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

Phase 2Active Not RecruitingNCT03692052

Agios Pharmaceuticals, Inc.20 enrolled

Overview

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 includes a core period (up to 24 weeks) followed by an extension period (up to 10 years) for eligible participants. 20 participants with NTDT were enrolled. The initial dose of AG-348 was 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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Thalassemia

Interventions

AG-348

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Informed consent; * 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 ≤10.0 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; * 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: be 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 following the last dose of study drug for women and 90 days following the last dose of study drug for men; * 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; * 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).

Outcomes

Primary Outcomes

Percentage of Participants Achieving a Hemoglobin Response (HR)

HR was 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 was defined as the average of all the participant's available Hb concentrations during the screening period up to the first dose of study drug.

Time frame: Up to 12 weeks

Secondary Outcomes

Average Change From Baseline in Hb Concentrations From Week 12 to Week 24

A participant's Baseline Hb concentration was defined as the average of all the participant's available Hb concentrations during the screening period up to the first dose of study drug.

Time frame: Baseline, Week 12 to Week 24

Percentage of Participants Achieving a Sustained Hb Response (sHR)

sHR was defined as achieving HR and achieving a ≥1.0 g/deciliter (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.

Time frame: Week 12 to Week 24

Percentage of Participants Achieving a Delayed Hb Response

Delayed Hb response was defined as not achieving HR and achieving a ≥1.0 g/dL increase in Hb concentration at 1 or more Hb assessments after Week 12.

Time frame: Week 12 to Week 24

Change From Baseline in Hb Concentration Over the Duration of the Extension Period

Time frame: Baseline up to approximately 10.5 years

Time to First ≥1.0 g/dL Increase in Hb Concentration

Time frame: Up to Week 24

Change From Baseline in Reticulocyte Count