A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)

NCT03548220 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: AG348-C-006
• Study Type: interventional
• Target: 80
• Locations: 16 countries
• Sites: 46

Brief Summary

Study AG348-C-006 evaluated the efficacy and safety of orally administered AG-348 as compared with placebo in participants with pyruvate kinase (PK) deficiency, who were not regularly receiving blood transfusions. Participants were randomized 1:1 to receive either AG-348 or a matching placebo.

Conditions

Pyruvate Kinase Deficiency; Anemia, Hemolytic

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR)

  Hemoglobin response (HR) is defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24. The baseline Hb concentration is the average of all available Hb concentrations for a participant during the Screening Period up to the first dose of study treatment. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).

  Baseline, Weeks 16, 20, 24

Secondary Outcomes (16)

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

  Baseline, Weeks 16, 20, 24

• Maximum Change From Baseline in Hb Concentration

  Baseline, up to Week 24

• Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More

  Baseline, up to Week 24

• Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24

  Baseline, Weeks 16, 20, 24

• Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24

  Baseline, Weeks 16, 20, 24

Other Outcomes (3)

• Percentage of Participants With Adverse Events of Special Interest (AESI)

  Through 4 weeks after last dose (approximately Week 31)

• Change From Baseline in Bone Mineral Density Z-Score at Week 24

  Baseline, Week 24

• Change From Baseline in Bone Mineral Density T-Score at Week 24

  Baseline, Week 24

Study Arms (4)

Placebo

PLACEBO COMPARATOR

Participants received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.

Drug: Placebo

AG-348, 5 mg

EXPERIMENTAL

Participants received AG-348 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 as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.

Drug: AG-348

AG-348, 20 mg

EXPERIMENTAL

Participants received AG-348 tablets, 5 mg 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 as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.

Drug: AG-348

AG-348, 50 mg

EXPERIMENTAL

Participants received AG-348 tablets, 5 mg 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 as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.

Drug: AG-348

Interventions

Placebo DRUG

Placebo matching AG-348 tablets, administered to maintain the blind.

Placebo

AG-348 DRUG

AG-348 tablets.

AG-348, 20 mg; AG-348, 5 mg; AG-348, 50 mg

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 or older;
• Documented clinical laboratory confirmation of pyruvate kinase (PK) deficiency, defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation;
• Hemoglobin (Hb) concentration less than or equal to 10.0 grams per deciliter (g/dL) regardless of gender (average of at least 2 Hb measurements \[separated by a minimum of 7 days\] during the Screening Period)
• Considered not regularly transfused, defined as having had no more than 4 transfusion episodes in the 12-month period up to the first day of study treatment and no transfusions in the 3 months prior to the first day of study treatment;
• Received at least 0.8 mg oral folic acid daily for at least 21 days prior to the first dose of study treatment, to be continued daily during study participation.
• Adequate organ function;
• Women of reproductive potential, have a negative serum pregnancy test;
• 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 treatment for women and 90 days for men following the last dose of study treatment;
• Willing to comply with all study procedures for the duration of the study;

You may not qualify if:

• Homozygous for the R479H mutation or have 2 non-missense mutations, without the presence of another missense mutation, in the PKLR gene;
• Significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound the interpretation of the study data;
• Splenectomy scheduled during the study treatment period or have undergone splenectomy within 12 months prior to signing informed consent;
• Currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Prior and subsequent participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted however, concurrent participation is not; participants enrolling in this current study will be expected to temporarily suspend participation in the NHS or Registry;
• Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study treatment;
• Prior treatment with a pyruvate kinase activator;
• Prior bone marrow or stem cell transplant;
• Currently pregnant or breastfeeding;
• History of major surgery within 6 months of signing informed consent;
• Currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to the first dose of study treatment;
• Currently receiving hematopoietic stimulating agents that have not been stopped for a duration of at least 28 days prior to the first dose of study treatment;
• History of allergy to sulfonamides if characterized by acute hemolytic anemia, drug induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis, or other serious clinical manifestations;
• History of allergy to AG-348 or its excipients;
• Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to treatment.

Sponsors & Collaborators

• Agios Pharmaceuticals, Inc.: lead

Study Sites (46)

University of Arkansas for Medical Sciences

Little Rock, Arkansas, 72205, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Indiana Hemophilia and Thrombosis Center

Indianapolis, Indiana, 46260, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

The Children's Hospital Corporation d/b/a Boston's Children Hospital

Boston, Massachusetts, 02115, United States

Location

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

Detroit, Michigan, 48304, United States

Location

Duke University

Durham, North Carolina, 27705, United States

Location

East Carolina University

Greenville, North Carolina, 27858, 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

Primary Children's Hospital Univ. of Utah

Salt Lake City, Utah, 84112, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

Location

Hospital Central da Faculdade de Medicina USP Cidade Universitaria

São Paulo, Brazil

Location

McMaster University - Health Sciences Centre

Hamilton, L8S 4LB, Canada

Location

Toronto General Hospital, University Health Network

Toronto, M5G 2C4, Canada

Location

Institute of Hematology and Blood Transfusion

Prague, Czechia

Location

University of Copenhagen, Herlev Hospital

Herlev, 2730, Denmark

Location

CHU Amiens Picardie

Amiens, 80054, France

Location

Hopital Saint-Andre

Bordeaux, France

Location

Hôpital Henri-Mondor

Créteil, 94010, France

Location

Hôpital de la Timone

Marseille, 13385, France

Location

Institut Claudius Regaud

Toulouse, France

Location

Charite University Medicine

Berlin, Germany

Location

Universitätsklinikum Würzburg

Würzburg, 97080, Germany

Location

Ospedale Galliera

Genova, 16128, Italy

Location

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Milan, 20122, Italy

Location

AOU Policlinico, Università della Campania "Luigi Vanvitelli"

Napoli, 80138, Italy

Location

Tohoku University Hospital

Sendai, Miyagi, Japan

Location

Kyoto Katsura Hospital

Kyoto, Japan

Location

Agios Investigative Site

Mie, Japan

Location

Osaka City General Hospital

Osaka, 534-0021, Japan

Location

Kansai Medical University, Department of Pediatrics, Hirakata Hospital

Osaka, Japan

Location

Toho University Omori Medical Center

Tokyo, Japan

Location

Universitair Medisch Centrum Utrecht

Utrecht, 3584, Netherlands

Location

Yeungnam University Hospital

Daegu 705-703, 42415, South Korea

Location

Hospital U. Vall d'Hebron Servicio de Hematología Clínica

Barcelona, 08035, Spain

Location

Hospital Clinico Universitario Virgen de la Arricaxa

El Palmar, 30120, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Centre Hospitalier Universitaire Vaudois (CHUV)

Lausanne, 1011, Switzerland

Location

Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj

Bangkok, 10700, Thailand

Location

Hacettepe University

Ankara, Turkey (Türkiye)

Location

Addenbrooke's Hospital

Cambridge, 94609, United Kingdom

Location

The Royal Liverpool and Broadgreen University

Liverpool, L7 8XP, United Kingdom

Location

Imperial College Healthcare NHS Trust, Hammersmith Hospital

London, W12 0NN, United Kingdom

Location

University College London

London, W12 0NN, United Kingdom

Location

Manchester Royal Infirmary

Manchester, M13 9WL, United Kingdom

Location

Related Publications (5)

• 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

• Andrae DA, Grace RF, Jewett A, Foster B, Klaassen RJ, Salek S, Li J, Tai F, Boscoe AN, Zagadailov E. Psychometric validation of the Pyruvate Kinase Deficiency Diary and Pyruvate Kinase Deficiency Impact Assessment in adults in the phase 3 ACTIVATE trial. J Patient Rep Outcomes. 2023 Nov 9;7(1):112. doi: 10.1186/s41687-023-00650-3.

  PMID: 37943362 DERIVED

• 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

• Al-Samkari H, Galacteros F, Glenthoj A, Rothman JA, Andres O, Grace RF, Morado-Arias M, Layton DM, Onodera K, Verhovsek M, Barcellini W, Chonat S, Judge MP, Zagadailov E, Xu R, Hawkins P, Beynon V, Gheuens S, van Beers EJ; ACTIVATE Investigators. Mitapivat versus Placebo for Pyruvate Kinase Deficiency. N Engl J Med. 2022 Apr 14;386(15):1432-1442. doi: 10.1056/NEJMoa2116634.

  PMID: 35417638 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

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: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2018
• First Posted: June 7, 2018
• Study Start: August 9, 2018
• Primary Completion: October 9, 2020
• Study Completion: October 9, 2020
• Last Updated: May 24, 2022
• Results First Posted: May 24, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

FR (5); CH (1); GB (5); JP (6); DE (2); KR (1); CA (2); BR (1); CZ (1); NL (1); ES (3); US (12); TH (1); DK (1); TU (1); IT (3)