A Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants With Non-transfusion-dependent Thalassemia

Sponsor:

Collaborators:

Information provided by (Responsible Party):

，

Tracking Information

First Submitted Date ^ICMJE

September 10, 2018

First Posted Date ^ICMJE

October 2, 2018

Last Update Posted Date

October 2, 2018

Actual Study Start Date ^ICMJE

November 2018

Estimated Primary Completion Date

December 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Percentage of Participants Achieving a Hemoglobin Response (HR)[ Time Frame: Up to 12 weeks ]

HR is defined as a ≥1.0 gram per deciliter (g/dL) increase in Hb concentration from baseline at 1 or more assessments between Week 4 and Week 12 (inclusive). A participant's baseline Hb concentration is defined as the average of all the participant's available Hb concentrations during the 42-day screening period up to the first dose of study drug.

Original Primary Outcome Measures ^ICMJE

Same as current

Current Secondary Outcome Measures ^ICMJE

Mean Change from Baseline in Hb Concentrations from Week 12 to Week 24[ Time Frame: Baseline, Week 12 to Week 24 ]
Percentage of Participants Achieving a Sustained Hb Response (sHR)[ Time Frame: Week 12 to Week 24 ]
sHR is defined as a ≥1.0 g/dL increase in Hb concentration at 2 or more evaluable Hb assessments out of the 4 scheduled assessments between the Week 12 Visit and Week 24 Visit
Change from Baseline in Hb Concentration over an Additional 2 Years in the Extension Period[ Time Frame: Baseline up to approximately 2.5 years ]
Time to Achieve HR[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Reticulocyte Count[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Bilirubin[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Lactate Dehydrogenase (LDH)[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Haptoglobin[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Nucleated Red Blood Cells (NRBCs)[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Erythropoietin (EPO)[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Soluble Transferrin Receptor[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Iron[ Time Frame: Up to Week 120 ]
Change from Baseline in Serum Ferritin[ Time Frame: Up to Week 120 ]
Change from Baseline in Total Iron-binding Capacity (TIBC)[ Time Frame: Up to Week 120 ]
Change from Baseline in Transferrin Saturation[ Time Frame: Up to Week 120 ]
Change from Baseline in Hepcidin[ Time Frame: Up to Week 120 ]
Change from Baseline in C-reactive Protein[ Time Frame: Up to Week 120 ]
Drug Concentrations over Time for AG-348[ Time Frame: Pre-dose at Weeks 1, 2, 3, 4, 6, 8, 16, 20, and 24 ]
Change from Baseline in Adenosine Triphosphate (ATP) Concentrations[ Time Frame: Pre-dose on Day 1 and at Weeks 6, 8, 12, and 24 ]
Change from Baseline in 2,3-DPG Concentrations[ Time Frame: Pre-dose on Day 1 and at Weeks 6, 8, 12, and 24 ]
Change from Baseline in Red Blood Cell (RBC)-specific Form of Pyruvate Kinase (PKR) Activity[ Time Frame: Pre-dose and at 2 hours post-dose on Day 1; pre-dose at Week 12 ]
Change from Baseline in PKR Protein Levels[ Time Frame: Pre-dose on Day 1 and at Weeks 12 and 24 ]
Change from Baseline in PKR Flux Assay Results[ Time Frame: Pre-dose on Day 1 and at Week 12 ]
Percentage of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Significant Interest (AESIs), and AEs Leading to Study Drug Dose Reduction, Study Drug Interruption, and Study Drug Discontinuation[ Time Frame: Up to approximately 2.5 years ]

Descriptive Information

Brief Title ^ICMJE

A Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants With Non-transfusion-dependent Thalassemia

Official Title ^ICMJE

A Phase 2, Open-label, Multicenter Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Subjects With Non-transfusion-dependent Thalassemia

Brief Summary

Study AG348-C-010 is a multicenter study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of treatment with AG-348 in adult participants with non-transfusion-dependent thalassemia (NTDT). This study will include a 24-week core period followed by a 2-year extension period for eligible participants. Approximately 17 participants with NTDT will be enrolled. The initial dose of AG-348 will be 50 milligrams (mg) twice daily (BID) with one potential dose-level increase to 100 mg BID, at the Week 6 visit based on the participant's safety and hemoglobin (Hb) concentrations.

Detailed Description

Study Type ^ICMJE

Interventional

Study Phase

Phase 2

Study Design ^ICMJE

Allocation:
Intervention Model: Single Group Assignment
Intervention Model Description:
Masking: Interventional
Masking Description:
Primary Purpose: Treatment

Condition ^ICMJE

Intervention ^ICMJE

Drug: AG-348
Core period: Participants will receive an initial AG-348 dose of 50 mg BID, oral tablets, and may undergo one potential dose-level increase to 100 mg BID, based on an evaluation of the participant's safety profile and Hb concentrations. Extension Period: Participants who achieve a Hb response with no safety issues will continue receiving treatment with AG-348 for up to 2 years at the same dose they were receiving at the Week 24 Visit.

Study Arms

Experimental: AG-348
Core period: Participants will receive AG-348 for up to 24 weeks. Depending on the safety observations and hemoglobin (Hb) concentrations, they may undergo one potential dose-level increase from 50 to 100 mg BID. Extension Period: Eligible participants will continue to receive AG-348 for up to 2 years at the same dose they were receiving at the Week 24 visit.

Recruitment Information

Recruitment Status ^ICMJE

Not yet recruiting

Estimated Enrollment ^ICMJE

Original Estimated Enrollment ^ICMJE

Same as current

Estimated Study Completion Date

December 2021

Estimated Primary Completion Date

December 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

Inclusion Criteria: - Informed consent; - Be aged 18 years or older; - Known medical history of thalassemia, including β-thalassemia intermedia, Hb E β-thalassemia, α-thalassemia (Hb H disease), or β-thalassemia with mutations of 1 or more α genes; - Documented clinical laboratory confirmation of thalassemia by Hb electrophoresis/high-performance liquid chromatography (HPLC) or deoxyribonucleic acid (DNA) analysis, either from medical records or during the screening period; - Hb concentration ≤9.0 grams per deciliter (g/dL), regardless of sex, based on an average of at least 2 Hb measurements (separated by a minimum of 7 days) during the screening period; - Considered non-transfusion-dependent, defined as having no more than 5 units of red blood cells (RBCs) transfused during the 24-week period up to the first day of study drug and no RBC transfusions in the 8 weeks prior to the first day of study drug; - Have adequate organ function; - For women of reproductive potential: negative serum pregnancy test during the screening period and a negative serum or urine pregnancy test on Day 1; - For women of reproductive potential as well as men with partners who are women of reproductive potential: abstinent as part of their usual lifestyle, or agreement 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 (both men and women) following the last dose of study drug; - Willingness to comply with all study procedures for the duration of the study; Exclusion Criteria: - Known history of diagnosis of Hb S or Hb C forms of thalassemia; - Significant medical condition that confers an unacceptable risk to participating in the study, and/or could confound the interpretation of the study data; - Splenectomy scheduled during the study treatment period or having 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; - Exposure to any investigational drug, device, or procedure within 3 months prior to the first day of study drug; - Prior exposure to sotatercept (ACE-011), luspatercept (ACE-536), ruxolitinib, or gene therapy; - Prior bone marrow or stem cell transplant; - Currently pregnant or breastfeeding; - History of major surgery within 6 months of signing informed consent; - Are 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 day of study drug; - Currently receiving chronic anticoagulant therapy, unless started and on a stable dose for at least 28 days prior to first day of study drug; - Currently receiving anabolic steroids, including testosterone preparations, if initiated ≤28 days prior to the first day of study drug; - Currently receiving hematopoietic stimulating agents (e.g., erythropoietins, granulocyte colony stimulating factors, thrombopoietins), if initiated ≤8 weeks prior to the first day 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; - History of allergy to AG-348 or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol).

Sex/Gender

Sexes Eligible for Study:

All

Ages

18 Years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Listed Location Countries ^ICMJE

Canada|United Kingdom|United States

Removed Location Countries

Administrative Information

Has Data Monitoring Committee

U.S. FDA-regulated Product

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

Plan to Share IPD:

Responsible Party

，

Study Sponsor ^ICMJE

Agios Pharmaceuticals, Inc.

Collaborators ^ICMJE

Investigators ^ICMJE

Study Chair: Medical Affairs Agios Pharmaceuticals, Inc.

PRS Account

Verification Date

September 2018

^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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