A Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants With Non-transfusion-dependent Thalassemia
Condition: Thalassemia
MeSH terms: Thalassemia
Intervention: AG-348
Intervention description: AG-348 tablet orally BID
Intervention MeSH terms: Mitapivat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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 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.
    

Eligibility criteria:

        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).