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

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 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Pyruvate Kinase Deficiency
• Intervention / Treatment: Drug: AG-348

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.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • University Health Network
• France
  • Ile-de-France
    • Créteil, Ile-de-France, France, 94010
      • Hopital Henri Mondor
  • Nord
    • Lille, Nord, France, 59000
      • Hôpital Saint-Vincent de Paul
• Italy
  • Milano, Italy, 20122
    • UOC Oncoematologia Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht
• United Kingdom
  • London, United Kingdom, W12 0NN
    • Hammersmith Hospital
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Boston Children's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University School of Medicine - Children's Hospital of Michigan
  • New York
    • New York, New York, United States, 10065
      • New York Presbyterian Hospital- Weil Cornell Medical College
  • Pennsylvania
    • Belleville, Pennsylvania, United States, 17004
      • Central Pennsylvania Clinic
    • Philadelphia, Pennsylvania, United States, 19104
      • Children Hospital of Philadelphia (CHOP)
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AG-348 50 mg BID; Participants with PK deficiency received AG-348, 50 milligrams (mg), as initial dose, twice daily (BID) for the Core Period (Week 24).	Drug: AG-348; 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.; Other Names: Mitapivat
Experimental: AG-348 300 mg BID; Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for the Core Period (Week 24).	Drug: AG-348; 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.; Other Names: Mitapivat

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Experiencing at Least One Adverse Event (AEs) in the Core Period	An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug-related.	Up to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Hemoglobin (Hb) Value at Week 24	Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased Hb values indicate improvement.	Baseline and Week 24
Change From Baseline in Hematocrit at Week 24	Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased hematocrit values indicate improvement.	Baseline and Week 24
Change From Baseline in Reticulocyte Count at Week 24	Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased reticulocyte count values indicate improvement.	Baseline and Week 24
Change From Baseline in Haptoglobin at Week 24	Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased haptoglobin values indicate improvement.	Baseline and Week 24
Change From Baseline in Carbon Monoxide at Week 24	Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased carbon monoxide values indicate improvement.	Baseline and Week 24
Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24	Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased LDH values indicate improvement.	Baseline and Week 24
Change From Baseline in Total Bilirubin at Week 24	Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased total bilirubin values indicate improvement.	Baseline and Week 24
Change From Baseline in Indirect Bilirubin at Week 24	Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased indirect bilirubin values indicate improvement.	Baseline and Week 24
Change From Baseline in Erythropoietin (EPO) at Week 24	Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased EPO values indicate improvement.	Baseline and Week 24
Change From Baseline in Hepcidin at Week 24	Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased hepcidin values indicate improvement.	Baseline and Week 24
Change From Baseline in Ferritin at Week 24	Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased ferritin values indicate improvement.	Baseline and Week 24
Change From Baseline in Transferrin Saturation at Week 24	Transferrin saturation is the ratio of serum iron to iron-binding capacity. Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased transferrin saturation values indicate improvement.	Baseline and Week 24
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	Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.	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
Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702	Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.	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
Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702	Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.	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
Apparent Clearance at Steady-State (Clss/F) for AG-348 and Its Metabolite AGI-8702	Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.	pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP)	Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline.	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
Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for 2,3 - Diphosphoglycerate (2,3-DPG)	Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline.	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
Percentage of Participants Experiencing at Least One AE Over the Duration of the Extension Period	An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug-related.	Up to approximately 8.5 years
Change From Baseline in Hb Value Over the Duration of the Extension Period	Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Increased Hb values indicate improvement.	Up to approximately 8.5 years
Change From Baseline in Hematocrit Over the Duration of the Extension Period	Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Increased hematocrit values indicate improvement.	Up to approximately 8.5 years
Change From Baseline in Reticulocyte Count Over the Duration of the Extension Period	Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased reticulocyte count values indicate improvement.	Up to approximately 8.5 years
Change From Baseline in Haptoglobin Over the Duration of the Extension Period	Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Increased haptoglobin values indicate improvement.	Up to approximately 8.5 years
Change From Baseline in Carbon Monoxide Over the Duration of the Extension Period	Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased carbon monoxide values indicate improvement.	Up to approximately 8.5 years
Change From Baseline in LDH Over the Duration of the Extension Period	Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased LDH values indicate improvement.	Up to approximately 8.5 years
Change From Baseline in Total Bilirubin Over the Duration of the Extension Period	Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased total bilirubin values indicate improvement.	Up to approximately 8.5 years
Change From Baseline in Indirect Bilirubin Over the Duration of the Extension Period	Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased indirect bilirubin values indicate improvement.	Up to approximately 8.5 years
Change From Baseline in EPO Over the Duration of the Extension Period	Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased EPO values indicate improvement.	Up to approximately 8.5 years
Change From Baseline in Hepcidin Over the Duration of the Extension Period	Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased hepcidin values indicate improvement.	Up to approximately 8.5 years
Change From Baseline in Ferritin Over the Duration of the Extension Period	Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased ferritin values indicate improvement.	Up to approximately 8.5 years
Change From Baseline in Transferrin Saturation Over the Duration of the Extension Period	Transferrin saturation is the ratio of serum iron to iron-binding capacity. Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased transferrin saturation values indicate improvement.	Up to approximately 8.5 years

Collaborators and Investigators

• Sponsor: Agios Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2015
• Primary Completion (Actual): May 8, 2017
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: June 10, 2015
• First Submitted That Met QC Criteria: June 17, 2015
• First Posted (Estimated): June 22, 2015

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: April 9, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Hemolytic anemia; Pyruvate Kinase Deficiency; Pyruvate Kinase Isoform R (PKR); Drive PK
• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia, Hemolytic, Congenital Nonspherocytic; Pyruvate Metabolism, Inborn Errors; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; Mitapivat
• Other Study ID Numbers: AG348-C-003; 2015-000484-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No