Extension Study of AG-348 in Adult Participants With Pyruvate Kinase Deficiency Previously Enrolled in AG-348-006 or AG348-C-007

NCT03853798 | Completed Phase 3 Results FDA Drug

• 2 other identifiers: AG348-C-0112018-003459-39
• Study Type: interventional
• Target: 90
• Locations: 16 countries
• Sites: 42

Brief Summary

This is an open-label, multicenter, extension study to evaluate the long-term safety, tolerability, and efficacy of treatment with mitapivat in participants who were previously enrolled in Study AG348-C-006 or Study AG348-C-007.

Conditions

Pyruvate Kinase Deficiency

Outcome Measures

Primary Outcomes (10)

• All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3

  A clinical adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study drug. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and include both serious and non-serious TEAEs. Severity of AEs was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE.

  Up to 197 weeks

• All Cohorts: Number of Participants With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation

  A clinical AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study drug. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and include both serious and non-serious TEAEs. Number of participants with TEAEs leading to dose reduction, treatment interruption and treatment discontinuation are reported.

  Up to 197 weeks

• All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs

  Clinical laboratory assessments including hematology, clinical chemistry, triglycerides, urate, coagulation, urinalysis, and liver function tests were performed in the study. Clinically significant treatment-emergent laboratory abnormalities were graded according to the NCI CTCAE; Version 4.03: grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE. Clinical significance was determined based on the judgment of the Investigator.

  Up to 197 weeks

• All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs

  Vital signs and physical examinations including height, weight, body mass index (BMI), systolic blood pressure, diastolic blood pressure, pulse rate, temperature were assessed. Number of participants who experienced clinically significant abnormalities in vital signs and physical examinations as TEAEs were reported. Clinical significance was determined based on the judgment of the Investigator.

  Up to 197 weeks

• All Cohorts: Number of Participants With Clinically Significant Abnormalities in Bone Mineral Density (BMD)

  BMD was measured by dual-energy X-ray absorptiometry (DXA) scans during the study. Number of participants with clinically significant abnormalities were reported. Clinical significance was determined based on the judgment of the Investigator.

  Up to 192 weeks

• All Cohorts: Change From Baseline in Adjusted Spine T-score

  T-score of adjusted spine were assessed by DXA scans. The T-score is the number of standard deviations that bone density is above or below the average. A score of ≥ -1 indicates normal bone density; score between \< -1 and \> -2.5 indicates a sign of osteopenia (bone density below normal), and score of ≤ -2.5 indicates a sign of osteoporosis.

  Baseline, Week 192

• All Cohorts: Change From Baseline in Adjusted Spine Z-score

  The Z-score is a statistical measure to describe whether a value was above or below the standard. A Z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.

  Baseline, Week 192

• All Cohorts: Change From Baseline in Femoral Total T-score

  T-score of femoral total were assessed by DXA scans. The T-score is the number of standard deviations that bone density is above or below the average. A score of ≥ -1 indicates normal bone density; score between \< -1 and \> -2.5 indicates a sign of osteopenia (bone density below normal), and score of ≤ -2.5 indicates a sign of osteoporosis.

  Baseline, Week 192

• All Cohorts: Change From Baseline in Femoral Total Z-score

  The Z-score is a statistical measure to describe whether a value was above or below the standard. A Z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.

  Baseline, Week 192

• All Cohorts: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters Reported as TEAEs

  The following ECG parameters including RR, PR, heart rate-corrected QT interval using the Fridericia's formula (QRS), QT, and QTc were assessed during the study. Number of Participants with clinically significant abnormalities in ECG parameters as TEAEs were reported. Clinical significance was determined based on the judgment of the Investigator.

  Up to 197 weeks

Secondary Outcomes (18)

• Cohort 1: Percentage of Participants Who Achieved a Hemoglobin (Hb) Response

  Baseline up to Week 24

• Cohort 1: Average Change From Baseline in Hb Concentration at Weeks 16, 20, and 24

  Baseline, Weeks 16, 20, and 24

• Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to 8-hours Post-dose (AUC0-8) of Mitapivat

  Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

• Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Mitapivat

  Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

• Cohort 1: Maximum Observed Plasma Concentration (Cmax) of Mitapivat

  Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

Study Arms (3)

Cohort 1

EXPERIMENTAL

Participants who received placebo in Study AG348-C-006 and met the eligibility criteria of this extension study were enrolled to receive mitapivat tablets, 5 milligrams (mg), twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined at Week 12, and participants then received that optimized dose for a period of 12 weeks (Weeks 13-24) as a fixed dose and from Week 25 to Week 193, until study withdrawal, or the study was closed.

Drug: Mitapivat

Cohort 2

EXPERIMENTAL

Participants who received mitapivat at a dose of 5 mg, 20 mg, or 50 mg, BID, in the fixed dose period of Study AG348-C-006 and met the eligibility criteria of this extension study continued to receive the same mitapivat dose up to Week 193 or until study withdrawal, or the study was closed.

Drug: Mitapivat

Cohort 3

EXPERIMENTAL

Participants who received mitapivat at a dose of 5 mg, 20 mg, or 50 mg, BID, in the fixed dose period of Study AG348-C-007 and met the eligibility criteria of this extension study continued to receive the same mitapivat dose up to Week 193 or until study withdrawal, or the study was closed.

Drug: Mitapivat

Interventions

Mitapivat DRUG

Tablets

Also known as: AG-348, AG-348 sulfate hydrate, Mitapivat sulfate

Cohort 1; Cohort 2; Cohort 3

Eligibility Criteria

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

You may qualify if:

• Be willing and able to comply with study visits and procedures.
• Have signed written informed consent prior to participating in this extension study.
• Have completed either antecedent study AG348-C-006 or AG348-C-007 through the Part 2 Week 24 Visit.
• Cohorts 2 and 3: Have demonstrated clinical benefit from mitapivat treatment in the antecedent study, in the opinion of the Investigator.
• For women of reproductive potential, have a negative pregnancy test during screening of this extension study.
• For women of reproductive potential as well as men with partners who are women of reproductive potential, be abstinent as part of their usual lifestyle, or agree to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of giving informed consent, during the study, and for 28 days following the last dose of study drug for women and 90 days following the last dose of study drug for men.

You may not qualify if:

• Have a significant medical condition (including clinically significant laboratory abnormality) that developed during his/her antecedent AG- 348 study that confers an unacceptable risk to participating in this extension study, that could confound the interpretation of the study data, and/or that compromises the ability of the participant to complete study visits and procedures.
• Are currently pregnant or breastfeeding.
• Have a splenectomy scheduled during the study treatment period.
• Meet the withdrawal criteria of his/her antecedent mitapivat study during screening of this extension study.
• Are currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4 that have not been stopped for a duration of at least 5 days or a time frame equivalent to 5 half-lives (whichever is longer) before start of study drug; or strong inducers of CYP3A4 that have not been stopped for a duration of at least 28 days or a time frame equivalent to 5 half-lives (whichever is longer) before start of study drug on this extension study.
• Have received anabolic steroids, including testosterone preparations, within 28 days prior to start of study drug on this extension study.
• Have received hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony stimulating factors, thrombopoietins) within 28 days prior to start of study drug on this extension study.
• Have exposure to any investigational drug other than mitapivat, device, or procedure within 3 months prior to start of study drug on this extension study.

Sponsors & Collaborators

• Agios Pharmaceuticals, Inc.: lead

Study Sites (42)

Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

Location

UCSF Benioff Children's Hospital, Oakland

Oakland, California, 95609, United States

Location

Emory-Children's Center

Atlanta, Georgia, 30322, United States

Location

Indiana Hemophilia & Thrombosis Center Inc.

Indianapolis, Indiana, 46260, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Wayne State University School of Medicine

Detroit, Michigan, 48201, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Houston Methodist Research Institute

Houston, Texas, 77030, United States

Location

University of Utah

Salt Lake City, Utah, 84113, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98195, United States

Location

UNICAMP - Hemocentro

São Paulo, 13083-878, Brazil

Location

McMaster University

Hamilton, Ontario, L8N3Z5, Canada

Location

Herlev University Hospital

Herlev, 2730, Denmark

Location

CHU Hopitaux de Bordeaux - Hôpital Saint-André

Bordeaux, 33000, France

Location

CHU Hôpital Henri Mondor

Créteil, 94010, France

Location

Hospital La Timone

Marseille, 13385, France

Location

Institut Universitaire du Cancer de Toulouse - Oncopole

Toulouse, 31100, France

Location

Charite - UB - CVK - Medizinische Klinik

Berlin, 10117, Germany

Location

Universitätsklinik Würzburg

Würzburg, 97080, Germany

Location

St James's Hospital

Dublin, Ireland

Location

Ospedale Galliera

Genova, 16128, Italy

Location

Osp Maggiore Policlinico Milano

Milan, 20122, Italy

Location

AORN Cardarelli

Napoli, 00165, Italy

Location

Università della Campania "Luigi Vanvitelli"

Napoli, 80318, Italy

Location

Mie University Hospital

Tsu, Mie-ken, 514-8507, Japan

Location

Tohoku University Hospital

Sendai, Miyagi, 980-8574, Japan

Location

Kyoto Katsura Hospital

Kyoto, 615-8256, Japan

Location

Kansai Medical University, Dep. of Pediatrics, Hirakata Hospital

Osaka, 573-1010, Japan

Location

Toho University Omori Medical Center

Tokyo, 8541, Japan

Location

Van Creveldkliniek

Utrecht, 3508 GA, Netherlands

Location

Yeungnam University Hospital

Daegu, 705-703, South Korea

Location

Hospital. U. Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Htal Clínico Universitario Virgen de la Arrixaca.

Murcia, 30120, Spain

Location

Centre Hospitalier Universitaire Vaudois (CHUV)

Vaud (Lausanne), 1011, Switzerland

Location

Faculty of Medicine Siriraj Hospital

Bangkok, 10700, Thailand

Location

Hacettepe University Faculty of Medicine

Ankara, 06100, Turkey (Türkiye)

Location

Addenbrooke's Hospital

Cambridge, CB2 0QQ, United Kingdom

Location

Imperial College Healthcare NHS Trust

London, W2 INY, United Kingdom

Location

University College London

London, WC1E 6BT, United Kingdom

Location

Related Publications (2)

• van Beers EJ, Al-Samkari H, Grace RF, Barcellini W, Glenthoj A, DiBacco M, Wind-Rotolo M, Xu R, Beynon V, Patel P, Porter JB, Kuo KHM. Mitapivat improves ineffective erythropoiesis and iron overload in adult patients with pyruvate kinase deficiency. Blood Adv. 2024 May 28;8(10):2433-2441. doi: 10.1182/bloodadvances.2023011743.

  PMID: 38330179 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

Interventions

mitapivat

Results Point of Contact

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

medinfo@agios.com

833-228-8474

Study Officials

• Medical Affairs

  Agios Pharmaceuticals, Inc.

  STUDY CHAIR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 22, 2019
• First Posted: February 26, 2019
• Study Start: March 21, 2019
• Primary Completion: July 3, 2024
• Study Completion: July 3, 2024
• Last Updated: November 18, 2025
• Results First Posted: November 18, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

JP (5); IT (4); DE (2); TH (1); US (12); DK (1); IE (1); TU (1); CA (1); NL (1); CH (1); ES (3); GB (3); FR (4); KR (1); BR (1)