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

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

Status

Active, not recruiting

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03692052

Enrollment

Registered

2018-10-02

Start date

2019-03-20

Completion date

2030-09-30

Last updated

2026-03-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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 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.

Interventions

DRUGAG-348

AG-348 tablet orally BID

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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).

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants Achieving a Hemoglobin Response (HR)	Up to 12 weeks	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.

Secondary

Measure	Time frame	Description
Average Change From Baseline in Hb Concentrations From Week 12 to Week 24	Baseline, 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.
Percentage of Participants Achieving a Sustained Hb Response (sHR)	Week 12 to Week 24	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.
Percentage of Participants Achieving a Delayed Hb Response	Week 12 to Week 24	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.
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	From signing the inform consent form up to data cut-off date: 20 August 2020 (Up to approximately 19 months)	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.

Countries

Canada, United Kingdom, United States

Contacts

STUDY_CHAIRMedical Affairs

Agios Pharmaceuticals, Inc.

Participant flow

Recruitment details

Participants took part in the study at 4 investigative sites in the United States, Canada, and United Kingdom from 28 December 2018 to 30 September 2030. Results are reported for the primary and secondary outcome measures for the 24-week Core Period (data cut-off date: 20 August 2020). The Extension Period of this study is ongoing.

Pre-assignment details

A total of 20 participants were enrolled in the Core Period of this study. The participants who completed the 24-week Core Period and achieved a hemoglobin (Hb) response or a delayed Hb response and had an acceptable safety profile were eligible to continue in the Extension Period.

Participants by arm

Arm	Count
AG-348 Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.	20
Total	20

Arm

Count

AG-348

Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.

Total

Baseline characteristics

Characteristic	AG-348
Age, Continuous	45.3 years STANDARD_DEVIATION 11.81
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	19 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	10 Participants
Race (NIH/OMB) Black or African American	1 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants
Race (NIH/OMB) White	4 Participants
Sex: Female, Male Female	15 Participants
Sex: Female, Male Male	5 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 20
other Total, other adverse events	17 / 20
serious Total, serious adverse events	1 / 20

Outcome results

Primary

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

Population: FAS included all participants who received at least 1 dose of study treatment.

Arm	Measure	Value (NUMBER)
AG-348	Percentage of Participants Achieving a Hemoglobin Response (HR)	80.0 percentage of participants

p-value: <0.0001Clopper-Pearson Method

Secondary

AUC0-8h: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours of AG-348

Time frame: Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12

Population: The PK Analysis Set included all participants who were enrolled and received a dose of study medication (AG-348), with at least one non-zero plasma concentration of AG-348 at Day 1 or Week 12 (or the Unscheduled Visit where intensive PK samples were assessed). Number analyzed is the number of participants with data available for analysis at the given time point.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
AG-348	AUC0-8h: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours of AG-348	AG-348 50 mg: Day 1	3083.3 nanogramshour per milliliter (ngh/mL)	Geometric Coefficient of Variation 25.6
AG-348	AUC0-8h: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours of AG-348	AG-348 100 mg: Week 12	3384.4 nanogramshour per milliliter (ngh/mL)	Geometric Coefficient of Variation 65.7

Secondary

AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration of AG-348

Time frame: Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
AG-348	AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration of AG-348	AG-348 50 mg: Day 1	3083.5 ng*h/mL	Geometric Coefficient of Variation 25.6
AG-348	AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration of AG-348	AG-348 100 mg: Week 12	3384.4 ng*h/mL	Geometric Coefficient of Variation 65.7

Secondary

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

Population: FAS included all participants who received at least 1 dose of study treatment. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm	Measure	Group	Value (MEAN)	Dispersion
AG-348	Average Change From Baseline in Hb Concentrations From Week 12 to Week 24	Baseline	79.44 grams per liter (g/L)	Standard Deviation 13.69
AG-348	Average Change From Baseline in Hb Concentrations From Week 12 to Week 24	Average Change from Baseline: Week 12 to 24	13.01 grams per liter (g/L)	Standard Deviation 6.283

Secondary