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

This is a Phase 2, open label, two arm, multicenter, randomized, dose-ranging study during which adult participants with PK deficiency will receive multiple doses of AG-348 for up to 24 weeks (Core Period); eligible participants may enter an Extension Period to receive AG-348 for up to 8 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 and pharmacodynamic (PD) profile of AG-348 and early indicators of clinical efficacy.

Inclusion criteria

• Informed consent
• Male or female, aged 18 years and older
• Known medical history of PK deficiency
• PK deficiency confirmed by enzymatic assay at Screening
• Genotypic characterization of PKR gene at Screening
• Genotypic characterization of uridine-5'-diphosphate-glucuronyltransferase-A1 (UGTA1) gene to document underlying Gilbert's disease (Gilbert's disease patients are eligible)
• Males Hb ≤ 12.0 g/dL, females Hb ≤ 11 g/dL
• 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
• Splenectomized patients must have had the procedure at least 6 months prior to Screening and must be up-to-date in recommended vaccinations
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Must be taking at least 1 mg folic acid daily in the 21 days prior to screening
• Adequate organ function defined by liver function, kidney function, platelet count and coagulation assessments
• Agreement to use approved contraceptive measures
• Women must not be breastfeeding

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

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

• Hb ˃ 12.0 g/dL if male, Hb ˃11.0 g/dL if female
• Additional diagnosis of other congenital or acquired blood disorder
• Iron overload sufficiently severe to result in cardiac, hepatic or pancreatic insufficiency
• Bone marrow or stem cell transplant
• Clinically symptomatic cholelithiasis or cholecystitis
• Currently enrolled in any other investigational trial. Participation in the PK Deficiency Natural History Study (NCT02053480) is permitted
• Exposure to any investigational drug, device or procedure within 28 days prior to screening or during trial participation
• 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
• Major surgery in the last 6 months
• Psychiatric disorder that could compromise the ability of the patient to cooperate with the study
• Serum bilirubin higher to the upper limit of normal attributable to factors other than hemolysis or Gilbert's Syndrome
• 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.
• 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
• Cardiac arrhythmias that are clinically significant or treated with drugs that are substrates of CYP3A4
• Allergy to sulfonamides if characterized by acute hemolytic anemia, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson Syndrome
• 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
• 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