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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Thalassemia

Intervention / Treatment
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* Drug: AG-348


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AG-348<br>Participants with alpha or beta thalassemia received AG-348 50 mg twice daily (BID), orally up to Week 6. Following Week 6, depending on the participants' safety and hemoglobin (Hb) concentrations, they could undergo one potential dose-level increase from 50 to 100 mg BID. After completion of the Core Period of 24 weeks, participants were eligible to continue to receive AG-348 in the Extension Period which is up to 10 years. | Drug: AG-348<br>* AG-348 tablet orally BID<br>* Other names: Mitapivat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | Week 12 to Week 24 | 
| Change From Baseline in Hb Concentration Over the Duration of the Extension Period |  | Baseline up to approximately 10.5 years | 
| Time to First ≥1.0 g/dL Increase in Hb Concentration |  | Up to Week 24 | 
| Change From Baseline in Reticulocyte Count |  | Up to approximately 10.5 years | 
| Change From Baseline in Bilirubin |  | Up to approximately 10.5 years | 
| Change From Baseline in Lactate Dehydrogenase (LDH) |  | Up to approximately 10.5 years | 
| Change From Baseline in Haptoglobin |  | Up to approximately 10.5 years | 
| Change From Baseline in Nucleated Red Blood Cells (NRBCs) |  | Up to approximately 10.5 years | 
| Change From Baseline in Erythropoietin (EPO) |  | Up to approximately 10.5 years | 
| Change From Baseline in Soluble Transferrin Receptor |  | Up to approximately 10.5 years | 
| Drug Concentrations Over Time for AG-348 |  | Predose (60 minutes) and 0.00 hour, 0.50 hour, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12 | 
| AUC0-8h: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours of AG-348 |  | Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12 | 
| AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration of AG-348 |  | Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12 | 
| Cmax: Maximum Observed Plasma Concentration of AG-348 |  | Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12 | 
| Tmax: Time to Reach the Maximum Plasma Radioactivity Concentration (Cmax) |  | Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12 | 
| Tlast: Time of the Last Quantifiable Concentration of AG-348 |  | Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12 | 
| Ctrough: Observed Plasma Concentration at the End of a Dosing Interval of AG-348 |  | Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12 | 
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), and TEAEs Leading to Study Drug Dose Reduction, Study Drug Interruption, and Study Drug Discontinuation | An AE is any unfavorable and unintended sign, symptom, or disease, whether or not related to the investigational product. A TEAE was defined as any AE with onset post study drug treatment. An SAE was defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically important. AESIs are predefined AEs that required close monitoring and prompt reporting to the sponsor. AESIs included protocol-specified transaminase increase. | From signing the inform consent form up to data cut-off date: 20 August 2020 (Up to approximately 19 months) |