Pyruvate Kinase Deficiency
Conditions
Keywords
Pyruvate Kinase Deficiency, Hemolytic anemia, Pyruvate Kinase Isoform R (PKR), Drive PK
Brief summary
Study AG348-C-003 is a multicenter study designed to evaluate the safety and efficacy of different dose levels of AG-348 (mitapivat) in participants with PK deficiency.
Detailed description
This is a Phase 2, open label, two arm, multicenter, randomized, dose-ranging study during which adult participants with PK deficiency will receive multiple doses of AG-348 for up to 24 weeks (Core Period); eligible participants may enter an Extension Period to receive AG-348 for up to 8 additional years. Data will be reviewed on a regular basis and study design, dose and schedule will be adapted based on these reviews. The study will evaluate the safety and tolerability of multiple doses of AG-348, pharmacokinetic and pharmacodynamic (PD) profile of AG-348 and early indicators of clinical efficacy.
Interventions
DRUGAG-348
Tablets
Sponsors
Agios Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Informed consent 2. Male or female, aged 18 years and older 3. Known medical history of PK deficiency 4. PK deficiency confirmed by enzymatic assay at Screening 5. Genotypic characterization of PKR gene at Screening 6. Genotypic characterization of uridine-5'-diphosphate-glucuronyltransferase-A1 (UGTA1) gene to document underlying Gilbert's disease (Gilbert's disease patients are eligible) 7. Males Hb ≤ 12.0 g/dL, females Hb ≤ 11 g/dL 8. Transfusion independent, defined as no more than 3 units of red blood cells (RBC) transfused in 12 months prior to the first day of study dosing and no transfusions within 4 months of first day of study dosing 9. Splenectomized patients must have had the procedure at least 6 months prior to Screening and must be up-to-date in recommended vaccinations 10. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 11. Must be taking at least 1 mg folic acid daily in the 21 days prior to screening 12. Adequate organ function defined by liver function, kidney function, platelet count and coagulation assessments 13. Agreement to use approved contraceptive measures 14. Women must not be breastfeeding For entry into the Extension Period, patients must meet criteria # 15-16: 15. Must have completed 24 weeks of treatment during the Core Period and tolerated AG-348 16. The treating Investigator agrees that there is a potential for clinical benefit to continued treatment and recommends participation in the Extension Period and the Medical Monitor approves
Exclusion criteria
1. Hb ˃ 12.0 g/dL if male, Hb ˃11.0 g/dL if female 2. Additional diagnosis of other congenital or acquired blood disorder 3. Iron overload sufficiently severe to result in cardiac, hepatic or pancreatic insufficiency 4. Bone marrow or stem cell transplant 5. Clinically symptomatic cholelithiasis or cholecystitis 6. Currently enrolled in any other investigational trial. Participation in the PK Deficiency Natural History Study (NCT02053480) is permitted 7. Exposure to any investigational drug, device or procedure within 28 days prior to screening or during trial participation 8. Concurrent medical condition such as poorly controlled hypertension, heart failure, active infection, frequent post-splenectomy sepsis, Hepatitis B or C, Human Immunodeficiency Virus type 1 (HIV1) or Human Immunodeficiency Virus type 2 (HIV2) infection, poorly controlled diabetes mellitus, history of primary malignancy with the exception of curatively treated nonmelanomatous skin cancer, cervical cancer of breast cancer in situ 9. Major surgery in the last 6 months 10. Psychiatric disorder that could compromise the ability of the patient to cooperate with the study 11. Serum bilirubin higher to the upper limit of normal attributable to factors other than hemolysis or Gilbert's Syndrome 12. Use of restricted products known to strongly inhibit cytochrome P450 (CYP) 3A4 metabolism within 5 days prior to Prior Day 1 dosing, or to strongly induce cytochrome P450 3A4 (CYP3A4) metabolism within 28 days prior to Day 1 dosing, or to strongly inhibit P-glycoprotein transporter within 5 days prior to Day 1 dosing, or digoxin within 5 days prior to Day 1 dosing. 13. Heart-rate corrected QT interval - Fridericia's method (QTcF) interval ˃ 450 ms in male, QTcF \> 470 ms in female, with the exception of patients with a left Bundle Branch Block 14. Cardiac arrhythmias that are clinically significant or treated with drugs that are substrates of CYP3A4 15. Allergy to sulfonamides if characterized by acute hemolytic anemia, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson Syndrome 16. Any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to participate in the study 17. Patients will not be permitted to enter the Extension Period if: The patient experienced AEs during the Core Period that are considered by the treating Investigator or the Sponsor's designated Medical Monitor to pose a significant safety risk to the patient if treatment were to be extended
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing at Least One Adverse Event (AEs) in the Core Period | Up to Week 24 | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug-related. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing at Least One AE up to Month 102 | Up to Month 102 | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug-related. Safety data for cumulative period (Core period and Extension period) has been reported in this outcome measure. |
| Change From Baseline in Hemoglobin (Hb) Value at Week 24 | Baseline and Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased Hb values indicate improvement. |
| Change From Baseline Hb Value up to Month 102 | Baseline, Months 12, 36, 60, 84, and 102 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased Hb values indicate improvement. |
| Change From Baseline in Hematocrit at Week 24 | Baseline and Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased hematocrit values indicate improvement. |
| Change From Baseline in Hematocrit up to Month 102 | Baseline, Months 12, 36, 60, 84, and 102 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased hematocrit values indicate improvement. |
| Change From Baseline in Reticulocyte Count at Week 24 | Baseline and Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased reticulocyte count values indicate improvement. |
| Change From Baseline in Reticulocyte Count up to Month 102 | Baseline, Months 12, 36, 60, 84, and 102 | Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased reticulocyte count values indicate improvement. |
| Change From Baseline in Haptoglobin at Week 24 | Baseline and Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased haptoglobin values indicate improvement. |
| Change From Baseline in Haptoglobin up to Month 102 | Baseline, Months 12, 36, 60, 84, and 102 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased haptoglobin values indicate improvement. |
| Change From Baseline in Carboxyhemoglobin (COHb) at Week 24 | Baseline and Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased COHb values indicate improvement. |
| Change From Baseline in COHb up to Month 30 | Baseline, Months 12, 18, 24, and 30 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased COHb values indicate improvement. |
| Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 | Baseline and Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased LDH values indicate improvement. |
| Change From Baseline in LDH up to Month 30 | Baseline, Months 12, 18, 24, and 30 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased LDH values indicate improvement. |
| Change From Baseline in Total Bilirubin at Week 24 | Baseline and Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased total bilirubin values indicate improvement. |
| Change From Baseline in Total Bilirubin up to Month 102 | Baseline, Months 12, 36, 60, 84, and 102 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased total bilirubin values indicate improvement. |
| Change From Baseline in Indirect Bilirubin at Week 24 | Baseline and Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased indirect bilirubin values indicate improvement. |
| Change From Baseline in Indirect Bilirubin up to Month 102 | Baseline, Months 12, 36, 60, 84, and 102 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased indirect bilirubin values indicate improvement. |
| Change From Baseline in Erythropoietin (EPO) at Week 24 | Baseline and Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased EPO values indicate improvement. |
| Change From Baseline in (EPO) up to Month 30 | Baseline, Months 12, 18, 24, and 30 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased EPO values indicate improvement. |
| Change From Baseline in Hepcidin at Week 24 | Baseline and Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased hepcidin values indicate improvement. |
| Change From Baseline in Hepcidin up to Month 30 | Baseline, Months 12, 18, 24, and 30 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased hepcidin values indicate improvement. |
| Change From Baseline in Ferritin at Week 24 | Baseline and Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased ferritin values indicate improvement. |
| Change From Baseline in Ferritin up to Month 102 | Baseline, Months 12, 36, 60, 84, and 102 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased ferritin values indicate improvement. |
| Change From Baseline in Transferrin Saturation at Week 24 | Baseline and Week 24 | Transferrin saturation is the ratio of serum iron to iron-binding capacity. Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased transferrin saturation values indicate improvement. |
| Change From Baseline in Transferrin Saturation up to Month 102 | Baseline, Months 12, 36, 60, 84, and 102 | Transferrin saturation is the ratio of serum iron to iron-binding capacity. Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased transferrin saturation values indicate improvement. |
| Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 | pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15 | Participants with pre-dose concentrations on Day 1 were excluded from the pharmacokinetics analysis, if any. |
| Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 | pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15 | Participants with pre-dose concentrations on Day 1 were excluded from the pharmacokinetics analysis, if any. |
| Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 | pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15 | Participants with pre-dose concentrations on Day 1 were excluded from the pharmacokinetics analysis, if any. |
| Apparent Clearance at Steady-State (Clss/F) for AG-348 and Its Metabolite AGI-8702 | pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15 | Participants with pre-dose concentrations on Day 1 were excluded from the pharmacokinetics analysis, if any. |
| Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP) | pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 | Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline. |
| Maximum Change From Baseline Response Value Over 8 Hours Post-dose at Steady State (BRmax ss) for ATP | pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15 | Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline. |
| BRmax for 2,3 - Diphosphoglycerate (2,3-DPG) | pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 | Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline. |
| BRmax ss for 2,3-DPG | pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15 | Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline. |
Countries
Canada, France, Italy, Netherlands, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study across multiple study sites in 6 countries from 26 June 2015 to 02 April 2025.
Pre-assignment details
A total of 52 participants were enrolled in the Core Period of the study. Participants were randomized 1:1 to receive AG-348 50 mg or AG-348 300 mg. Participants who completed the 24-week Core Period, had clinical activity, and tolerated the AG-348 dose entered the Extension Period for up to 102 months.
Participants by arm
| Arm | Count |
|---|---|
| AG-348 50 mg BID Participants with PK deficiency received AG-348, 50 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348. | 27 |
| AG-348 300 mg BID Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants were assigned to initial doses, however, over the course of the Core Period were treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. If participants chose not to enroll, they were followed up to four weeks after the last dose of AG-348. | 25 |
| Total | 52 |
Baseline characteristics
| Characteristic | AG-348 300 mg BID | Total | AG-348 50 mg BID |
|---|---|---|---|
| Age, Continuous | 37.6 years STANDARD_DEVIATION 12.02 | 34.0 years STANDARD_DEVIATION 12.01 | 30.6 years STANDARD_DEVIATION 11.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 47 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Race White | 21 Participants | 43 Participants | 22 Participants |
| Sex: Female, Male Female | 11 Participants | 20 Participants | 9 Participants |
| Sex: Female, Male Male | 14 Participants | 32 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 25 |
| other Total, other adverse events | 27 / 27 | 25 / 25 |
| serious Total, serious adverse events | 12 / 27 | 7 / 25 |
Outcome results
Primary
Percentage of Participants Experiencing at Least One Adverse Event (AEs) in the Core Period
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug-related.
Time frame: Up to Week 24
Population: The Safety Analysis Set included all participants who had received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AG-348 50 mg BID | Percentage of Participants Experiencing at Least One Adverse Event (AEs) in the Core Period | 96.3 percentage of participants |
| AG-348 300 mg BID | Percentage of Participants Experiencing at Least One Adverse Event (AEs) in the Core Period | 100.0 percentage of participants |
Secondary
Apparent Clearance at Steady-State (Clss/F) for AG-348 and Its Metabolite AGI-8702
Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.
Time frame: pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
Population: The Pharmacokinetic Analysis Set included all participants from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess pharmacokinetic parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Apparent Clearance at Steady-State (Clss/F) for AG-348 and Its Metabolite AGI-8702 | Day 15: AG-348 | 12.27 liter per hour (L/hr) | Geometric Coefficient of Variation 40.3 |
| AG-348 50 mg BID | Apparent Clearance at Steady-State (Clss/F) for AG-348 and Its Metabolite AGI-8702 | Day 15: AGI-8702 | 91.50 liter per hour (L/hr) | Geometric Coefficient of Variation 31 |
| AG-348 300 mg BID | Apparent Clearance at Steady-State (Clss/F) for AG-348 and Its Metabolite AGI-8702 | Day 15: AG-348 | 25.31 liter per hour (L/hr) | Geometric Coefficient of Variation 11.7 |
| AG-348 300 mg BID | Apparent Clearance at Steady-State (Clss/F) for AG-348 and Its Metabolite AGI-8702 | Day 15: AGI-8702 | 128.2 liter per hour (L/hr) | Geometric Coefficient of Variation 18.8 |
Secondary
Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702
Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.
Time frame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
Population: The Pharmacokinetic Analysis Set included all participants from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess pharmacokinetic parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 | Day 1: AG-348 | 3287 nanograms*hours per milliliter(hr*ng/mL) | Geometric Coefficient of Variation 20.9 |
| AG-348 50 mg BID | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 | Day 15: AG-348 | 3609 nanograms*hours per milliliter(hr*ng/mL) | Geometric Coefficient of Variation 38.2 |
| AG-348 50 mg BID | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 | Day 1: AGI-8702 | 235.6 nanograms*hours per milliliter(hr*ng/mL) | Geometric Coefficient of Variation 32.6 |
| AG-348 50 mg BID | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 | Day 15: AGI-8702 | 425.8 nanograms*hours per milliliter(hr*ng/mL) | Geometric Coefficient of Variation 21.8 |
| AG-348 300 mg BID | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 | Day 15: AGI-8702 | 2235 nanograms*hours per milliliter(hr*ng/mL) | Geometric Coefficient of Variation 19.4 |
| AG-348 300 mg BID | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 | Day 1: AG-348 | 27930 nanograms*hours per milliliter(hr*ng/mL) | Geometric Coefficient of Variation 38.1 |
| AG-348 300 mg BID | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 | Day 1: AGI-8702 | 2637 nanograms*hours per milliliter(hr*ng/mL) | Geometric Coefficient of Variation 34.9 |
| AG-348 300 mg BID | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 | Day 15: AG-348 | 11610 nanograms*hours per milliliter(hr*ng/mL) | Geometric Coefficient of Variation 11.3 |
Secondary
Change From Baseline in Carbon Monoxide at Week 24
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased carbon monoxide values indicate improvement.
Time frame: Baseline and Week 24
Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Change From Baseline in Carbon Monoxide at Week 24 | Baseline | 5.263 percentage Hb bound to carbon monoxide | Standard Deviation 1.727 |
| AG-348 50 mg BID | Change From Baseline in Carbon Monoxide at Week 24 | Change at Week 24 | -1.063 percentage Hb bound to carbon monoxide | Standard Deviation 2.294 |
| AG-348 300 mg BID | Change From Baseline in Carbon Monoxide at Week 24 | Baseline | 6.200 percentage Hb bound to carbon monoxide | Standard Deviation 2.3079 |
| AG-348 300 mg BID | Change From Baseline in Carbon Monoxide at Week 24 | Change at Week 24 | -1.706 percentage Hb bound to carbon monoxide | Standard Deviation 3.2742 |
Secondary
Change From Baseline in Carbon Monoxide Over the Duration of the Extension Period
Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased carbon monoxide values indicate improvement.
Time frame: Up to approximately 8.5 years
Secondary
Change From Baseline in EPO Over the Duration of the Extension Period
Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased EPO values indicate improvement.
Time frame: Up to approximately 8.5 years
Secondary
Change From Baseline in Erythropoietin (EPO) at Week 24
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased EPO values indicate improvement.
Time frame: Baseline and Week 24
Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Change From Baseline in Erythropoietin (EPO) at Week 24 | Baseline | 85.448 international units per liter (IU/L) | Standard Deviation 159.409 |
| AG-348 50 mg BID | Change From Baseline in Erythropoietin (EPO) at Week 24 | Change at Week 24 | -7.738 international units per liter (IU/L) | Standard Deviation 33.1934 |
| AG-348 300 mg BID | Change From Baseline in Erythropoietin (EPO) at Week 24 | Baseline | 60.900 international units per liter (IU/L) | Standard Deviation 19.5188 |
| AG-348 300 mg BID | Change From Baseline in Erythropoietin (EPO) at Week 24 | Change at Week 24 | -13.675 international units per liter (IU/L) | Standard Deviation 26.5065 |
Secondary
Change From Baseline in Ferritin at Week 24
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased ferritin values indicate improvement.
Time frame: Baseline and Week 24
Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Change From Baseline in Ferritin at Week 24 | Baseline | 860.852 ng/mL | Standard Deviation 682.6346 |
| AG-348 50 mg BID | Change From Baseline in Ferritin at Week 24 | Change at Week 24 | 68.875 ng/mL | Standard Deviation 388.1866 |
| AG-348 300 mg BID | Change From Baseline in Ferritin at Week 24 | Baseline | 859.680 ng/mL | Standard Deviation 490.2734 |
| AG-348 300 mg BID | Change From Baseline in Ferritin at Week 24 | Change at Week 24 | -37.870 ng/mL | Standard Deviation 308.0896 |
Secondary
Change From Baseline in Ferritin Over the Duration of the Extension Period
Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased ferritin values indicate improvement.
Time frame: Up to approximately 8.5 years
Secondary
Change From Baseline in Haptoglobin at Week 24
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased haptoglobin values indicate improvement.
Time frame: Baseline and Week 24
Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Change From Baseline in Haptoglobin at Week 24 | Baseline | 0.246 gram per liter (g/L) | Standard Deviation 0.1474 |
| AG-348 50 mg BID | Change From Baseline in Haptoglobin at Week 24 | Change at Week 24 | 0.128 gram per liter (g/L) | Standard Deviation 0.2845 |
| AG-348 300 mg BID | Change From Baseline in Haptoglobin at Week 24 | Baseline | 0.240 gram per liter (g/L) | Standard Deviation 0.2082 |
| AG-348 300 mg BID | Change From Baseline in Haptoglobin at Week 24 | Change at Week 24 | 0.139 gram per liter (g/L) | Standard Deviation 0.2726 |
Secondary
Change From Baseline in Haptoglobin Over the Duration of the Extension Period
Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Increased haptoglobin values indicate improvement.
Time frame: Up to approximately 8.5 years
Secondary
Change From Baseline in Hb Value Over the Duration of the Extension Period
Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Increased Hb values indicate improvement.
Time frame: Up to approximately 8.5 years
Secondary
Change From Baseline in Hematocrit at Week 24
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased hematocrit values indicate improvement.
Time frame: Baseline and Week 24
Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Change From Baseline in Hematocrit at Week 24 | Baseline | 0.289 volume per volume (V/V) | Standard Deviation 0.047 |
| AG-348 50 mg BID | Change From Baseline in Hematocrit at Week 24 | Change at Week 24 | 0.033 volume per volume (V/V) | Standard Deviation 0.0414 |
| AG-348 300 mg BID | Change From Baseline in Hematocrit at Week 24 | Baseline | 0.268 volume per volume (V/V) | Standard Deviation 0.0367 |
| AG-348 300 mg BID | Change From Baseline in Hematocrit at Week 24 | Change at Week 24 | 0.045 volume per volume (V/V) | Standard Deviation 0.0499 |
Secondary
Change From Baseline in Hematocrit Over the Duration of the Extension Period
Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Increased hematocrit values indicate improvement.
Time frame: Up to approximately 8.5 years
Secondary
Change From Baseline in Hemoglobin (Hb) Value at Week 24
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased Hb values indicate improvement.
Time frame: Baseline and Week 24
Population: The Efficacy Analysis Set included all participants who enrolled and received any study treatment for at least 3 weeks. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Change From Baseline in Hemoglobin (Hb) Value at Week 24 | Baseline | 9.243 grams per deciliter (g/dL) | Standard Deviation 1.4757 |
| AG-348 50 mg BID | Change From Baseline in Hemoglobin (Hb) Value at Week 24 | Change at Week 24 | 1.205 grams per deciliter (g/dL) | Standard Deviation 1.4181 |
| AG-348 300 mg BID | Change From Baseline in Hemoglobin (Hb) Value at Week 24 | Baseline | 8.636 grams per deciliter (g/dL) | Standard Deviation 1.1664 |
| AG-348 300 mg BID | Change From Baseline in Hemoglobin (Hb) Value at Week 24 | Change at Week 24 | 1.611 grams per deciliter (g/dL) | Standard Deviation 1.7058 |
Secondary
Change From Baseline in Hepcidin at Week 24
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased hepcidin values indicate improvement.
Time frame: Baseline and Week 24
Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Change From Baseline in Hepcidin at Week 24 | Baseline | 3.392 nanomoles per liter (nmol/L) | Standard Deviation 3.4013 |
| AG-348 50 mg BID | Change From Baseline in Hepcidin at Week 24 | Change at Week 24 | 0.095 nanomoles per liter (nmol/L) | Standard Deviation 1.4795 |
| AG-348 300 mg BID | Change From Baseline in Hepcidin at Week 24 | Baseline | 4.988 nanomoles per liter (nmol/L) | Standard Deviation 4.0416 |
| AG-348 300 mg BID | Change From Baseline in Hepcidin at Week 24 | Change at Week 24 | -2.310 nanomoles per liter (nmol/L) | Standard Deviation 2.5061 |
Secondary
Change From Baseline in Hepcidin Over the Duration of the Extension Period
Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased hepcidin values indicate improvement.
Time frame: Up to approximately 8.5 years
Secondary
Change From Baseline in Indirect Bilirubin at Week 24
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased indirect bilirubin values indicate improvement.
Time frame: Baseline and Week 24
Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Change From Baseline in Indirect Bilirubin at Week 24 | Baseline | 4.752 mg/dL | Standard Deviation 2.3629 |
| AG-348 50 mg BID | Change From Baseline in Indirect Bilirubin at Week 24 | Change at Week 24 | -1.967 mg/dL | Standard Deviation 1.8318 |
| AG-348 300 mg BID | Change From Baseline in Indirect Bilirubin at Week 24 | Baseline | 5.208 mg/dL | Standard Deviation 3.4272 |
| AG-348 300 mg BID | Change From Baseline in Indirect Bilirubin at Week 24 | Change at Week 24 | -3.195 mg/dL | Standard Deviation 2.5537 |
Secondary
Change From Baseline in Indirect Bilirubin Over the Duration of the Extension Period
Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased indirect bilirubin values indicate improvement.
Time frame: Up to approximately 8.5 years
Secondary
Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased LDH values indicate improvement.
Time frame: Baseline and Week 24
Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 | Baseline | 282.074 units per liter (U/L) | Standard Deviation 188.3558 |
| AG-348 50 mg BID | Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 | Change at Week 24 | -26.292 units per liter (U/L) | Standard Deviation 145.3151 |
| AG-348 300 mg BID | Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 | Baseline | 254.840 units per liter (U/L) | Standard Deviation 122.3587 |
| AG-348 300 mg BID | Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 | Change at Week 24 | -8.913 units per liter (U/L) | Standard Deviation 139.8509 |
Secondary
Change From Baseline in LDH Over the Duration of the Extension Period
Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased LDH values indicate improvement.
Time frame: Up to approximately 8.5 years
Secondary
Change From Baseline in Reticulocyte Count at Week 24
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased reticulocyte count values indicate improvement.
Time frame: Baseline and Week 24
Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Change From Baseline in Reticulocyte Count at Week 24 | Baseline | 493.248 cells * 10^9/liter | Standard Deviation 234.2242 |
| AG-348 50 mg BID | Change From Baseline in Reticulocyte Count at Week 24 | Change at Week 24 | -99.248 cells * 10^9/liter | Standard Deviation 309.9473 |
| AG-348 300 mg BID | Change From Baseline in Reticulocyte Count at Week 24 | Baseline | 549.436 cells * 10^9/liter | Standard Deviation 291.5301 |
| AG-348 300 mg BID | Change From Baseline in Reticulocyte Count at Week 24 | Change at Week 24 | -46.222 cells * 10^9/liter | Standard Deviation 351.9823 |
Secondary
Change From Baseline in Reticulocyte Count Over the Duration of the Extension Period
Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased reticulocyte count values indicate improvement.
Time frame: Up to approximately 8.5 years
Secondary
Change From Baseline in Total Bilirubin at Week 24
Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased total bilirubin values indicate improvement.
Time frame: Baseline and Week 24
Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Change From Baseline in Total Bilirubin at Week 24 | Baseline | 5.152 milligrams per deciliter (mg/dL) | Standard Deviation 2.3407 |
| AG-348 50 mg BID | Change From Baseline in Total Bilirubin at Week 24 | Change at Week 24 | -1.921 milligrams per deciliter (mg/dL) | Standard Deviation 1.9465 |
| AG-348 300 mg BID | Change From Baseline in Total Bilirubin at Week 24 | Baseline | 5.608 milligrams per deciliter (mg/dL) | Standard Deviation 3.4625 |
| AG-348 300 mg BID | Change From Baseline in Total Bilirubin at Week 24 | Change at Week 24 | -3.017 milligrams per deciliter (mg/dL) | Standard Deviation 2.5848 |
Secondary
Change From Baseline in Total Bilirubin Over the Duration of the Extension Period
Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased total bilirubin values indicate improvement.
Time frame: Up to approximately 8.5 years
Secondary
Change From Baseline in Transferrin Saturation at Week 24
Transferrin saturation is the ratio of serum iron to iron-binding capacity. Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased transferrin saturation values indicate improvement.
Time frame: Baseline and Week 24
Population: The Safety Analysis Set included all participants who had received at least one dose of study drug. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Change From Baseline in Transferrin Saturation at Week 24 | Baseline | 50.143 percentage of saturation | Standard Deviation 23.7388 |
| AG-348 50 mg BID | Change From Baseline in Transferrin Saturation at Week 24 | Change at Week 24 | -3.625 percentage of saturation | Standard Deviation 16.1777 |
| AG-348 300 mg BID | Change From Baseline in Transferrin Saturation at Week 24 | Baseline | 64.292 percentage of saturation | Standard Deviation 22.0779 |
| AG-348 300 mg BID | Change From Baseline in Transferrin Saturation at Week 24 | Change at Week 24 | -5.750 percentage of saturation | Standard Deviation 19.8968 |
Secondary
Change From Baseline in Transferrin Saturation Over the Duration of the Extension Period
Transferrin saturation is the ratio of serum iron to iron-binding capacity. Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased transferrin saturation values indicate improvement.
Time frame: Up to approximately 8.5 years
Secondary
Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for 2,3 - Diphosphoglycerate (2,3-DPG)
Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline.
Time frame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
Population: The PD Analysis Set included all participants from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess PD parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for 2,3 - Diphosphoglycerate (2,3-DPG) | Change at Day 1 | 42.25 microgram per milliliter (µg/mL) | Standard Deviation 38.836 |
| AG-348 50 mg BID | Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for 2,3 - Diphosphoglycerate (2,3-DPG) | Change at Day 15 | -65.50 microgram per milliliter (µg/mL) | Standard Deviation 69.745 |
| AG-348 300 mg BID | Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for 2,3 - Diphosphoglycerate (2,3-DPG) | Change at Day 1 | 59.57 microgram per milliliter (µg/mL) | Standard Deviation 58.569 |
| AG-348 300 mg BID | Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for 2,3 - Diphosphoglycerate (2,3-DPG) | Change at Day 15 | 8.200 microgram per milliliter (µg/mL) | Standard Deviation 195.13 |
Secondary
Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP)
Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline.
Time frame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
Population: The Pharmacodynamic (PD) Analysis Set included all participants from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess PD parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP) | Change at Day 1 | 16.50 µg/mL | Standard Deviation 11.79 |
| AG-348 50 mg BID | Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP) | Change at Day 15 | 1.500 µg/mL | Standard Deviation 31.032 |
| AG-348 300 mg BID | Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP) | Change at Day 1 | 20.67 µg/mL | Standard Deviation 6.8896 |
| AG-348 300 mg BID | Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP) | Change at Day 15 | 45.50 µg/mL | Standard Deviation 60.995 |
Secondary
Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702
Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.
Time frame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
Population: The Pharmacokinetic Analysis Set included all participants from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess pharmacokinetic parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| AG-348 50 mg BID | Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 | Day 1: AG-348 | 870.0 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 9.2 |
| AG-348 50 mg BID | Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 | Day 15: AG-348 | 943.4 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 30.7 |
| AG-348 50 mg BID | Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 | Day 1: AGI-8702 | 41.03 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 43.6 |
| AG-348 50 mg BID | Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 | Day 15: AGI-8702 | 71.94 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 22 |
| AG-348 300 mg BID | Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 | Day 15: AGI-8702 | 533.7 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 25.6 |
| AG-348 300 mg BID | Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 | Day 1: AG-348 | 7606 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 41.8 |
| AG-348 300 mg BID | Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 | Day 1: AGI-8702 | 414.7 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 35.6 |
| AG-348 300 mg BID | Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 | Day 15: AG-348 | 5259 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 35.6 |
Secondary
Percentage of Participants Experiencing at Least One AE Over the Duration of the Extension Period
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug-related.
Time frame: Up to approximately 8.5 years
Secondary
Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702
Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.
Time frame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15
Population: The Pharmacokinetic Analysis Set included all participants from Core Period, without major protocol violation, who were enrolled and received any dose of study treatment, with sufficient plasma sample or whole blood data to assess pharmacokinetic parameters. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AG-348 50 mg BID | Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 | Day 1: AG-348 | 1.92 hour (hr) |
| AG-348 50 mg BID | Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 | Day 15: AG-348 | 1.00 hour (hr) |
| AG-348 50 mg BID | Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 | Day 1: AGI-8702 | 2.00 hour (hr) |
| AG-348 50 mg BID | Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 | Day 15: AGI-8702 | 2.00 hour (hr) |
| AG-348 300 mg BID | Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 | Day 15: AGI-8702 | 1.00 hour (hr) |
| AG-348 300 mg BID | Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 | Day 1: AG-348 | 1.97 hour (hr) |
| AG-348 300 mg BID | Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 | Day 1: AGI-8702 | 1.97 hour (hr) |
| AG-348 300 mg BID | Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 | Day 15: AG-348 | 1.00 hour (hr) |