A Study Evaluating the Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)

NCT03559699 | Completed Phase 3 Results FDA Drug

• 2 other identifiers: AG348-C-0072017-003803-22
• Study Type: interventional
• Target: 27
• Locations: 9 countries
• Sites: 19

Brief Summary

Study AG348-C-007 was a multicenter study designed to evaluate the efficacy and safety of treatment with AG-348 in a minimum of 20, with up to 40, participants with pyruvate kinase (PK) deficiency, who were regularly receiving blood transfusions. The study was composed of two parts. During Part 1, Dose Optimization Period, participants started on a dose of 5 mg AG-348 administered twice daily. Over the course of Part 1 each participant's dose of AG-348 was sequentially increased to 20 mg twice a day, followed by 50 mg twice a day depending on their tolerance. During Part 2, Fixed-Dose Period, participants received AG-348 at their optimized dose from Part 1.

Conditions

Pyruvate Kinase Deficiency; Anemia, Hemolytic

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants Achieving a Reduction in Transfusion Burden in Part 2

  Reduction in transfusion burden is defined as a ≥33% reduction in the number of RBC units transfused during the Fixed Dose Period standardized to 24 weeks compared with the historical transfusion burden standardized to 24 weeks (Standardized Control Period). The on-study (Fixed Dose Period) transfusion burden was calculated as the total number of transfused RBC units received in the Fixed Dose Period standardized to 24 weeks.

  From Part 2, Day 1 to Part 2 Week 24

Secondary Outcomes (5)

• Annualized Number of RBC Units Transfused During the Study

  Part 1 Day 1 to Part 2 Week 24

• Number of Transfusion Episodes in Part 2

  From Part 2 Day 1 to Part 2 Week 24

• Percentage of Transfusion-Free Participants in Part 2

  From Part 2 Day 1 to Part 2 Week 24

• Percentage of Participants Achieving Normal Hemoglobin (Hb) Concentrations in Part 2

  From Part 2 Day 1 to Part 2 Week 24

• Percentage of Participants With Adverse Events

  Through 4 weeks after last dose (approximately Part 2, Week 31)

Other Outcomes (3)

• Percentage of Participants Experiencing an Adverse Event of Special Interest (AESI)

  From Part 1 Day 1 to end of Part 2, including follow-up (Day 197)

• Bone Mineral Density Z-Score

  Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24

• Bone Mineral Density T-Score

  Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24

Study Arms (1)

AG-348

EXPERIMENTAL

Participants received AG-348 tablets, administered orally, at a starting dose of 5 milligrams (mg), twice daily (BID), followed by two sequential dose level increases to 20 mg and 50 mg BID, for a period of 16 weeks in Part 1. This was followed by optimized dose BID, as determined by the investigator in Part 1, for a period of 24 weeks in Part 2.

Drug: AG-348

Interventions

AG-348 DRUG

Part 1 (Dose Optimization Period): Participants began by receiving 5 mg orally, BID. Each participant's dose of AG-348 was sequentially increased to 20 mg BID followed by 50 mg BID depending on their response to AG-348 and their tolerance. Part 2 (Fixed Dose Period): Optimized dose determined in Part 1.

AG-348

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 or older;
• Presence of at least 2 mutant alleles in the Pyruvate Kinase Liver and RBC (PKLR) gene, of which at least 1 is a missense mutation;
• History of a minimum of 6 transfusion episodes in the 52-week period prior to date of informed consent;
• Complete records of transfusion history for the 52 weeks prior to the date of informed consent, including all transfusion dates, number of blood units transfused for all the transfusions, and Hb concentrations within 1 week prior to transfusion for at least 80% of the transfusions;
• Have received at least 0.8 mg of oral folic acid daily for at least 21 days prior to the first dose of study drug, to be continued daily during study participation;
• Have adequate organ function;
• Negative serum pregnancy test for women of reproductive potential;
• For women of reproductive potential as well as fertile men and their partners who are women of reproductive potential: be abstinent 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 AG-348;
• Willing to comply with all study procedures, in particular the individual transfusion trigger (TT) calculated based on 52 weeks of transfusion history, 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 participate in the study, and/or that could confound the interpretation of the study data;
• History of transfusions occurring on average more frequently than once every 3 weeks during the 52 weeks prior to date of informed consent;
• 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. Prior participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted;
• Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study drug;
• 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 CYP3A4, 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 5 times their half-lives (whichever is longer) prior to start of study drug;
• Currently receiving hematopoietic stimulating agents (eg, erythropoietins \[EPOs\], granulocyte colony stimulating factors, thrombopoietins) that have not been stopped for a duration of at least 28 days prior to the first dose of study drug;
• 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;
• Allergy to AG-348 or its excipients;
• Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to the first dose of study drug.

Sponsors & Collaborators

• Agios Pharmaceuticals, Inc.: lead

Study Sites (19)

UCSF Benioff Children's Hospital

Oakland, California, 94609, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02115, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

Location

Toronto General Hospital, University Health Network

Toronto, M5G 2C4, Canada

Location

University of Copenhagen, Herlev Hospital

Herlev, 2730, Denmark

Location

Hopital Universitaire Henri Mondor

Créteil, 94010, France

Location

Hôpital de la Timone

Marseille, 13385, France

Location

St James's Hospital Department of Haematology

Dublin, Ireland

Location

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Milan, 20122, Italy

Location

AORN Cardarelli

Napoli, 80131, Italy

Location

Ospedale Galliera

Napoli, 80131, Italy

Location

AOU Policlinico, Università della Campania "Luigi Vanvitelli"

Napoli, 80138, Italy

Location

Universitair Medisch Centrum Utrecht

Utrecht, 3584, Netherlands

Location

Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University

Bangkok, 10700, Thailand

Location

Addenbrooke's Hospital

Cambridge, CB2 0QQ, United Kingdom

Location

Imperial College Healthcare NHS Trust, Hammersmith Hospital

London, W12 0NN, United Kingdom

Location

University College London

London, WC1E 6BT, United Kingdom

Location

Manchester Royal Infirmary

Manchester, M13 9WL, United Kingdom

Location

Related Publications (3)

• 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

• Glenthoj A, van Beers EJ, Al-Samkari H, Viprakasit V, Kuo KHM, Galacteros F, Chonat S, Porter J, Zagadailov E, Xu R, Oluyadi A, Hawkins P, Gheuens S, Beynon V, Barcellini W; ACTIVATE-T investigators. Mitapivat in adult patients with pyruvate kinase deficiency receiving regular transfusions (ACTIVATE-T): a multicentre, open-label, single-arm, phase 3 trial. Lancet Haematol. 2022 Oct;9(10):e724-e732. doi: 10.1016/S2352-3026(22)00214-9. Epub 2022 Aug 18.

  PMID: 35988546 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: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 26, 2018
• First Posted: June 18, 2018
• Study Start: June 26, 2018
• Primary Completion: November 12, 2020
• Study Completion: November 12, 2020
• Last Updated: January 4, 2022
• Results First Posted: December 10, 2021

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

TH (1); CA (1); DK (1); US (4); IE (1); FR (2); NL (1); IT (4); GB (4)