X 
 
Urinalysis15 
X 
 
 
 
 
 
X 
 
 
X 
 
Lipids16 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
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Table 5: 
Schedule of Assessments for Cohorts 2 and 3 Only (Day 1-Week 24) 
Visit: 
SCRN/D11 
W12 
W242 
Safety Follow-up3 
Study Day: 
1 
85 
169 
28 days after the last dose of AG-348 
Visit Window: 
0  
±3 D 
±3 D 
±4 D 
Procedures: 
Informed consent 
X 
 
 
 
Eligibility 
X 
 
 
 
Demographics4 
X 
 
 
 
Physical examination5 
X 
X 
X 
 
Vital signs6 
X 
X 
X 
X 
12-lead ECG7 
X 
X 
X 
X 
DXA Scan 
X 
 
X 
 
 
 
 
 
 
AEs/SAEs/AESIs8 
X 
Concomitant medications/non-drug therapies 
X 
On-study transfusion records9 
X 
Clinical Laboratory Evaluations: 
Hematology10 
X 
X 
X 
X 
Haptoglobin and LDH 
X 
X 
X 
X 
Serum chemistry11 
X 
X 
X 
X 
LFTs12 
X 
X 
X 
X 
Coagulation studies13 
X 
X 
X 
 
Urinalysis14 
X 
X 
X 
 
Lipids15 
X 
X 
X 
X 
Sex Steroids16 
X 
X 
X 
X 
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Table 5: 
Schedule of Assessments for Cohorts 2 and 3 Only (Day 1-Week 24) 
Visit: 
SCRN/D11 
W12 
W242 
Safety Follow-up3 
Study Day: 
1 
85 
169 
28 days after the last dose of AG-348 
Visit Window: 
0  
±3 D 
±3 D 
±4 D 
 CRP 
X 
X 
X 
 
EPO
 
X 
X 
X 
 
T4, TSH, PTH, fructosamine, and Vitamin D 
X 
X 
X 
 
FSH19 
X 
 
 
 
Pregnancy test (local laboratory and home testing) 20 
X 
X 
X 
X 
HRQoL Assessments and Other eDiary Assessments:21 
PKDD22 
 
X 
X 
 
PKDIA 
 
X 
X 
 
Dispense eDiary 
X 
 
 
 
Menstrual cycle eDiary 
X 
Return eDiary 
 
 
 
X 
Study Drug: 
Dispense study drug23 
X 
X 
X 
 
Study drug administration 
X 
 
Return study drug 
 
X 
X 
X 
Abbreviations: aPTT = activated partial thromboplastin time; BUN = blood urea nitrogen; CBC = complete blood count; CO2 = carbon dioxide; CRP = C-reactive protein; 
D = day; DXA = dual-energy X-ray absorptiometry; ECG = electrocardiogram; eDiary = electronic diary; EPO = erythropoietin; FSH = follicle-stimulating hormone; Hb = 
hemoglobin; HCT = hematocrit; HDL-C = high-density lipoprotein cholesterol; HRQoL = health-related quality of life; ICF = informed consent forum; INR = international 
normalized ratio; IRF = immature reticulocyte fraction; LDH = lactate dehydrogenase; LDLC = low-density lipoprotein cholesterol; LFT = liver function test; MCH = mean 
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; 
 NRBC = nucleated red 
blood cells; 
 PE = physical examination; PKDD = Pyruvate Kinase Deficiency Diary; PKDIA = Pyruvate Kinase Deficiency Impact 
Assessment; PTH = parathyroid hormone; RBC = red blood cell; RDW = red cell distribution width; SCRN = Screening; T4 = thyroxine; 
TSH 
= thyroid-stimulating hormone; W = week; WBC = white blood cell. 
Whenever more than one assessment is scheduled for the same nominal time, the assessments should be performed in the order of least invasive to most invasive assessment 
(eg, vital signs, ECG, blood draw). The timing of these assessments should allow the blood draw to occur at the exact nominal time (if applicable). The order of procedures may be 
revised with prior discussion between the Sponsor’s Medical Monitor, or designee, and the site. 
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1 A subject’s first visit of this extension study should coincide with his/her last visit of their antecedent study (ie, Study AG348-C-006 or Study AG348-C-007). Assessments that 
overlap between the last visit of the antecedent study and screening of this extension study only need to be performed once. All assessments for eligibility for this extension study 
must be completed before a subject can start study drug in this extension study. The first visit of this extension study for subjects on Cohorts 2 and 3 will consist of screening, 
confirmation of eligibility, and the start of study drug on this extension study. 
2 If a subject in Cohort 2 or 3 is continuing in the study beyond the Week 24 Visit, refer to the schedule of assessments in Table 6 for all assessments beyond Week 24. 
3 A Safety Follow-up Visit will be performed for all subjects who permanently discontinue study drug. The visit will occur 28±4 days after the last dose of study drug (including 
the time required to dose taper). 
4 Subject demographic data will include gender and year of birth only, as other demographic data will have been collected as part of the antecedent study. 
5 Complete PE with weight will be collected. Additional PEs may be performed when clinically indicated, at the discretion of the Investigator. 
6 Vital signs will include systolic and diastolic blood pressure, heart rate, and body temperature. 
7 The 12-lead ECGs will be conducted using the equipment provided by the vendor and according to the vendor manual, after 5 minutes of recumbence and in triplicate. The 
ECGs will be read promptly by a qualified physician at the study site to detect any safety issue. In addition to the local read, the ECGs will be sent promptly to the central vendor 
for a data-analysis read.  
8 AEs/SAEs/AESIs will be collected and recorded as detailed in Section 11.1. The Investigator should ask the subject for information regarding sleep patterns, signs, and 
symptoms associated with insomnia. 
9 Transfusion records will be kept while subjects are on study and will include the date of the transfusion and the number of RBC units transfused. 
10 Hematology parameters (ie, CBC with differential) include HCT, Hb, RBC count, percent reticulocyte, absolute reticulocyte count, immature reticulocyte fraction (IRF-H and 
IRF-M+H) (if available), MCV, MCH, MCHC, RDW, NRBC, WBC count with differential, and platelet count. 
11 Serum chemistry parameters include sodium, potassium, chloride, calcium, magnesium, phosphorus, CO2 or bicarbonate, albumin, total protein, glucose, BUN or urea, 
creatinine, and uric acid.  
12 Liver function tests include ALP, ALT, AST, and total, direct, and indirect bilirubin. 
13 Coagulation parameters include fibrinogen, aPTT, and INR. 
14 Urinalysis will be performed by a dipstick method and include assessments of protein, glucose, leukocytes, and blood. 
15 For lipid testing, samples for total cholesterol, LDL-C, HDL-C, and triglycerides will be collected after an overnight fast (see central laboratory vendor manual for detail). If the 
subject reports that they did not adhere to an overnight fast, these samples should not be collected at the scheduled visit. Instead, these samples should be collected within 
2 weeks of the original time point at an unscheduled visit, after the subject has adhered to an overnight fast. 
16 Sex steroid testing includes estrone, estradiol, and testosterone (total and free). 
  
18 Remaining sample may be used for analysis of lipoproteins (only in subjects who have agreed to this optional analysis in the ICF). 
19 The FSH assessment will be performed only at screening for female subjects for confirmation of postmenopausal status (ie, female subjects who have not menstruated at all for 
at least the preceding 12 months), unless an elevated FSH level indicative of menopause was obtained at screening of the antecedent study. Samples should be drawn in the 
morning (does not need to be fasting). 
20 For women of reproductive potential on Cohorts 2 and 3, a local urine pregnancy test must be completed during screening and documented to be negative before the subject can 
start study drug in this extension study. A urine or serum pregnancy test must also be done every 4 weeks and at any point throughout the study if pregnancy is clinically 
suspected. A local urine or serum pregnancy test should be performed at the study site at the scheduled visits and a urine pregnancy test should be performed by the subject at 
home when required testing occurs between the scheduled visits. Results of the home pregnancy tests will be recorded in the eDiary. 
21 All subjects will use an eDiary to record responses to HRQoL assessments and results of home pregnancy tests (women of reproductive potential only). The HRQoL assessments 
will be completed by the subject in the evening (between 5:00-11:00 pm) within the window for the relevant study visit. In addition, menstruating female subjects will record 
their menstrual cycles (start date, stop date, and change in characteristics) in the eDiary; the menstrual diary can be completed at any time of day. Subjects should return their 
eDiary to the study site once they complete the study at the Safety Follow-up Visit. 
22 The PKDD assessment will be collected for 6 days prior to and on the day of the PKDIA assessment.  
23 Study drug is expected to be dispensed to the subject at the study site. Under exceptional circumstances and with agreement of the Sponsor (or representative), study drug can be 
provided at the subject’s home (if acceptable by practice and allowed by local regulations). All subjects who discontinue or interrupt AG-348 at any time should undergo the 
recommended dose taper per protocol (Section 9.3), unless an emergency situation justifies discontinuing or interrupting the study drug abruptly. Whether the dose taper is 
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performed or not, subjects discontinuing or interrupting AG-348 should be monitored for signs of hemolysis and worsening of anemia. Study drug will be dispensed to these 
subjects until study drug is completely stopped. 
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Table 6: 
Schedule of Assessments for All Cohorts, Continued Treatment Period (W37D1-W193D1) 
Visit: 
W37D1 
W61D1 
W85D1 
W49D1 
W97D1 
W73D1 
W109D1 
W133D1 
W157D1 
W181D1 
(Telemedicine1) 
W121D1 
W169D1 
W145D1 
W193D12 
Safety 
Follow-up2,3 
28 days after the 
last dose of 
AG-348 
Visit window: 
±14 D 
±14 D 
±14 D 
±14 D 
±14 D 
±14 D 
 
±4 D 
Procedures: 
Physical examination4 
 
 
 
 
 
 
X 
 
Vital signs5 
X 
X 
X 
 
X 
X 
X 
X 
DXA scan2 
 
X 
X 
 
 
X 
X 
 
  
 
 
 
 
 
 
 
 
Reproductive potential6 
 X 
AEs/SAEs7 
X 
Concomitant medications/non-drug therapies 
X 
Record on-study transfusions8 
X 
Clinical laboratory evaluations: 
Hematology9 
X 
X 
X 
 
X 
X 
X 
X 
Haptoglobin and LDH 
X 
X 
X 
 
X 
X 
X 
X 
Serum chemistry10 
 
X 
X 
 
X 
X 
X 
X 
LFTs11 
X 
X 
X 
 
X 
X 
X 
X 
Coagulation studies12 
 
X 
X 
 
 
X 
X 
 
Lipids13 
 
 
X 
 
X 
 
 
X 
Sex Steroids14 
X 
X 
X 
 
X 
X 
X 
X 
 
 CRP 
X 
X 
X 
 
X 
X 
X 
 
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4 Complete PE with weight will be collected. Additional PEs may be performed when clinically indicated, at the discretion of the Investigator. 
5 Vital signs will include systolic and diastolic blood pressure, heart rate, and body temperature. 
6 Changes in reproductive potential of female subjects (as defined in Appendix 1) will be recorded, including the date of the change. 
7 AEs/SAEs will be collected and recorded as detailed in Section 11.1. The Investigator should ask the subject for information regarding sleep patterns, signs, and symptoms 
associated with insomnia. 
 
 
8 Transfusion records will be kept while subjects are on study and will include the date of the transfusion and the number of RBC units transfused. 
9 Hematology parameters (ie, CBC with differential) include HCT, Hb, RBC count, percent reticulocyte, absolute reticulocyte count, immature reticulocyte fraction (IRF-H and 
IRF-M+H) (if available), MCV, MCH, MCHC, RDW, NRBC, WBC count with differential, and platelet count. 
10 Serum chemistry parameters include sodium, potassium, chloride, calcium, magnesium, phosphorus, CO2 or bicarbonate, albumin, total protein, glucose, BUN or urea, 
creatinine, and uric acid. 
11 Liver function tests include ALP, ALT, AST, and total, direct, and indirect bilirubin. 
12 Coagulation parameters include fibrinogen, aPTT, and INR. 
13 Lipid tests include total cholesterol, LDL-C, HDL-C, and triglycerides.  
14 Sex steroid testing includes estrone, estradiol, and testosterone (total and free). 
  
16 Remaining sample may be used for analysis of lipoproteins (only in subjects who have agreed to this optional analysis in the ICF). 
17 Study drug is expected to be dispensed to the subject at the study site during scheduled on-site study visits; under exceptional circumstances and with agreement of the Sponsor 
(or representative), study drug that was intended to be dispensed during scheduled on-site study visits can be provided at the subject’s home (if acceptable by practice and 
allowed by local regulations). For scheduled telemedicine study visits, study drug will be shipped by the site to the subject’s home if acceptable by practice and allowed by local 
regulations. All subjects who discontinue or interrupt AG-348 at any time should undergo the recommended dose taper per protocol (Section 9.3), unless an emergency situation 
justifies discontinuing or interrupting the study drug abruptly. Whether the dose taper is performed or not, subjects discontinuing or interrupting AG-348 should be monitored for 
signs of hemolysis and worsening of anemia. Study drug will be dispensed to these subjects until study drug is completely stopped. 
 
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10.2. 
Screening Assessments 
10.2.1. 
Informed Consent 
Informed consent will be obtained after the completion of all assessments at the subject’s last 
visit of his/her antecedent study and, for subjects in Cohorts 1 and 2, after the subject, 
Investigator, and site personnel are unblinded to the Study AG348-C-006 treatment allocation 
(ie, AG-348 or placebo), but before screening assessments not overlapping with the last visit of 
the antecedent study are performed and eligibility for this extension study is assessed by the 
Investigator.  
A description of the study is to be presented to each potential subject and a signed and dated ICF 
is to be obtained before any study-specific procedures are performed. The ICF will contain a 
separate section regarding the option to use leftover biological samples for analysis of additional 
biomarkers or assessment of AG-348 metabolism; subjects may opt-in or decline; this will not 
affect the subjects’ eligibility for the study. 
10.2.2. 
Confirmation of Eligibility 
A subject’s eligibility will be assessed by the Investigator at screening. Assessments to be 
performed at screening are provided in the schedule of assessments for Cohort 1 in Table 4 and 
for Cohorts 2 and 3 in Table 5. 
10.3. 
Medical History 
Medical history will not be collected in this extension study, as this information will have 
already been collected as part of the antecedent study. 
10.4. 
Demographics 
Demographic data will include gender and year of birth only, as other demographic data will 
have been collected as part of the antecedent study. 
10.5. 
Assessments of Safety 
The timing of safety assessments is provided in the Schedule of Assessments (Section 10.1; 
Table 4, Table 5, and Table 6). Assessments of safety will include the following: 
• Adverse event reporting, as discussed in Section 11.1  
• Concomitant medications and non-drug therapies, as discussed in Section 9.5.3 and 
Section 9.5.4, respectively 
• Physical examinations and vital sign collections 
• Procedural assessments: ECG and DXA as detailed in Section 10.5.1 and 
Section 10.5.2, respectively 
• Laboratory assessments as detailed in Section 10.5.3 
• Menstrual cycle diary and reproductive potential as detailed in Section 10.5.4 
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10.5.1. 
Electrocardiogram  
The 12-lead ECGs should be performed after 5 minutes of recumbence and in triplicate, using 
the ECG machine provided by the central vendor and according to the vendor manual. For 
Cohort 1 only, the ECG at Week 12 will be performed before, but within the same window as, 
the pharmacokinetic sample collected 1 hour (±5 minutes) after the study drug dose 
administration to align with the approximate Tmax of the study drug. 
The ECGs will be read promptly by a qualified physician at the study site to detect any safety 
issue. In addition to the local read, the ECGs will be sent promptly to the central vendor for a 
data-analysis read. 
An ECG will be repeated if clinically significant abnormalities are observed, if artifacts are 
present, or if machine/equipment errors occur.  
As of Protocol Amendment 4, Version 4.0, ECGs are no longer required to be assessed after the 
Week 24 visit; however, ECGs may be performed at the discretion of the Investigator when 
clinically indicated. 
10.5.2. 
Dual-Energy X-Ray Absorptiometry Scans 
The DXA scans of the lumbar spine and proximal femur (trochanter and inter-trochanter, which 
comprise the total hip and femoral neck) will be performed according to the instructions 
provided by the central vendor (see vendor’s manual for details). The DXA scans will be 
transmitted promptly to the central vendor for assessment of technical adequacy and may have to 
be repeated if not technically adequate. The DXA scans will be read and interpreted by the 
central vendor. 
10.5.3. 
Safety Laboratory Assessments 
All clinical laboratory evaluations are to be analyzed by a central laboratory, except for urine or 
serum pregnancy tests, which can be performed and analyzed by a local laboratory at scheduled 
visits or by home testing (urine) for tests required between scheduled visits. If results from a 
central laboratory are not available to support necessary clinical decision-making, then results 
from a local laboratory may be used. Blood samples for the Week 10 assessments in Cohort 1 
may be collected outside of the study site and sent to the central laboratory by qualified 
personnel (eg, home health care nurse), if allowed by local regulations. 
If Investigators believe that it is clinically indicated to obtain safety laboratory results from their 
own local laboratories on the day of the subject’s visit, they are free to exercise their discretion to 
do so.  
Blood samples for clinical laboratory evaluations will be collected according to the Schedule of 
Assessments (Section 10.1; Table 4, Table 5, and Table 6). All clinically significant laboratory 
abnormalities noted on testing will be followed by repeat testing and further investigation 
according to the judgment of the Investigator.  
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The following safety laboratory parameters will be measured:  
• Complete blood count (CBC) with differential  
• Serum chemistry  
• LFTs  
• Coagulation studies  
• Sex steroids 
• Lipids, measured by standard method and nuclear magnetic resonance 
• Urinalysis 
• Serum or urine pregnancy tests (for women of reproductive potential) 
− As of Protocol Amendment 4, Version 4.0, pregnancy tests are no longer required 
to be assessed after the Week 24 visit; however, pregnancy testing should occur 
more frequently if clinically indicated (ie, if there is suspicion of pregnancy) or 
required by local regulations.  
10.5.4. 
Menstrual Cycle Diary and Assessments of Reproductive Potential 
Menstruating female subjects will be required to fill out an electronic menstrual cycle diary 
according to the Schedule of Assessments (Section 10.1; Table 4 and Table 5). Subjects will 
record the start date, stop date, and change in characteristics of each menstrual cycle in the 
eDiary provided during screening. The menstrual cycle diary can be completed at any time of 
day. 
After Week 24, female subjects will no longer fill out the menstrual cycle diary. Subjects should 
return the eDiary to the site at or before the End of Study visit. 
Starting at Week 73, changes in reproductive potential of female subjects (as defined in 
Appendix 1) will be recorded in the source documents and eCRF, including the date of the 
change. 
10.6. 
Assessments of Efficacy 
The timing of efficacy assessments is provided in the Schedule of Assessments (Section 10.1; 
Table 4, Table 5, and Table 6).  
All clinical laboratory evaluations for efficacy are to be performed by the central laboratory. If 
results from a central laboratory are not available to support necessary clinical decision-making, 
then results from a local laboratory may be used. 
10.6.1. 
Hemoglobin Laboratory Assessment 
Hemoglobin concentrations (as part of the CBC with differential) will be collected to support 
efficacy (and safety) assessments. 
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10.6.2. 
Transfusions 
Transfusion data will be collected from signing of ICF for this extension study until completion 
of the study as noted in Section 9.5.4. 
10.6.3. 
Additional Laboratory Assessments for Efficacy 
The following laboratory parameters will be collected for additional efficacy assessments: 
• RBC parameters, including reticulocyte counts and percentages 
• Haptoglobin 
• Bilirubin  
• LDH 
• EPO 
• Erythroferrone 
• Soluble transferrin receptor 
10.7. 
Pharmacokinetic Assessments 
10.7.1. 
Blood Sample Collection 
Blood samples for a full pharmacokinetic profile will be collected from subjects in Cohort 1 at 
the Week 12 Visit at multiple time points as specified in the Schedule of Assessments 
(Section 10.1; Table 4).  
Sparse blood samples for pharmacokinetics will be collected from subjects in Cohort 1 on the 
first day of study drug, Week 2, Week 6, and Week 16 visits. For details on the sparse sampling 
schedule, please refer to the Schedule of Assessments (Section 10.1; Table 4). 
On days where a predose blood sample collection is required, the study drug must be 
administered after the predose sample is taken. On the first day of study drug, after the predose 
sample is collected, the study drug must be administered at the study site. Starting from Week 2, 
on visits when pharmacokinetic blood sample collection is required, the morning dose of study 
drug must be administered at the study site. 
The actual date and time of sample collection will be recorded in the source documents and 
eCRF. An explanation should be provided in the source documents for any missed or mishandled 
pharmacokinetic samples, as well as for any samples collected outside the time windows. 
10.7.2. 
Sample Analysis 
Pharmacokinetic samples will be analyzed for AG-348 using a validated liquid 
chromatography-tandem mass spectrometry method. Remaining samples may be used for 
analyses of AG-348 metabolism (only in subjects who have agreed to this optional analysis in 
the ICF).  
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Plasma pharmacokinetic parameters will be computed, when data allow, using standard 
noncompartmental methods, based on observed plasma AG-348 concentrations and on actual 
sample collection times. These parameters will include, but may not be limited to, the following:  
• AUC0-last: The area under the plasma concentration × time curve from time 0 to the 
time of the last measurable concentration  
• Tlast: Time of last measurable concentration  
• Cmax: Maximum (peak) concentration  
• Tmax: Time to maximum (peak) concentration  
• λz: Apparent terminal elimination rate constant, calculated from a semi-log plot of the 
plasma concentration versus time curve  
• t1/2: Terminal half-life  
• CL/F: The apparent total plasma clearance (CLp) after oral (extravascular) dosing  
• Vz/F: Volume of distribution during the terminal elimination phase after oral 
(extravascular) dosing  
10.9. 
Health-Related Quality of Life Assessments 
The timing of HRQoL assessments is provided in the Schedule of Assessments (Section 10.1; 
Table 4 and Table 5). The following HRQoL assessments will be performed: 
• PKDD: The PKDD is a 7-item PRO measure of the core signs and symptoms 
associated with PK deficiency in adults. Subjects rate their experience with symptoms 
of PK deficiency on the present day. The symptoms include those associated with 
tiredness, jaundice, bone pain, shortness of breath, and energy level. 
• PKDIA: The PKDIA is a 12-item PRO measure of the common impacts of 
PK deficiency on activities of daily living. Subjects rate how PK deficiency has 
impacted aspects of daily living in the past 7 days, including impacts on relationships; 
perceived appearance; work performance; and leisure, social, mental, and physical 
activities.  
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11. 
ADVERSE EVENTS 
11.1. 
Reporting Period for Adverse Events and Serious Adverse Events 
 
 
Monitoring of AEs, including frequency, severity, and characterization of SAEs, AESIs, and 
AEs leading to discontinuation will be conducted throughout the study. Beginning at the signing 
of the ICF of this extension study, all new, worsening, or ongoing AEs and SAEs will be 
recorded in the source documentation and eCRF for this extension study through the subject’s 
completion of study or withdrawal of consent, whichever occurs first.  
All AEs will be monitored until resolution of the AE to baseline (ie, baseline of the study during 
which AE onset occurred), the AE is considered stable within the context of the study, the 
subject is lost to follow-up, or until 28 days after the last dose of study drug.  
All SAEs will be followed until final outcome of the SAE is known or the subject is lost to 
follow-up. Any SAEs that are assessed as related to the study drug that occur ≥28 days post 
treatment are to be reported to the Sponsor directly by the Investigator. 
Adverse events will be evaluated by the Investigator and recorded as per Section 11.3. Any AEs 
already documented at a previous assessment and designated as ongoing will be reviewed at 
subsequent visits or assessment time points as necessary. If these AEs have resolved, this will be 
documented. 
All AEs will be graded using the National Cancer Institute (NCI) CTCAE v4.03 grading system. 
11.2. 
Definition of Adverse Events 
11.2.1. 
Adverse Event 
A clinical AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with the study drug. An AE can, therefore, be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
Withdrawal hemolysis is to be reported as a study drug-related AE. 
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11.2.2. 
Serious Adverse Event 
An AE or suspected adverse reaction is considered serious if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
• Death 
• Life-threatening (meaning that the subject was at immediate risk of death from the 
reaction as it occurred; but it does not include a reaction that hypothetically might 
have caused death had it occurred in a more severe form) 
• Inpatient hospitalization or prolongation of existing hospitalization. Hospitalization 
admissions and/or surgical operations scheduled to occur during the study period, but 
planned before study entry are not considered AEs if the illness or disease existed 
before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected manner during the study (eg, surgery performed earlier than planned). 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• Congenital anomaly/birth defect 
• Important medical event. An important medical event is an event that may not result 
in death, be life-threatening, or require hospitalization, but may be considered an SAE 
when, based upon appropriate medical judgment, it may jeopardize the subject and 
may require medical or surgical intervention to prevent 1 of the outcomes listed in the 
definitions for SAEs. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
11.2.3. 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, cascade events or clinical sequelae) 
should be identified by their primary cause, with the exception of severe or serious secondary 
events. However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the AE eCRF. Please refer to the 
eCRF completion guidance for examples of how to record events occurring secondary to other 
events. 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to whether 
the events are associated. 
11.2.4. 
Preexisting Medical Conditions 
Preexisting medical conditions will not be collected in this extension study, as this information 
will have already been collected as part of the antecedent study. 
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11.2.5. 
Abnormal Laboratory Values 
Abnormal laboratory tests should be repeated as soon as possible for confirmation. Not every 
laboratory abnormality qualifies as an AE. A laboratory test result should be reported as an AE if 
it meets any of the following criteria: 
• Accompanied by clinical symptoms 
• Results in a change in study drug (eg, dosage modification, treatment interruption, or 
treatment discontinuation) 
• Results in a medical intervention (eg, potassium supplementation for hypokalemia) or 
a change in concomitant therapy 
• Clinically significant in the Investigator’s judgment 
It is the Investigator’s responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome, only the 
diagnosis should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event eCRF, along with a descriptor 
indicating if the test result is above or below the normal range. 
11.2.6. 
Adverse Events of Special Interest 
 
An AESI can be serious or nonserious. Ongoing monitoring and rapid communication (within 
24 hours) by the Investigator to the Sponsor is required to allow for further characterization and 
reporting to regulatory authorities. 
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11.3. 
Procedures for Reporting Adverse Events, Adverse Events of Special 
Interest, and Serious Adverse Events 
Each subject must be carefully monitored for the development of any AEs. This information 
should be obtained in the form of nonleading questions (eg, “How are you feeling?”) and from 
signs and symptoms detected during each examination, observations of study personnel, and 
spontaneous reports from subjects. 
The Investigator should ask the subject for information regarding sleep patterns, signs, and 
symptoms associated with insomnia. 
All AEs (serious and nonserious) spontaneously reported by the subject and/or in response to an 
open question from study personnel or revealed by observation, PE, or other diagnostic 
procedures will be recorded on the appropriate page of the eCRF. Any clinically relevant 
deterioration in laboratory assessments or other clinical finding is considered an AE and must be 
recorded on the appropriate pages of the eCRF. When possible, signs and symptoms indicating a 
common underlying pathology should be noted as 1 comprehensive event. 
Any deaths and any AEs assessed as life-threatening are to be reported immediately. All SAEs 
are to be reported within 24 hours from the point in time when the Investigator becomes aware of 
the SAE on the appropriate page of the eCRF. All SAEs must be reported whether or not they are 
considered causally related to the study drug. 
In the event that the electronic data capture (EDC) system is unavailable, a paper SAE and fax 
coversheet should be completed and faxed/emailed to the Sponsor within no more than 24 hours 
after learning of the event using the contact details provided to Investigators in the Serious 
Adverse Event Report Form Completion Guidelines. 
Excessive Hb responses should only be reported as an AE if they meet the criteria for Hb 
increased per CTCAE (ie, Hb concentration higher than the subject’s ULN as applies to men and 
women). Any reports of excessive Hb response should be graded using the CTCAE grading 
system. 
If there are serious, unexpected adverse drug reactions associated with the use of AG-348, the 
Sponsor will notify the appropriate regulatory agency(ies) and all participating Investigators on 
an expedited basis. The local IRB/IEC will be promptly notified based on local regulations 
where required by the IRB/IEC of all serious, unexpected adverse drug reactions involving risk 
to human subjects. 
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11.3.1. 
Intensity 
The intensity of all AEs will be graded according to the NCI CTCAE. It is important to 
distinguish between SAEs and AEs with a severe intensity. An AE of severe intensity may not be 
considered serious. Severity is a measure of intensity, whereas seriousness is defined by the 
criteria in Section 11.2.2. For example, a severe headache without any further findings would not 
be considered an SAE. Alternatively, a mild presentation of a serious event, such as a myocardial 
infarction assessed as mild by a cardiologist, that leads to hospitalization would be considered an 
SAE. 
Severity of all AEs, including clinically significant treatment-emergent laboratory abnormalities, 
will be graded according to the NCI CTCAE. Adverse events not listed by the NCI CTCAE will 
be graded as follows: 
• Mild (Grade 1): The event is noticeable to the subject but does not interfere with 
routine activity. 
• Moderate (Grade 2): The event interferes with routine activity but responds to 
symptomatic therapy or rest. 
• Severe (Grade 3): The event significantly limits the subject’s ability to perform 
routine activities despite symptomatic therapy. 
• Life-threatening (Grade 4): An event in which the subject was at risk of death at the 
time of the event. 
• Fatal (Grade 5): An event that results in the death of the subject. 
11.3.2. 
Relationship to Study Drug 
Relationship to study drug administration will be determined by the Investigator according to the 
following criteria: 
• Not Related: AEs will be considered related, unless they fulfill the criteria as 
specified below:  
− Evidence exists that the AE has an etiology other than the study drug 
(eg, preexisting medical condition, underlying disease, intercurrent illness, 
concomitant medication); and/or  
− The AE has no plausible temporal relationship to the administration of the study 
drug (eg, cancer diagnosed 2 days after the first dose of study drug). 
• Related: AEs will be considered related if they fulfill the criteria as specified below: 
− There is a plausible temporal relationship between the onset of the AE and 
administration of the study drug, and the AE cannot be readily explained by the 
subject’s clinical state, intercurrent illness, or concomitant therapies; and/or 
− The AE follows a known pattern of response to the study drug; and/or 
− The AE abates or resolves upon interruption of the study drug or dose reduction 
and, if applicable, reappears upon re-challenge. 
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11.4. 
Pregnancy Reporting 
Pregnancy is neither an AE nor an SAE, unless a complication relating to the pregnancy occurs 
(eg, spontaneous abortion, which may qualify as an SAE). However, any pregnancy in a 
participating female subject that occurs during this study or within 28 days after the last dose of 
study drug must be reported to the Sponsor’s Medical Monitor, or designee, within 24 hours of 
being notified of the pregnancy.  
The Investigator must follow up and document the course and outcome of all pregnancies even if 
the subject was discontinued from the study or if the study has finished. The female subject 
should receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus. Monitoring should continue until conclusion of the pregnancy. 
All outcomes of pregnancy in a female study participant must be reported by the Investigator to 
the Sponsor or Sponsor’s designee on a Pregnancy Outcome Report form within 28 days after 
he/she has gained knowledge of the delivery or elective abortion. 
Any SAE that occurs during pregnancy in a female study participant must be recorded on the 
SAE report form (eg, maternal serious complications, spontaneous or therapeutic abortion, 
ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, or birth defect) and reported 
within 24 hours in accordance with the procedure for reporting SAEs. 
Women of reproductive potential must agree to be abstinent as part of their usual lifestyle or 
agree to use 2 forms of contraception, 1 of which must be considered highly effective, from the 
time of giving informed consent, during the study, and for 28 days after the last dose of study 
drug. Periodic abstinence (eg, calendar, symptothermal, and postovulation methods) and 
withdrawal are not acceptable methods of contraception. 
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12. 
STATISTICAL METHODS 
12.1. 
Analysis Sets 
All subjects refers to all subjects enrolled in Study AG348-C-011.  
• Safety Analysis Set (SAS) is defined as all subjects who are exposed to any amount 
of study drug in this extension study. The SAS will be used for both efficacy and 
safety analyses unless otherwise specified in the detailed Statistical Analysis Plan 
(SAP). 
12.2. 
Statistical Analysis 
12.2.1. 
General Methods 
The analysis will only focus on data from this extension study (ie, not the antecedent studies). 
Details will be specified in the SAP. 
All individual subject data will be presented for all subjects in data listings. 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, standard deviation (SD), median, minimum value, and 
maximum value.  
Categorical variables will be summarized using counts and percentages.  
Baseline value: The baseline value is defined as the most recent measurement before intake of 
the first dose of AG-348, except if specified otherwise. The first dose of AG-348 refers to the 
first dose in this extension study for Cohort 1, while it refers to the first dose in the antecedent 
study for Cohorts 2 and 3. 
• The individual subject’s baseline Hb and transaminase (AST and ALT) is defined as 
the average of all available Hb concentrations and transaminase (AST and ALT) 
values, respectively, collected for that subject within 42 days before the first dose of 
AG-348. 
Change (Absolute Change) from baseline: will be calculated as postbaseline value – baseline 
value. 
Relative change from baseline: will be calculated and presented in percentage as 
100 × (postbaseline value – baseline value)/baseline value. 
Treatment-emergent period: is defined as the time from the first dose of study drug in this 
extension study to 28 days after the last dose of study drug. 
12.2.2. 
Background Characteristics 
Subject disposition, demographic and baseline characteristics, concomitant medications, study 
drug exposure, and other background characteristics will be summarized. All subject data will be 
presented in subject data listings. All summaries will be based on the SAS unless otherwise 
specified in the SAP.  
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12.2.2.1. Subject Disposition 
The number and percentage of subjects in the following categories will be summarized: 
• All Subjects 
• SAS 
The number and percentage of subjects in the following disposition categories will also be 
summarized. The percentage will be calculated based on the SAS. 
• Completed treatment 
• Prematurely discontinued treatment and the reasons for treatment discontinuations 
• Completed study 
• Prematurely discontinued the study and the reasons for study discontinuations 
12.2.2.2. Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized and presented for the SAS. 
12.2.2.3. Prior and Concomitant Medications and Procedures 
Medications used in this study will be coded using the World Health Organization Drug 
Dictionary Enhanced and categorized as follows:  
• Prior medication: not collected in this trial 
• Concomitant medication/procedure: medication/procedure continued or newly 
received from signing the ICF on this extension study to 28 days after the last dose of 
study drug 
• Posttreatment medication: medication continued or newly received after the 
treatment-emergent period 
A given medication can be classified as a concomitant medication, a posttreatment medication, 
or a concomitant and posttreatment medication. If a medication has a missing or partially 
missing start/end date or time and it cannot be determined whether it was taken before, during, or 
after the treatment-emergent period, it will be considered as a concomitant and posttreatment 
medication. 
Concomitant medications will be summarized descriptively based on the SAS. Concomitant 
medications and posttreatment medications will all be listed for each subject.  
Concomitant procedures will be listed.  
12.2.3. 
Study Drug Exposure and Compliance 
12.2.3.1. Study Drug Exposure 
Duration of study drug exposure is defined as follows: last dose date – first dose date + 1 day, 
regardless of any interruptions in dosing. If the last dose date of study drug is missing, the 
subject’s drug discontinuation or completion date will be used for analysis purpose. 
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Duration of study drug exposure will be summarized descriptively as a quantitative variable 
(number, mean, SD, median, minimum, and maximum). 
Exposure summaries will be based on the SAS. 
12.2.3.2. Study Drug Compliance 
Study drug compliance will be assessed by percentage of tablets taken.  
The percent of tablets taken will be calculated as follows:  
100 × (Total number of tablets administered) / (Expected number of tablets taken during the 
study) 
Both percentage of days on study drug and percentage of tablets taken will be summarized 
descriptively as quantitative variables (number, mean, SD, median, minimum, and maximum). 
The number and percentage of subjects whose compliance is <80% or ≥80% will be 
summarized. 
Study drug compliance will be based on the SAS.  
12.3. 
Efficacy Analyses 
12.3.1. 
Analysis for the Primary Endpoint 
Not applicable, as the study’s primary endpoint is safety (Section 12.4).  
12.3.2. 
Analyses for the Secondary Endpoints 
12.3.2.1. Hemoglobin-related Secondary Endpoints 
The number and percentage of subjects experiencing an Hb response will be summarized for 
Cohort 1 subjects in the SAS based on the extension study assessments. If less than 2 out of the 
targeted 3 assessments are available, the subject will be considered a non-responder. Hemoglobin 
values assessed within 2 months (61 days) of a transfusion will be excluded from the analysis.  
The average changes from baseline in Hb concentrations at Week 16, 20, and 24 in this extension 
study for Cohort 1 will be summarized. The change from baseline in Hb concentration will also 
be summarized for all cohorts by visit. 
12.3.2.2. Change from Baseline in Markers of Hemolysis and Markers of Erythropoiesis 
A summary of actual values and change from corresponding baseline at each visit will be 
provided. Change in markers of hemolysis will be summarized separately for Cohort 1 by Hb 
response status.  
12.3.2.3. Number of Transfusion Events 
The number of transfusion events and number of RBC units transfused will be summarized by 
cohort based on the SAS and adjusted for the duration on study drug during this extension study. 
Transfusions received over up to 3 consecutive days will be considered as a single transfusion 
event. 
Additional modeling may be planned and described in detail in the SAP. 
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12.3.2.4. Patient Reported Outcome-related Endpoints 
For PKDD and PKDIA, summary statistics will be provided based on the validated algorithm 
once available from Study AG348-C-006. 
12.4. 
Safety Analyses 
Evaluating the long-term safety and tolerability of AG-348 is the primary objective of this study. 
The overall safety profile of AG-348 will be assessed in terms of the following: 
• Treatment-emergent AEs (TEAEs), including serious TEAEs, AESIs, and TEAEs 
leading to dose reduction, interruption, and discontinuation 
• Clinical laboratory values 
• Bone mineral density and its T- and Z-scores 
• Vital signs 
• ECGs  
Only a descriptive analysis of safety will be performed (ie, no formal statistical testing will be 
performed). 
12.4.1. 
Adverse Events 
Treatment-emergent AEs will be summarized based on the SAS.  
For analysis purposes, AEs will be classified as TEAEs or posttreatment AEs.  
• TEAE: any AE that increased in severity or newly developed during the 
treatment-emergent period. 
• Posttreatment AE: any AE that increased in severity or newly developed after the 
treatment-emergent period. 
An overview of the TEAE profile will be provided, including the total number of TEAEs, with 
the number and percentage of subjects for the following categories: (1) All TEAEs, 
(2) Grades 3/4 TEAEs, (3) TEAEs by relationship to study drug, (4) TEAEs by maximum 
severity, (5) TEAEs leading to treatment interruption, (6) TEAEs leading to treatment 
discontinuation, (7) TEAEs leading to dose reduction, (8) Serious TEAEs, (9) Related serious 
TEAEs, (10) TEAEs leading to death, and (11) AESIs. A summary of the number and percentage 
of subjects, as well as the number of events per 100 patient-years (number of events adjusted for 
the total duration of exposure), will be provided. 
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Adverse event summary tables will be presented for TEAEs and will include the following: 
• All TEAEs 
• Grades 3/4 TEAEs 
• TEAEs by relationship to study drug 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• TEAEs leading to dose reduction 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to death  
• AESIs 
Summaries will be presented by MedDRA SOC and PT using the number and percentages of 
subjects as well as the number of events per 100 patient-years (number of events adjusted for the 
total duration of exposure). When summarizing the number and percentage of subjects with an 
event, subjects with multiple occurrences of the same AE or a continuing AE will be counted 
once. Only the maximum severity level will be presented in the severity summaries and the 
worst/highest relationship level in the relationship summaries.  
Additional summary tables will be presented for TEAEs showing the number and percentage of 
subjects with any TEAEs by PT. 
In addition, 3 listings containing individual subject AE data will be provided: all deaths, SAEs, 
and permanent discontinuations due to AE.  
12.4.2. 
Laboratory Assessments 
A summary of actual values and change from baseline values at each visit will be provided for 
the continuous laboratory results in SI units based on the SAS.  
 
Results of urinalysis and the serum and urine pregnancy tests will be listed in individual subject 
data listings only. In addition, a listing containing individual subject hematology, chemistry, and 
coagulation values outside the reference ranges will be provided. This listing will include data 
from scheduled and unscheduled visits. 
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12.4.3. 
Bone Mineral Density Findings 
For bone mineral density measured by DXA scans, the actual values, T- and Z-scores, and their 
change from baseline values will be summarized for each scanned area and at each scheduled 
assessment.  
The number and percentage of subjects with a decrease from baseline in DXA Z-score of >7% 
will be provided.  
A listing will be provided for each subject’s bone mineral density and its corresponding T- and 
Z-scores.  
12.4.4. 
Vital Signs 
For vital signs measurements, the actual values and change from baseline values will be 
summarized at each scheduled assessment: systolic blood pressure (BP) and diastolic BP 
(mmHg), body temperature (C), and heart rate (beats per minute). 
12.4.5. 
Electrocardiogram Findings 
The average of ECG triplicates will be used for each scheduled assessment. A summary of actual 
values and change from baseline values will be provided at each for the following standard 
digital ECG measurements: PR, QRS, QT, and QT corrected for heart rate intervals (heart 
rate-corrected QT interval by Bazett’s method [QTcB] and heart rate-corrected QT interval by 
Fridericia’s method [QTcF]), QRS duration, and heart rate. 
The number and percentage of subjects will be summarized by maximum QTcB and QTcF 
intervals, categorized as ≤450 msec, >450 to ≤480 msec, >480 to ≤500 msec, and >500 msec, as 
well as maximum change from baseline, categorized as <30 msec, >30 to ≤60 msec, and 
>60 msec. 
12.4.6. 
Physical Examination 
Physical examination findings will be presented as a data listing only. 
12.5. 
Pharmacokinetic/Pharmacodynamic Analyses 
12.5.1. 
Pharmacokinetic Analyses 
For Cohort 1 only, the plasma pharmacokinetic parameters of AG-348 will be computed using 
non-compartmental methods based on observed plasma concentrations of the parent and actual 
sample collection times. Descriptive statistics (ie, n, mean, SD, coefficient of variation, median, 
minimum, and maximum, geometric mean, and geometric coefficient of variation) will be used 
to summarize the pharmacokinetic parameters for AG-348. 
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12.6. 
Sample Size and Power Considerations 
This is an extension study that plans to enroll subjects from qualifying previous studies 
(Study AG348-C-006 and Study AG348-C-007) who meet the eligibility requirements for this 
study. Approximately 96, with up to 116, subjects are potentially eligible to be enrolled in this 
extension study: approximately 76 subjects from Study AG348-C-006 and approximately 20, 
with up to 40, subjects from Study AG348-C-007, if eligible. Given the primary safety objective 
and endpoint, Table 7 provides the 95% exact CIs assuming different observed incidence of AEs. 
Table 7: 
95% Exact Confidence Intervals Assuming Different Observed Incidences of 
Adverse Events (N=116) 
Observed incidence of Adverse Events 
n/N (%) 
95% Confidence Interval 
10/116 (0.09) 
(0.04, 0.15) 
20/116 (0.17) 
(0.11, 0.25) 
30/116 (0.26) 
(0.18, 0.35) 
40/116 (0.34) 
(0.26, 0.44) 
Abbreviations: n=incidence; N=number of subjects in the study. 
 
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13. 
ADMINISTRATIVE REQUIREMENTS 
13.1. 
Good Clinical Practices 
The study will be conducted in accordance with the International Council for Harmonisation 
(ICH) for GCP and the appropriate regulatory requirement(s). The Investigator will be 
thoroughly familiar with the appropriate use of the study drug as described in the protocol and 
the IB. Essential clinical documents will be maintained to demonstrate the validity of the study 
and the integrity of the data collected. Master files should be established at the beginning of the 
study, maintained for the duration of the study, and retained according to the appropriate 
regulations.  
13.2. 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. 
The Investigator must obtain IRB/IEC approval for the investigation and must submit written 
documentation of the approval to the Sponsor before he or she can enroll any subject into the 
study. The IRB/IEC will review all appropriate study documentation to safeguard the rights, 
safety, and well-being of the subjects. The study will only be conducted at sites where IRB/IEC 
approval has been obtained. The protocol, IB, ICF, advertisements (if applicable), written 
information given to the subjects, safety updates, annual progress reports, and any revisions to 
these documents will be provided to the IRB/IEC.  
The IRB/IEC is to be notified of any amendment to the protocol in accordance with local 
requirements. Progress reports and notifications of serious unexpected adverse drug reactions are 
to be provided to the IRB/IEC according to local regulations and guidelines. 
13.3. 
Subject Information and Informed Consent 
The Investigator or trained designee will ensure that the subject is given full and adequate oral 
and written information about the nature, purpose, possible risk, and benefit of the study. 
Subjects must also be notified that they are free to discontinue from the study at any time. The 
subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
After the study has been fully explained, written informed consent will be obtained from the 
subject before study participation.  
The subject’s signed and dated informed consent must be obtained before conducting any 
study-related procedures. The Investigator must maintain the original, signed consent form. 
A copy of the signed form must be given to the subject. 
The method of obtaining and documenting the informed consent and the contents of the consent 
will comply with ICH-GCP and all applicable regulatory requirement(s). 
13.4. 
Subject Confidentiality 
To maintain subject privacy, all source documents, study drug accountability records, study 
reports and communications will identify the subject by the assigned subject number. The 
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Investigator will grant monitor(s) and auditor(s) from the Sponsor or the Sponsor’s designee and 
regulatory authority(ies) access to the subject’s original medical records for verification of data 
gathered on the source documents and to audit the data collection process. The subject’s 
confidentiality will be maintained and will not be made publicly available to the extent permitted 
by the applicable laws and regulations. 
13.5. 
Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol. Modifications to the 
protocol should not be made without agreement of both the Investigator and the Sponsor. 
Changes to the protocol will require written IRB/IEC approval/favorable opinion before 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
subjects. The IRB/IEC may provide, if applicable, where regulatory authority(ies) permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC. The Sponsor or designee will submit all 
protocol modifications to the regulatory authority(ies) in accordance with the governing 
regulations.  
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Medical Monitor (or Medical Director), or designee, if 
circumstances permit, to discuss the planned course of action. Any departures from the protocol 
must be fully documented in the source documents/database. 
13.6. 
Data Management 
All data for the subjects recruited for the trial will be entered onto the eCRFs via an EDC system 
provided by the Sponsor or designee. Only authorized staff may enter data onto the eCRFs. If an 
entry error is made, the corrections to the eCRFs will be made according to eCRF guidelines by 
an authorized member of the site staff. 
Electronic case report forms will be checked for correctness against source document data by the 
Sponsor’s monitor. If any entries into the eCRF are incorrect or incomplete, the monitor will ask 
the Investigator or the study site staff to make appropriate corrections, and the corrected eCRF 
will again be reviewed for completeness and consistency. Any discrepancies will be noted in the 
eCRF system by means of electronic data queries. Authorized site staff will be asked to respond 
to all electronic queries according to the eCRF guidelines. 
13.7. 
Source Documentation and Electronic Case Report Form 
Completion 
Source documents will be completed for each study subject. It is the Investigator’s responsibility 
to ensure the accuracy, completeness, and timeliness of the data reported in the subject’s source 
document/eCRF. The source document should indicate the subject’s participation in the study 
and should document the dates and details of study procedures, AEs, and subject status. 
The Investigator, or designated representative, should complete the source document as soon as 
possible after information is collected for a subject’s examination, treatment, or any other study 
procedure. Any outstanding entries must be completed after the final examination. 
An explanation should be given for all missing data. 
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The Investigator will retain all completed source documents. 
13.8. 
Direct Access to Source Data 
The study will be monitored by the Sponsor or the Sponsor’s designee. Monitoring will be done 
by personal visits from a representative of the Sponsor (Site Monitor) and will include on-site 
review of the source documents for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters will be performed. The review of medical 
records will be performed in a manner to ensure that subject confidentiality is maintained. 
The Site Monitor will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent communications (letter, telephone, e-mail, and fax). 
All unused study drug and other study materials should be destroyed or returned to the Sponsor 
or designee after the study has been completed, as directed by the Sponsor. 
Regulatory authorities, the IRB/IEC, and/or the Sponsor’s clinical quality assurance group or 
designee may request access to all source documents, database, and any other applicable study 
documentation for an on-site audit or inspection. Direct access to these documents must be 
guaranteed by the Investigator, who must provide support at all times for these activities. 
13.9. 
Record Retention 
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s). Records will be retained for at least 2 years after the last marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product or according to applicable regulatory requirement(s). If the Investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility. The Sponsor must be notified in writing if a custodial change occurs. 
13.10. 
Liability and Insurance 
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its legal 
liability for injuries caused to participating persons and arising out of this research performed 
strictly in accordance with the scientific protocol as well as with applicable law and professional 
standards. 
13.11. 
Publication of Study Findings and Use of Information 
All information regarding AG-348 supplied by the Sponsor or designee to the Investigator is 
privileged and confidential information. The Investigator agrees to use this information only to 
conduct the study and not to use it for any other purpose without explicit consent from the 
Sponsor. 
It is understood that there is an obligation on the Investigator’s part to provide the Sponsor with 
the complete data obtained during the study. Such information will be used in the clinical 
development of AG-348 and may be disclosed to regulatory authorities, other Investigators, 
corporate partners, or consultants, as required. 
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14. 
LIST OF REFERENCES 
 
Aizawa S, Kohdera U, Hiramoto M, et al. Ineffective erythropoiesis in the spleen of a patient 
with pyruvate kinase deficiency. Am J Hematol. 2003;74(1):68-72. doi:10.1002/ajh.10380 
Beutler E, Gelbart T. Estimating the prevalence of pyruvate kinase deficiency from the gene 
frequency in the general white population. . Blood. 2000;95(11):3585-3588.  
Bianchi P, Fermo E, Lezon-Geyda K, et al. Genotype-Phenotype Correlation and Molecular 
Heterogeneity in Pyruvate Kinase Deficiency: Data from the PKD Natural History Study. In: 
59th American Society of Hematology Annual Meeting; San Diego, CA, USA  
Bianchi P, Fermo E, Lezon-Geyday K, et al. Molecular Characterization of 140 Patients in the 
Pyruvate Kinase Deficiency (PKD) Natural History Study (NHS): Report of 20 New Variants. 
In: American Society for Hematology (ASH) 57th Annual Meeting & Exposition; Orlando, FL, 
USA  
Carey P, Chandler J, Hendrick A, Reid M, Saunders P, Tinegate H. Prevalence of pyruvate 
kinase deficiency in northern European population in the north of England. Northern Region 
Haematologists Group. . Blood. 2000;96(12):4005-4006.  
de Medicis E, Ross P, Friedman R, et al. Hereditary nonspherocytic hemolytic anemia due to 
pyruvate kinase deficiency: a prevalence study in Quebec (Canada). Hum Hered. 
1992;42(3):179-183.  
Grace RF, Bianchi P, van Beers EJ, et al. The Clinical Spectrum of Pyruvate Kinase Deficiency: 
Data from the Pyruvate Kinase Deficiency Natural History Study. Blood. 2018.  
Grace RF, Holmes-Morton D, Barcellini W, et al. The Phenotypic Spectrum of Pyruvate Kinase 
Deficiency (PKD) from the PKD Natural History Study (NHS): Description of Four Severity 
Groups By Anemia Status. In: American Society of Hematology 57th Annual Meeting & 
Exposition; Orlando, FL, USA  
Grace RF, Layton DM, Galacteros F, et al. Result Update from the DRIVE PK Study: Effects of 
AG-348, a pyruvate kinase activator, in patients with pyruvate kinase deficiency: Updated results 
from the DRIVE PK study [Abstract 2194]. at: American Society of Hematology (ASH) 59th 
Annual Meeting & Exposition; 9 December; Atlanta, GA. 
Grace RF, Rose C, Layton DM, et al. Effects of AG-348, a Pyruvate Kinase Activator, on 
Anemia and Hemolysis in Patients with Pyruvate Kinase Deficiency: Data from the DRIVE PK 
Study. In: 21st European Hematology Association; Copenhagen, Denmark  
Hirono A, Kanno H, Miwa S, Beutler E. Pyruvate Kinase Deficiency and Other Enzymopathies 
of the Erythrocyte. In: The Online Metabolic & Molecular Bases of Inherited Disease. McGraw 
Hill; 2014:chap 182. 
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Pyruvate Kinase Deficiency (PKD) Natural History Study. ClinicalTrials.gov identifier: 
NCT02053480; Posted 03 February 2014. https://clinicaltrials.gov/ct2/show/NCT02053480 
Oski FA, Bowman H. A low Km phosphoenolpyruvate mutant in the Amish with red cell 
pyruvate kinase deficiency. Br J Haematol. 1969;17(3):289-297.  
PYRUKYND (mitapivat). USPI. Agios Pharmaceuticals; 2022. 
Rider NL, Strauss KA, Brown K, et al. Erythrocyte pyruvate kinase deficiency in an old-order 
Amish cohort: longitudinal risk and disease management. Am J Hematol. 2011;86(10):827-834. 
doi:10.1002/ajh.22118 
Tanaka KR, Valentine WN, Miwa S. Pyruvate kinase (PK) deficiency hereditary nonspherocytic 
hemolytic anemia. Blood. 1962;19(3):267-295. doi:10.1182/blood-2016-02-702365 
van Wijk R, van Solinge W. The energy-less red blood cell is lost: erythrocyte enzyme 
abnormalities of glycolysis. Blood. 2005;106(13):4034-4042. doi:10.1182/blood-2005-04-1622 
Zanella A, Fermo E, Bianchi P, Chiarelli LR, Valentini G. Pyruvate kinase deficiency: the 
genotype-phenotype association. Blood Reviews. 2007;21(4):217-231.  
Zanella A, Fermo E, Bianchi P, Valentini G. Red cell pyruvate kinase deficiency: molecular and 
clinical aspects. Br J Haematol. 2005;130(1):11-25. doi:10.1111/j.1365-2141.2005.05527.x 
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15. 
APPENDICES 
 
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APPENDIX 1. DEFINITION OF WOMEN OF REPRODUCTIVE 
POTENTIAL 
Definition of Women of Reproductive Potential 
A woman is considered fertile after menarche and until becoming postmenopausal unless 
permanently sterile. If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a 
menstrual cycle cannot be confirmed before administration of the first dose of study drug, 
additional evaluation should be considered. 
A woman is not considered a woman of reproductive potential if any of the following apply: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study eligibility. 
Documentation can come from the subject’s medical records, medical examination, or 
medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
− A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormone 
replacement therapy; however, in the absence of 12 months of amenorrhea, 
confirmation with >1 FSH measurement is required.  
 
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