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

An Open-Label, Multicenter, Extension Study of AG-348 in Adult Subjects With Pyruvate Kinase Deficiency Previously Enrolled in AG-348 Studies

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.

Study Overview

• Status: Completed
• Conditions: Pyruvate Kinase Deficiency
• Intervention / Treatment: Drug: Mitapivat

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil, 13083-878
    • UNICAMP - Hemocentro
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N3Z5
      • McMaster University
• Denmark
  • Herlev, Denmark, 2730
    • Herlev University Hospital
• France
  • Bordeaux, France, 33000
    • CHU Hopitaux de Bordeaux - Hôpital Saint-André
  • Créteil, France, 94010
    • CHU Hôpital Henri Mondor
  • Marseille, France, 13385
    • Hospital La Timone
  • Toulouse, France, 31100
    • Institut Universitaire du Cancer de Toulouse - Oncopole
• Germany
  • Berlin, Germany, 10117
    • Charité - UB - CVK - Medizinische Klinik
  • Würzburg, Germany, 97080
    • Universitätsklinik Würzburg
• Ireland
  • Dublin, Ireland
    • St James's Hospital
• Italy
  • Genova, Italy, 16128
    • Ospedale Galliera
  • Milan, Italy, 20122
    • Osp Maggiore Policlinico Milano
  • Napoli, Italy, 00165
    • AORN Cardarelli
  • Napoli, Italy, 80318
    • Università della Campania "Luigi Vanvitelli"
• Japan
  • Kyoto, Japan, 615-8256
    • Kyoto Katsura Hospital
  • Osaka, Japan, 573-1010
    • Kansai Medical University, Dep. of Pediatrics, Hirakata Hospital
  • Tokyo, Japan, 8541
    • Toho University Omori Medical Center
  • Mie-ken
    • Tsu, Mie-ken, Japan, 514-8507
      • Mie University Hospital
  • Miyagi
    • Sendai, Miyagi, Japan, 980-8574
      • Tohoku University Hospital
• Netherlands
  • Utrecht, Netherlands, 3508 GA
    • Van Creveldkliniek
• South Korea
  • Daegu, South Korea, 705-703
    • Yeungnam University Hospital
• Spain
  • Barcelona, Spain, 08035
    • Hospital. U. Vall d'Hebron
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Murcia, Spain, 30120
    • Htal Clínico Universitario Virgen de la Arrixaca.
• Switzerland
  • Vaud (Lausanne), Switzerland, 1011
    • Centre Hospitalier Universitaire Vaudois (CHUV)
• Thailand
  • Bangkok, Thailand, 10700
    • Faculty of Medicine Siriraj Hospital
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye), 06100
    • Hacettepe University Faculty of Medicine
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrooke's Hospital
  • London, United Kingdom, WC1E 6BT
    • University College London
  • London, United Kingdom, W2 INY
    • Imperial College Healthcare NHS Trust
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • Oakland, California, United States, 95609
      • UCSF Benioff Children's Hospital, Oakland
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory-Children's Center
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Indiana Hemophilia & Thrombosis Center Inc.
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University School of Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist Research Institute
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98195
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; 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; Tablets; Other Names: AG-348; AG-348 sulfate hydrate; Mitapivat sulfate
Experimental: Cohort 2; 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; Tablets; Other Names: AG-348; AG-348 sulfate hydrate; Mitapivat sulfate
Experimental: Cohort 3; 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; Tablets; Other Names: AG-348; AG-348 sulfate hydrate; Mitapivat sulfate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort 1: Percentage of Participants Who Achieved a Hemoglobin (Hb) Response	The Hb response was defined as a greater than or equal to (≥)1.5 grams per deciliter (g/dL) (0.93 millimoles per liter [mmol/L]) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments, excluding those within 2 months (61 days) of transfusion. The baseline value for cohort 1 participants was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment is available.	Baseline up to Week 24
Cohort 1: Average Change From Baseline in Hb Concentration at Weeks 16, 20, and 24	The baseline value for participants was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment is available. The mean of average change from baseline in Hb concentration across Weeks 16, 20 and 24 is reported.	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
Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat		Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12
Cohort 1: Time of Last Quantifiable Concentration (Tlast) of Mitapivat		Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12
Cohort 1: Plasma Concentration (Ctrough) at the End of a Dosing Interval of Mitapivat		Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12
Cohort 1: Exposure-response (E-R) Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters		First dose to up to 24 weeks
Cohorts 1 and 2: Change From Baseline in Hb Concentration	The baseline value for cohort 1 participant was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment was available. The baseline value for cohort 2 was from Study AG348-C-006.	Baseline, Week 192
Cohorts 1 and 2: Change From Baseline in Indirect Bilirubin	The baseline value for cohort 1 participant was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment is available. The baseline value for cohort 2 was from Study AG348-C-006.	Baseline, Week 192
Cohorts 1 and 2: Change From Baseline in Lactate Dehydrogenase (LDH)	The baseline value for cohort 1 participant was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment was available. The baseline value for cohort 2 was from Study AG348-C-006.	Baseline, Week 192
Cohorts 1 and 2: Change From Baseline in Haptoglobin Levels	The baseline value for Cohort 1 participant was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment was available. The baseline value for Cohort 2 was from Study AG348-C-006.	Baseline, Week 192
Cohorts 1 and 2: Change From Baseline in Reticulocytes/Erythrocytes Ratio	The baseline value for Cohort 1 participants was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment was available. The baseline value for Cohort 2 was from Study AG348-C-006.	Baseline, Week 192
Cohort 3: Change From Baseline in Number of Transfusion Episodes	Number of transfusions at baseline was determined based on the transfusion data during the 52 weeks before informed consent for Cohort 3. Number of on-study transfusions was based on transfusions collected up to the end of the fixed dose period and standardized to 52 weeks. The change from baseline in number of transfusions was summarized for Cohort 3.	Baseline, Week 192
Cohort 3: Change From Baseline in Number of Red Blood Cell (RBC) Units Transfused	Annualized total number of RBC units transfused (units/52-week) during the study, including data up to end of study (EOS), was the total number of RBC units transfused during the entire study*52 / [(date of EOS - date of start of study treatment + 1)/7]. Number of RBC units were determined based on the transfusion data during the 52 weeks before informed consent of the antecedent study for Cohort 3. Number of on-study RBC units was based on transfusion data collected up to the end of the fixed dose period and standardized to 52 weeks.	Baseline, Week 192
All Cohorts: Change From Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD)	The PKDD is a validated, daily 7-item PRO instrument with a recall period of 24 hours that measures the core signs and symptoms associated with pyruvate kinase deficiency in adults. The symptoms include tiredness, jaundice, bone pain, shortness of breath, and energy level. PKDD daily scores were calculated based on the participant's response to the PKDD questionnaire. Score ranges from 25 to 76, with higher scores indicating more severe symptoms and a higher disease burden. The change from baseline in weekly mean scores was summarized. A negative change from baseline indicates a lower disease burden. Baseline of weekly mean score was defined as average of daily scores collected within 7 days before start of study treatment (mitapivat). For Cohort 1, last measurement before the start of study treatment in AG348-C-011 was used as baseline; if baseline was missing, then baseline value from AG348-C-006 was used. For Cohorts 2 & 3 baseline values from -006 and-007, respectively, were used.	Baseline, Week 24
All Cohorts: Change From Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA)	PKDIA is a 12-item PRO measure of common impacts of PK deficiency on activities of daily living. Participants rated how PK deficiency has impacted aspects of daily living in past 7 days, including impacts on relationships & leisure and social, mental, and physical activities. PKDIA score at each visit was based on 8 items that were retained after in-trial psychometric validation and calculated at each visit based on participant's response to PKDIA questionnaire. Score ranges from 30 to 76, with higher scores indicating higher disease burden. Negative change from baseline indicates lower disease burden. Baseline was defined as the last complete assessment (with no missing item in response) before start of study treatment. For Cohort 1, last measurement before start of study treatment in AG348-C-011 was used as baseline; if baseline was missing, then baseline value from AG348-C-006 was used. For Cohorts 2 and 3, the baseline values from 006 and 007, respectively, were used.	Baseline, Week 24

Collaborators and Investigators

• Sponsor: Agios Pharmaceuticals, Inc.
• Investigators: Study Chair: Medical Affairs, 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2019
• Primary Completion (Actual): July 3, 2024
• Study Completion (Actual): July 3, 2024

Study Registration Dates

• First Submitted: February 22, 2019
• First Submitted That Met QC Criteria: February 22, 2019
• First Posted (Actual): February 26, 2019

Study Record Updates

• Last Update Posted (Estimated): November 18, 2025
• Last Update Submitted That Met QC Criteria: November 4, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Pyruvate Kinase Deficiency of Red Cells; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; mitapivat
• Other Study ID Numbers: AG348-C-011; 2018-003459-39 (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