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 a multicenter, open-label, extension study to evaluate the long-term safety, tolerability, and efficacy of treatment with AG-348 in participants who were previously enrolled in Study AG348-C-006 or Study AG348-C-007.

Study Overview

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

• 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
    • Charite - UB - CVK - Medizinische Klinik
  • Würzburg, Germany, 97080
    • Universitätsklinik Würzburg
• Ireland
  • Dublin 8, Ireland
    • St James's Hospital
• Italy
  • Genova, Italy, 16128
    • Ospedale Galliera
  • Milano, 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
    • Tsu-shi, Mie, Japan, 514-8507
      • Mie University Hospital
  • Miyagi
    • Sendai, Miyagi, Japan, 980-8574
      • Tohoku University Hospital
• Korea, Republic of
  • Daegu, Korea, Republic of, 705-703
    • Yeungnam University Hospital
• Netherlands
  • Utrecht, Netherlands, 3508 GA
    • Van Creveldkliniek
• 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
  • Ankara, Turkey, 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
  • 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 AG-348 treatment in the antecedent study, in the opinion of the Investigator;
• For women of reproductive potential, have a negative pregnancy test during screening;
• 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 AG-348 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 AG-348, 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 will enroll in Cohort 1. Part 1 (Dose Optimization Period, 12 weeks): Participants will begin by receiving 5 milligrams (mg) orally, twice a day. Each participant's dose of AG-348 may be increased to 20 mg twice a day and then to 50 mg twice a day depending on their response to AG-348 and tolerability. Part 2 (Fixed Dose Period, 12 weeks): Last dose received in Part 1, twice a day. After completion of Part 2, participants who, in the opinion of the Investigator, have demonstrated clinical benefit from AG-348 treatment will continue AG-348 treatment in the Continued Treatment Period.	Drug: AG-348; Participants will receive 5, 20, or 50 mg twice a day for up to 192 weeks (not including dose taper) unless the dose is modified for reasons related to safety.
Experimental: Cohort 2; Participants who received AG-348 in Study AG348-C-006 will enroll in Cohort 2. Participants will continue the AG-348 dose regimen they were receiving at the last visit of Study AG348-C-006.	Drug: AG-348; Participants will receive 5, 20, or 50 mg twice a day for up to 192 weeks (not including dose taper) unless the dose is modified for reasons related to safety.
Experimental: Cohort 3; Participants who received AG-348 in Study AG348-C-007 will enroll in Cohort 3. Participants will continue the AG-348 dose regimen they were receiving at the last visit of Study AG348-C-007.	Drug: AG-348; Participants will receive 5, 20, or 50 mg twice a day for up to 192 weeks (not including dose taper) unless the dose is modified for reasons related to safety.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)	From baseline to safety follow-up (up to 198 weeks)
Number of Participants with AEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation	From baseline to safety follow-up (up to 198 weeks)

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage of Participants Achieving a Hemoglobin (Hb) Response in Participants Who Previously Received Placebo in Study AG348-C-006	Weeks 16, 20, 24
Area Under the Concentration-Time Curve (AUC) of AG-348 in Participants Who Previously Received Placebo in Study AG348-C-006	Week 12: pre-dose, post-dose at 30 minutes, 1 hour (h), 2 h, 4 h, 8 h
Maximum Observed Concentration of AG-348 in Participants Who Previously Received Placebo in Study AG348-C-006	Week 12: pre-dose, post-dose at 30 minutes, 1 h, 2 h, 4 h, 8 h
Change from Baseline in Hb Concentration	From baseline up to Week 193 (Day 1)
Change from Baseline in Bilirubin	From baseline up to Week 193 (Day 1)
Change from Baseline in Lactate Dehydrogenase (LDH)	From baseline up to Week 193 (Day 1)
Change from Baseline in Haptoglobin Levels	From baseline up to Week 193 (Day 1)
Change from Baseline in Reticulocyte Percentages	From baseline up to Week 193 (Day 1)
Change from Baseline in Number of Transfusion Events	From baseline up to Week 193 (Day 1)
Change from Baseline in Number of Red Blood Cell (RBC) Units Transfused	From baseline up to Week 193 (Day 1)
Change from Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD)	From baseline up to Week 193 (Day 1)
Change from Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA)	From baseline up to Week 193 (Day 1)

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.

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2019
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 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 (Actual): April 12, 2024
• Last Update Submitted That Met QC Criteria: April 10, 2024
• Last Verified: April 1, 2024

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; Anemia, Hemolytic, Congenital Nonspherocytic; Pyruvate Metabolism, Inborn Errors; 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