Clinical trial NCT02476916: A Study of AG-348 in Adult Participants With Pyruvate Kinase (PK) Deficiency
Official title: A Phase 2, Open Label, Randomized, Dose Ranging, Safety, Efficacy, Pharmacokinetic and Pharmacodynamic Study of AG-348 in Adult Patients With Pyruvate Kinase Deficiency
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pyruvate Kinase Deficiency
Keywords: Pyruvate Kinase Deficiency
Hemolytic anemia
Pyruvate Kinase Isoform R (PKR)
Drive PK
Lead sponsor: Agios Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2015-06-22
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

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

Primary outcomes:
measure: Percentage of Participants Experiencing at Least One Adverse Event (AEs) in the Core Period
timeFrame: Up to Week 24
Secondary outcomes:
measure: Percentage of Participants Experiencing at Least One AE Over the Duration of the Extension Period
timeFrame: Up to approximately 8.5 years
measure: Change From Baseline in Hemoglobin (Hb) Value at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Hb Value Over the Duration of the Extension Period
timeFrame: Up to approximately 8.5 years
measure: Change From Baseline in Hematocrit at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Hematocrit Over the Duration of the Extension Period
timeFrame: Up to approximately 8.5 years
measure: Change From Baseline in Reticulocyte Count at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Reticulocyte Count Over the Duration of the Extension Period
timeFrame: Up to approximately 8.5 years
measure: Change From Baseline in Haptoglobin at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Haptoglobin Over the Duration of the Extension Period
timeFrame: Up to approximately 8.5 years
measure: Change From Baseline in Carbon Monoxide at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Carbon Monoxide Over the Duration of the Extension Period
timeFrame: Up to approximately 8.5 years
measure: Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in LDH Over the Duration of the Extension Period
timeFrame: Up to approximately 8.5 years
measure: Change From Baseline in Total Bilirubin at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Total Bilirubin Over the Duration of the Extension Period
timeFrame: Up to approximately 8.5 years
measure: Change From Baseline in Indirect Bilirubin at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Indirect Bilirubin Over the Duration of the Extension Period
timeFrame: Up to approximately 8.5 years
measure: Change From Baseline in Erythropoietin (EPO) at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in EPO Over the Duration of the Extension Period
timeFrame: Up to approximately 8.5 years
measure: Change From Baseline in Hepcidin at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Hepcidin Over the Duration of the Extension Period
timeFrame: Up to approximately 8.5 years
measure: Change From Baseline in Ferritin at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Ferritin Over the Duration of the Extension Period
timeFrame: Up to approximately 8.5 years
measure: Change From Baseline in Transferrin Saturation at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Transferrin Saturation Over the Duration of the Extension Period
timeFrame: Up to approximately 8.5 years
measure: Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702
timeFrame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
measure: Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702
timeFrame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
measure: Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702
timeFrame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
measure: Apparent Clearance at Steady-State (Clss/F) for AG-348 and Its Metabolite AGI-8702
timeFrame: pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
measure: Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP)
timeFrame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
measure: Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for 2,3 - Diphosphoglycerate (2,3-DPG)
timeFrame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University School of Medicine - Children's Hospital of Michigan
state: Michigan
city: New York
country: United States
facility: New York Presbyterian Hospital- Weil Cornell Medical College
state: New York
city: Belleville
country: United States
facility: Central Pennsylvania Clinic
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children Hospital of Philadelphia (CHOP)
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Créteil
country: France
facility: Hôpital Henri Mondor
state: Ile-de-France
city: Lille
country: France
facility: Hôpital Saint-Vincent de Paul
state: Nord
city: Milano
country: Italy
facility: UOC Oncoematologia Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: London
country: United Kingdom
facility: Hammersmith Hospital
Study officials:
References:
citation: Grace RF, Rose C, Layton DM, Galacteros F, Barcellini W, Morton DH, van Beers EJ, Yaish H, Ravindranath Y, Kuo KHM, Sheth S, Kwiatkowski JL, Barbier AJ, Bodie S, Silver B, Hua L, Kung C, Hawkins P, Jouvin MH, Bowden C, Glader B. Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency. N Engl J Med. 2019 Sep 5;381(10):933-944. doi: 10.1056/NEJMoa1902678.
citation: Rab MAE, Van Oirschot BA, Kosinski PA, Hixon J, Johnson K, Chubukov V, Dang L, Pasterkamp G, Van Straaten S, Van Solinge WW, Van Beers EJ, Kung C, Van Wijk R. AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes. Haematologica. 2021 Jan 1;106(1):238-249. doi: 10.3324/haematol.2019.238865.