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

NCT02476916 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: AG348-C-0032015-000484-13
• Study Type: interventional
• Target: 52
• Locations: 6 countries
• Sites: 13

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.

Conditions

Pyruvate Kinase Deficiency

Keywords

Pyruvate Kinase Deficiency; Hemolytic anemia; Pyruvate Kinase Isoform R (PKR); Drive PK

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (33)

• Percentage of Participants Experiencing at Least One AE up to Month 102

  Up to Month 102

• Change From Baseline in Hemoglobin (Hb) Value at Week 24

  Baseline and Week 24

• Change From Baseline Hb Value up to Month 102

  Baseline, Months 12, 36, 60, 84, and 102

• Change From Baseline in Hematocrit at Week 24

  Baseline and Week 24

• Change From Baseline in Hematocrit up to Month 102

  Baseline, Months 12, 36, 60, 84, and 102

Study Arms (2)

AG-348 50 mg BID

EXPERIMENTAL

Participants with Pyruvate Kinase (PK) deficiency will receive AG-348, 50 milligrams (mg), as initial dose, twice daily (BID) for 24 weeks (Core Period). Participants will be assigned to initial doses, however, over the course of the Core Period they will be treated across a range of doses due to treatment emergent adverse events (AEs) and hemoglobin (Hb) levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who have safely tolerated AG-348 and demonstrating clinical activity in response to AG-348 will be rolled over to the Extension Period. During the extension period, participants will continue to receive AG-348 50 mg, BID, for up to 102 months.

Drug: AG-348

AG-348 300 mg BID

EXPERIMENTAL

Participants with PK deficiency will receive AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants will be assigned to initial doses, however, over the course of the Core Period they will be treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who have safely tolerated AG-348 and demonstrating clinical activity in response to AG-348 will be rolled over to the Extension Period. During the extension period, participants will continue to receive AG-348 300 mg, BID, up to 102 months.

Drug: AG-348

Interventions

AG-348 DRUG

Tablets

Also known as: Mitapivat

AG-348 300 mg BID; AG-348 50 mg BID

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Informed consent
• Male or female, aged 18 years and older
• Known medical history of PK deficiency
• PK deficiency confirmed by enzymatic assay at Screening
• Genotypic characterization of PKR gene at Screening
• Genotypic characterization of uridine-5'-diphosphate-glucuronyltransferase-A1 (UGTA1) gene to document underlying Gilbert's disease (Gilbert's disease patients are eligible)
• Males Hb ≤ 12.0 g/dL, females Hb ≤ 11 g/dL
• 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
• Splenectomized patients must have had the procedure at least 6 months prior to Screening and must be up-to-date in recommended vaccinations
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Must be taking at least 1 mg folic acid daily in the 21 days prior to screening
• Adequate organ function defined by liver function, kidney function, platelet count and coagulation assessments
• Agreement to use approved contraceptive measures
• Women must not be breastfeeding
• For entry into the Extension Period, patients must meet criteria # 15-16:

You may not qualify if:

• Hb ˃ 12.0 g/dL if male, Hb ˃11.0 g/dL if female
• Additional diagnosis of other congenital or acquired blood disorder
• Iron overload sufficiently severe to result in cardiac, hepatic or pancreatic insufficiency
• Bone marrow or stem cell transplant
• Clinically symptomatic cholelithiasis or cholecystitis
• Currently enrolled in any other investigational trial. Participation in the PK Deficiency Natural History Study (NCT02053480) is permitted
• Exposure to any investigational drug, device or procedure within 28 days prior to screening or during trial participation
• 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
• Major surgery in the last 6 months
• Psychiatric disorder that could compromise the ability of the patient to cooperate with the study
• Serum bilirubin higher to the upper limit of normal attributable to factors other than hemolysis or Gilbert's Syndrome
• 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.
• 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
• Cardiac arrhythmias that are clinically significant or treated with drugs that are substrates of CYP3A4
• Allergy to sulfonamides if characterized by acute hemolytic anemia, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson Syndrome

Sponsors & Collaborators

• Agios Pharmaceuticals, Inc.: lead

Study Sites (13)

Stanford University

Palo Alto, California, 94304, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02215, United States

Location

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

Detroit, Michigan, 48201, United States

Location

New York Presbyterian Hospital- Weil Cornell Medical College

New York, New York, 10065, United States

Location

Central Pennsylvania Clinic

Belleville, Pennsylvania, 17004, United States

Location

Children Hospital of Philadelphia (CHOP)

Philadelphia, Pennsylvania, 19104, United States

Location

University of Utah

Salt Lake City, Utah, 84113, United States

Location

University Health Network

Toronto, Ontario, M5G 2C4, Canada

Location

Hôpital Saint-Vincent de Paul

Lille, Nord, 59000, France

Location

Hôpital Henri Mondor

Créteil, Île-de-France Region, 94010, France

Location

UOC Oncoematologia Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, 20122, Italy

Location

Universitair Medisch Centrum Utrecht

Utrecht, 3584 CX, Netherlands

Location

Hammersmith Hospital

London, W12 0NN, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 31483964 RESULT

• 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.

  PMID: 36594181 DERIVED

• 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.

  PMID: 31974203 DERIVED

MeSH Terms

Conditions

Pyruvate Kinase Deficiency of Red Cells; Anemia, Hemolytic

Interventions

mitapivat

Condition Hierarchy (Ancestors)

Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Medical Affairs
• Organization: Agios Pharmaceuticals, Inc.

medinfo@agios.com

833-228-8474

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 10, 2015
• First Posted: June 22, 2015
• Study Start: June 26, 2015
• Primary Completion: May 8, 2017
• Study Completion: April 2, 2025
• Last Updated: May 1, 2026
• Results First Posted: June 11, 2020

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

FR (2); IT (1); GB (1); US (7); CA (1); NL (1)