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

NCT ID: NCT02476916

Last Updated: 2025-05-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-06-26
• Study Completion Date: 2025-04-02

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.

Conditions

Pyruvate Kinase Deficiency

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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).

Group Type: EXPERIMENTAL

AG-348

Intervention Type: DRUG

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.

AG-348 300 mg BID

Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for the Core Period (Week 24).

Group Type: EXPERIMENTAL

AG-348

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

Mitapivat

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Agios Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Stanford University

Palo Alto, California, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Wayne State University School of Medicine - Children's Hospital of Michigan

Detroit, Michigan, United States

New York Presbyterian Hospital- Weil Cornell Medical College

New York, New York, United States

Central Pennsylvania Clinic

Belleville, Pennsylvania, United States

Children Hospital of Philadelphia (CHOP)

Philadelphia, Pennsylvania, United States

University of Utah

Salt Lake City, Utah, United States

University Health Network

Toronto, Ontario, Canada

Hôpital Saint-Vincent de Paul

Lille, Nord, France

Hôpital Henri Mondor

Créteil, Île-de-France Region, France

UOC Oncoematologia Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, , Italy

Universitair Medisch Centrum Utrecht

Utrecht, , Netherlands

Hammersmith Hospital

London, , United Kingdom

Countries

United States; Canada; France; Italy; Netherlands; United Kingdom

References

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.

Reference Type: RESULT

PMID: 31483964 (View on PubMed)

Al-Samkari H, Grace RF, Glenthoj A, Andres O, Barcellini W, Galacteros F, Kuo KHM, Layton DM, Morado Arias M, Viprakasit V, Dong Y, Tai F, Hawkins P, Gheuens S, Morales-Arias J, Gilroy KS, Porter JB, van Beers EJ. Early-onset reduced bone mineral density in patients with pyruvate kinase deficiency. Am J Hematol. 2023 Mar;98(3):E57-E60. doi: 10.1002/ajh.26830. Epub 2023 Jan 9. No abstract available.

Reference Type: DERIVED

PMID: 36594181 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31974203 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2015-000484-13

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

AG348-C-003

Identifier Type: -

Identifier Source: org_study_id