A Study of AG-348 in Adult Participants With Pyruvate Kinase (PK) Deficiency
Condition: Pyruvate Kinase Deficiency
MeSH terms: Anemia, Hemolytic, Congenital Nonspherocytic; Pyruvate Metabolism, Inborn Errors
Intervention: AG-348
Intervention description: Participants with PK deficiency were randomized to either receive AG-348, 50 or 300 mg, as initial doses, BID for the Core Period (Week 24). At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. Participants were assigned to initial doses, however, over the course of the core period were treated across a range of doses due to treatment emergent adverse events (AEs) and hemoglobin (Hb) levels exceeding mid-point of sex-adjusted ranges.
Intervention MeSH terms: Mitapivat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 52.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Pyruvate Kinase Deficiency; Hemolytic anemia; Pyruvate Kinase Isoform R (PKR); Drive PK

Summary:

      Study AG348-C-003 is a multicenter study designed to evaluate the safety and efficacy of
      different dose levels of AG-348 (mitapivat) in participants with PK deficiency.
    

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 patients 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