A Study of AG-348 in Adult Patients With Pyruvate Kinase Deficiency

This is a Phase 2, open label, two arm, multicenter, randomized, dose-ranging study during
which adult patients with PK deficiency will receive multiple doses of AG-348 for up to 24
weeks (Core Period); eligible patients may enter an Extension Period to receive AG-348 for up
to 4 additional years. Data will be reviewed on a regular basis and study design, dose and
schedule will be adapted based on these reviews. The study will evaluate the safety and
tolerability of multiple doses of AG-348, pharmacokinetic (PK) and pharmacodynamic (PD)
profile of AG-348 and early indicators of clinical efficacy.

Inclusion Criteria:

1. Informed consent

2. Male or female, aged 18 years and older

3. Known medical history of PK deficiency

4. PK deficiency confirmed by enzymatic assay at Screening

5. Genotypic characterization of PKR gene at Screening

6. Genotypic characterization of uridine-5'-diphosphate-glucuronyltransferase-A1 (UGTA1)
gene to document underlying Gilbert's disease (Gilbert's disease pts are eligible)

7. Males Hb ≤ 12.0 g/dL, females Hb ≤ 11 g/dL

8. Transfusion independent, defined as no more than 3 units of red blood cells (RBC)
transfused in 12 months prior to the first day of study dosing and no transfusions
within 4 months of first day of study dosing

9. Splenectomized patients must have had the procedure at least 6 months prior to
Screening and must be up-to-date in recommended vaccinations

10. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

11. Must be taking at least 1 mg folic acid daily in the 21 days prior to screening

12. Adequate organ function defined by liver function, kidney function, platelet count and
coagulation assessments

13. Agreement to use approved contraceptive measures

14. Women must not be breastfeeding

For entry into the Extension Period, patients must meet criteria # 15-16:

15. Must have completed 24 weeks of treatment during the Core Period and tolerated AG-348

16. The treating Investigator agrees that there is a potential for clinical benefit to
continued treatment and recommends participation in the Extension Period and the
Medical Monitor approves

Exclusion criteria

1. Hb ˃ 12.0 g/dL if male, Hb ˃11.0 g/dL if female

2. Additional diagnosis of other congenital or acquired blood disorder

3. Iron overload sufficiently severe to result in cardiac, hepatic or pancreatic
insufficiency

4. Bone marrow or stem cell transplant

5. Clinically symptomatic cholelithiasis or cholecystitis

6. Currently enrolled in any other investigational trial. Participation in the PK
Deficiency Natural History Study (NCT02053480) is permitted

7. Exposure to any investigational drug, device or procedure within 28 days prior to
screening or during trial participation

8. Concurrent medical condition such as poorly controlled hypertension, heart failure,
active infection, frequent post-splenectomy sepsis, Hepatitis B or C, Human
Immunodeficiency Virus type 1 (HIV1) or Human Immunodeficiency Virus type 2 (HIV2)
infection, poorly controlled diabetes mellitus, history of primary malignancy with the
exception of curatively treated nonmelanomatous skin cancer, cervical cancer of breast
cancer in situ

9. Major surgery in the last 6 months

10. Psychiatric disorder that could compromise the ability of the patient to cooperate
with the study

11. Serum bilirubin higher to the upper limit of normal attributable to factors other than
hemolysis or Gilbert's Syndrome

12. Use of restricted products known to strongly inhibit cytochrome P450 (CYP) 3A4
metabolism within 5 days prior to Prior Day 1 dosing, or to strongly induce cytochrome
P450 3A4 (CYP3A4) metabolism within 28 days prior to Day 1 dosing, or to strongly
inhibit P-glycoprotein transporter within 5 days prior to Day 1 dosing, or digoxin
within 5 days prior to Day 1 dosing.

13. Heart-rate corrected QT interval - Fridericia's method (QTcF) interval ˃ 450 ms in
male, QTcF > 470 ms in female, with the exception of patients with a left Bundle
Branch Block

14. Cardiac arrhythmias that are clinically significant or treated with drugs that are
substrates of CYP3A4

15. Allergy to sulfonamides if characterized by acute hemolytic anemia, anaphylaxis, rash
of erythema multiforme type or Stevens-Johnson Syndrome

16. Any other medical or psychological condition deemed by the Investigator to be likely
to interfere with a patient's ability to participate in the study

17. Patients will not be permitted to enter the Extension Period if: The patient
experienced AEs during the Core Period that are considered by the treating
Investigator or the Sponsor's designated Medical Monitor to pose a significant safety
risk to the patient if treatment were to be extended