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

Status: Recruiting
DFCI Protocol ID:

Study AG348-C-003 is a multicenter study designed to evaluate the safety and efficacy of different dose levels of AG-348 in patients with PK deficiency.

Conducting Institutions:

Children's Hospital Boston, Dana-Farber Cancer Institute

Overall PI:

Rachael Grace, MD, Children's Hospital Boston

Site-responsible Investigators:


Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP, ctip@partners.org

Eligibility Criteria

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

  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

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