Pharmacokinetic and Pharmacodynamic Study of AG-348 in Adult Patients with Pyruvate Kinase Deficiency

Principal Investigator: Hassan Yaish
Keywords: Pyruvate , Kinase , PKD , AG-348 Department: Pediatric Administration
IRB Number: 00080742 Co Investigator:  
Specialty: Pediatric Hematology and Oncology
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Kolenya  Holly
kolenya.holly@hsc.utah.edu
(801)734-0165

Brief Summary

Objectives:

Primary:
- Evaluate the safety and tolerability of up to 24 weeks of AG-348 administration in patients with pyruvate kinase deficiency (PK Deficiency).

Secondary:
- Evaluate the pharmacokinetics (PK) of AG-348 and the metabolite AGI-8702.
- Evaluate the pharmacodynamic (PD) response of adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG) after administration of AG-348.
-Evaluate indicators of clinical activity of AG-348 in patients with PK Deficiency, including changes in hemoglobin (Hb), hematocrit (HCT), reticulocyte count, haptoglobin (Hp), carboxyhemoglobin (COHb), lactate dehydrogenase (LDH), total and indirect bilirubin, erythropoietin (EPO), end tidal carbon monoxide (ETCO), ferritin, hepcidin, and transferrin saturation (serum iron/iron binding capacity).


Exploratory:
- Evaluate the relationship of additional PD biomarkers including pyruvate kinase R (PKR) activity assay, glycolytic flux assays, and total PKR protein levels in whole blood, after administration of AG-348.
-Evaluate the relationship of AG-348 exposure and PD effects with changes in indicators of clinical activity.

Extension Period
Primary:
• Evaluate the safety and tolerability of up to 30 months of AG-348 administration in patients with PK deficiency.
Secondary:
• Evaluate the PK of AG-348 and the metabolite AGI-8702.
• Evaluate the PD response of ATP and 2,3-DPG after administration of AG-348.
• Evaluate indicators of clinical activity of AG-348 in patients with PK deficiency, including changes in Hb, HCT, reticulocyte count, Hp, COHb, LDH, total and indirect bilirubin, EPO, hepcidin, ferritin, and transferrin saturation (serum iron/iron binding capacity).
Exploratory:
• Evaluate the relationship of total PKR protein levels in whole blood after administration of AG-348.
• Evaluate the relationship of AG-348 exposure and PD effects with changes in indicators of clinical activity.

Inclusion Criteria

8.2. Inclusion Criteria
For entry into the study, patients must meet all of the following criteria during the Screening or other specified period:


1. Signed written informed consent obtained prior to performing any study procedure, including screening procedures.
2. Male or female, aged 18 years and older.
3. Known medical history of PK Deficiency.
4. All patients must have documented clinical laboratory confirmation of PK deficiency by RBC pyruvate kinase enzymatic assay performed at Screening either by a designated central laboratory or by any participating investigative site’s local hematology laboratory. Patients with prior documentation of PK deficiency by RBC enzymatic assay will have a reconfirmation of this result during Screening as a condition of enrollment.
 a. In the event that a patient’s screening pyruvate kinase enzymatic assay is negative (i.e., shows normal pyruvate kinase activity), the patient will be eligible for enrollment if the genotyping shows a mutant genotype that has been previously documented in the literature to be associated with pyruvate kinase deficiency. If the genotyping shows a previously undescribed mutation in the PKR gene, then the eligibility for enrollment will be determined on a case-by-case basis by the Coordinating Investigator and Medical Monitor in discussion with the Investigator. If no mutation is defined, then the patient will not be eligible.
5. ALL patients must have a blood sample for genotypic characterization of the mutant PKR gene performed by the designated central laboratory at Screening. The designated central laboratory-determined genotype will generally serve as the basis for genotyping for enrollment. However, patients whose genotype has already been determined by another laboratory may be enrolled on the basis of that report, with the approval of the Medical Monitor, in case of unexpected delay in return of the designated central laboratory result during the Screening Period. Enrollment on the basis of a result from a laboratory other than the designated central genotyping laboratory does not relieve the inclusion requirement that ALL patients must have a sample sent to the designated central genotyping laboratory.
6. All patients must have genotypic characterization of the UGT1A1 gene performed by a designated central laboratory to document whether they may have underlying Gilbert's Disease. Patients with Gilbert’s Disease are eligible to enroll.
7. Males must have Hb ≤ 12.0 g/dL; females must have Hb ≤ 11.0 g/dL.
8. All patients must be considered transfusion independent as defined by: no greater than 3 units of RBCs transfused in the 12-month period up to the first day of study dosing and no transfusions within 4 months of first day of study dosing. Patients who have received more transfusion support than described above will evaluated for eligibility on a case-by-case basis by the Medical Monitor.
9. Eligible patients may still have their spleens in place, or may have undergone prior splenectomy.

For splenectomized patients:
a. Must have undergone their procedure at least 6 months prior to Screening.

b. Must be current in their vaccinations for Pneumococcal Conjugate (PCV13), Pneumococcal Polysaccharide (PPSV23), Quadrivalent Meningococcal vaccine, and Haemophilus influenzae type b as recommended by Centers for Disease Control and Prevention's (CDC) Advisory Committee on Immunization Practices (ACIP) or immunization advisory groups in Canada and the European Union (for patients enrolled in Canada and the EU). [http://www.cdc.gov/vaccines/schedules/downloads/adult/adult-schedule.pdf] [Any missing vaccinations may be administered starting with the Screening Period and during the trial following the initiation of AG-348 dosing as necessary according to recommended vaccination guidance.]

10. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.
11. Patients must be taking at least 1 mg of folic acid daily for at least 21 days prior to first dose and continued daily during study participation.
12. Adequate organ function, defined as:
a. Serum aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN; unless the increased AST is assessed by the Investigator as due to hemolysis and/or hepatic iron deposition); and alanine aminotransferase (ALT) ≤ 2.5 × ULN (unless the increased ALT is assessed by the Investigator as due to hepatic iron deposition).
b. Normal or elevated levels of serum bilirubin. In patients with serum bilirubin > ULN, the elevation must be attributed to hemolysis with or without Gilbert's syndrome and must not be choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular disease.
c. Serum creatinine ≤ 1.25 × ULN. If serum creatinine > 1.25 × ULN, then 24-hour measured or calculated (Cockcroft-Gault) glomerular filtration rate (GFR) ≥ 60 mL/min.
d. Absolute neutrophil count (ANC)≥ 1.0 × 109/L.
e. Platelet count ≥ 100 × 109/L.
f. Activated partial thromboplastin time (aPTT) and international normalized ratio (INR) ≤ 1.25 × ULN, unless the patient is receiving therapeutic anticoagulants.
13. Women of childbearing potential (WOCBP) must agree to abstain from sexual intercourse or to use an acceptable/effective method of contraception (i.e., condom plus spermicide, condom plus oral contraceptive, condom plus intrauterine device [IUD], condom plus diaphragm with spermicide) from as soon as feasible during the Screening period until 30 days following the last dose of AG-348. Abstinence is an acceptable method only when this is in line with the normal life style of the patient, meaning that the patient plans to remain abstinent continuously throughout the duration of the study and for at least 30 days after the last dose of study drug. Periodic abstinence, e.g., calendar, sympathothermal and post-ovulation methods, and withdrawal are not acceptable methods of contraception.
a. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, and/or bilateral oophorectomy) or is not post-menopausal. Post-menopausal is defined as:
i. Amenorrhea ≥ 12 consecutive months without another cause, and a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL;
ii. Amenorrhea≥ 12 consecutive months in women ≥ 62 years old (FSH testing is not required).

14. WOCBP must have a negative serum or urine pregnancy test within 72 hours before start of AG-348 dosing.
15. Women must not be breastfeeding.
16. Male patients, with the exception of those who have undergone vasectomy at least 6 months prior to Screening, must agree to abstain from sexual intercourse or, if sexually active, to use a condom with spermicide as contraception (regardless of their female partner's childbearing potential or their partner's use of their own contraception) from Day 1 of dosing until 30 days following the last dose of AG-348.

For entry into the Extension Period, patients must meet the following criteria:

17. Signed written informed consent obtained prior to performing any study procedure during the Extension Period.
18. Patient must have completed 24 weeks of treatment during the Core Period and tolerated AG 348 (defined as having completed 24 weeks with or without permitted dose modifications)
19. The patient’s treating Investigator agrees that there is a potential for clinical benefit to continued treatment and recommends participation in the Extension Period
20. The Sponsor's designated Medical Monitor or Responsible Medical Officer approves the patient’s participation in the Extension Period
21. As applicable, the patient must agree to continue to follow the same sexual abstinence/contraception rules as stated in Inclusion Criteria 13 and 16.

Exclusion Criteria

8.3. Exclusion Criteria
Patients who meet any of the following criteria at Screening or prior to dosing on Day 1 will not be enrolled in the study:
1. Hemoglobin level > 12.0 g/dL if male; Hb > 11.0 g/dL if female.
2. Additional diagnosis of any other congenital or acquired blood disorder, including glucose-6-phosphate-dehydrogenase (G6PD) deficiency, or any other hemolytic anemia process except for mild allo-immunization as a consequence of transfusion therapy.
3. Iron overload (hemosiderosis or concurrent hemochromatosis) sufficiently severe to result in a clinical diagnosis by the Investigator of cardiac, hepatic, or pancreatic insufficiency.
4. Prior bone marrow or stem cell transplant.
5. Clinically symptomatic cholelithiasis or cholecystitis. (Prior cholecystectomy is not exclusionary. Patients with symptomatic cholelithiasis or cholecystitis may be rescreened once the disorder has been treated and clinical symptoms have resolved.)
6. Currently enrolled in another therapeutic clinical trial involving on-going therapy with any investigational or marketed product or placebo. Concurrent participation in the Pyruvate Kinase 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 that could compromise participation in the study such as:
a. Poorly controlled hypertension (defined as systolic blood pressure (BP) > 150 mm Hg or diastolic BP > 90 mm Hg) refractory to medical management.
b. History of recent (within < 6 months from Screening date) congestive heart failure; myocardial infarction or unstable angina pectoris; or hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism.
c. Currently active infection requiring the use of parenteral anti-microbial agents or that is ≥ Grade 3 (CTCAEv4.03) within 6 months of first dose.

d. A pattern or frequency of post-splenectomy sepsis that in the assessment of the Investigator could reasonably be expected to interfere with the ability of the patient to complete the 24 week core period study participation.
e. Positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody with signs of active Hepatitis B or C virus infection.
f. Positive test for human immunodeficiency virus (HIV) 1 or 2 antibody.
g. Diabetes mellitus judged to be in poor control by the Investigator or requiring > 3 anti-diabetic agents counting insulin; use of insulin per se is not exclusionary.
h. History of any primary malignancy with the exception of: curatively treated non-melanomatous skin cancer; curatively treated cervical or breast carcinoma in situ; or other primary tumor treated with curative intent and no known active disease present and no treatment administered during the last 3 years.
9. Undergone major surgery within 6 months of first dose.
10. Current or recent history of psychiatric disorder that in the opinion of the Investigator or Medical Monitor could compromise the ability of the patient to cooperate with study visits and procedures.
11. Use of any of the restricted list of products known to strongly inhibit CYP3A4 metabolism (Appendix 15.3, Table 7) within 5 days prior to Day 1 dosing; or to strongly induce CYP3A4 metabolism (Appendix 15.3, Table 8) within 28 days prior to Day 1 dosing; or to strongly inhibit P-gp transporter (Appendix 15.3, Table 9) within 5 days prior to Day 1 dosing; or digoxin within 5 days prior to Day 1 dosing.
12. Serum bilirubin > ULN attributable to factors other than hemolysis and/or Gilbert's syndrome.
13. Male patients with heart-rate corrected QT (Fridericia's correction factor) QTcF interval > 450 msec, or female patients with QTcF interval > 470 msec with the exception of patients with a left bundle branch block (LBBB). Medical Monitor approval needed in patients with a LBBB.
14. Cardiac dysrhythmias judged as clinically significant by the Investigator or requiring therapy with drugs that are primarily substrates of CYP3A4.
15. History of allergy to sulfonamides if characterized by acute hemolytic anemia, anaphylaxis, or 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 understand and sign informed consent; cooperate with study visits, tests, and procedures; or otherwise safely and reliably participate in the study.

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