Transfusion-dependent Alpha-Thalassemia, Transfusion-dependent Beta-Thalassemia
Conditions
Brief summary
The primary objective of this study was to compare the effect of mitapivat versus placebo on transfusion burden in participants with α- or β-transfusion-dependent thalassemia.
Detailed description
The mitapivat group included 171 participants. The placebo group included 87 participants.
Interventions
Tablets
DRUGMitapivat
Tablets
Sponsors
Agios Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Greater than or equal to (≥)18 years of age at the time of providing informed consent; * Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene mutations, hemoglobin E (HbE)/β-thalassemia, or α-thalassemia/hemoglobin H (HbH) disease) based on deoxyribonucleic acid (DNA) analysis; * Considered transfusion-dependent, defined as 6 to 20 red blood cells (RBC) units transfused and ≤6-week transfusion-free period during the 24-week period before randomization; * If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization; * Women of childbearing potential (WOCBP) must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle or agree to use two forms of contraception, one of which must be considered highly effective, from the time of providing informed consent, throughout the study, and for 28 days after the last dose of study drug. The second form of contraception can be an acceptable barrier method; * Written informed consent before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.
Exclusion criteria
* Pregnant, breastfeeding, or parturient; * Documented history of homozygous or heterozygous sickle hemoglobin (Hb S) or hemoglobin C (Hb C); * Prior exposure to gene therapy or prior bone marrow or stem cell transplantation; * Currently receiving treatment with luspatercept; the last dose must have been administered ≥36 weeks before randomization; * Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥36 weeks before randomization; * History of malignancy (active or treated) ≤5 years before providing informed consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ; * History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent; * Hepatobiliary disorders; * Estimated glomerular filtration rate \<45 milliliters per minute (mL/min)/1.73 meter (m)\^2 by Chronic Kidney Disease Epidemiology Collaboration creatinine equation; * Nonfasting triglycerides \>440 milligrams per deciliter (mg/dL) (5 millimoles per liter \[mmol/L\]); * Active infection requiring systemic antimicrobial therapy at the time of providing informed consent; * Positive test for hepatitis C virus antibody (HCVAb) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg); * Positive test for human immunodeficiency virus (HIV)-1 antibody (Ab) or HIV-2 Ab; * History of major surgery (including splenectomy) ≤6 months before providing informed consent and/or a major surgical procedure planned during the study; * Current enrollment or past participation (≤12 weeks before administration of the first dose of study drug or a timeframe equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational treatment or device; * Receiving strong CYP3A4/5 inhibitors that have not been stopped for ≥5 days or a timeframe equivalent to 5 half-lives (whichever is longer); or strong CYP3A4 inducers that have not been stopped for ≥4 weeks or a timeframe equivalent to 5 half-lives (whichever is longer), before randomization; * Receiving anabolic steroids that have not been stopped for at least 4 weeks before randomization. Testosterone replacement therapy to treat hypogonadism is allowed. The testosterone dose and preparation must be stable for ≥12 weeks before randomization; * Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate, Opadry® II Blue \[hypromellose, titanium dioxide, lactose monohydrate, triacetin, and Federal Food, Drug, and Cosmetic (FD\&C) Blue #2\]); * Any medical, hematological, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data. Also excluded are: * Participants who are institutionalized by regulatory or court order * Participants with any condition(s) that could create undue influence (including but not limited to incarceration, involuntary psychiatric confinement, and financial or familial affiliation with the Investigator or Sponsor).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Double-blind Period: Percentage of Participants Who Achieved Transfusion Reduction Response (TRR) | Double-blind Period: Baseline through Week 48 | TRR is defined as ≥50% reduction in transfused red blood cells (RBC) units with a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline transfusion burden standardized to 12 weeks. Baseline transfusion burden standardized to 12 weeks= (12/24) × total number of RBC units transfused during 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 12 (Day 85) were considered nonresponders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Double-blind Period: Percentage of Participants Who Achieved TRR2 | Double-blind period: Baseline through Week 48 | TRR2, defined as a ≥50% reduction in transfused RBC units in any consecutive 24-week period through Week 48 compared with the 24-week baseline transfusion burden, is reported. Baseline transfusion burden standardized to 24 weeks is the total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 24 (Day 169) were considered nonresponders. |
| Double-blind Period: Percentage of Participants Who Achieved TRR3 | Double-blind period: Baseline up to Week 13 through Week 48 | TRR3, defined as a ≥33% reduction in transfused RBC units from Week 13 through Week 48 compared with the baseline transfusion burden standardized to 36 weeks, is reported. Baseline transfusion burden standardized to 36 weeks= (36/24) × total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 48 were considered nonresponders. |
| Double-blind Period: Percentage of Participants Who Achieved TRR4 | Double-blind period: Baseline up to Week 13 through Week 48 | TRR4, defined as a ≥50% reduction in transfused RBC units from Week 13 through Week 48 compared with the baseline transfusion burden standardized to 36 weeks, is reported. Baseline transfusion burden standardized to 36 weeks = (36/24) × total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 48 were considered nonresponders. |
| Double-blind Period: Percent Change From Baseline in Transfused RBC Units | Double-blind Period: Baseline, Week 13 through Week 48 | Transfusion burden from Week 13 through Week 48 standardized to 36 weeks is defined as number of transfused RBC units from Day 85 through Week 48 in the Double-blind Period ×36/(Number of days from Day 85 through Week 48 in the Double-blind Period/7). Baseline transfusion burden standardized to 36 weeks= (36/24)× is the total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or within 168 days before the start of study treatment for participants randomized and dosed. |
| Double-blind Period: Percentage of Participants Who Achieved Transfusion-Independence | Double-blind Period: Baseline through Week 48 | Transfusion-independence is defined as transfusion-free for ≥8 consecutive weeks through Week 48 in the double-blind period. |
| Double-blind Period: Change From Baseline in Iron Levels | Double-blind Period: Baseline through Week 48 | Iron metabolism was assessed based on Iron levels. |
| Double-blind Period: Change From Baseline in Serum Ferritin Levels | Double-blind Period: Baseline through Week 48 | Iron metabolism was assessed based on serum ferritin levels. |
| Double-blind Period: Change From Baseline in Total Iron Binding Capacity | Double-blind Period: Baseline through Week 48 | Iron metabolism was assessed based on total iron binding capacity. |
| Double-blind Period: Change From Baseline in Transferrin Saturation (TSAT) Levels | Double-blind Period: Baseline through Week 48 | Iron metabolism was assessed based on TSAT levels. Transferrin saturation is reported by dividing value of serum iron by total iron binding capacity. |
| Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Double-blind Period: From first dose of study drug up to week 48 | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and includes both serious \& non-serious TEAEs. Severity of AEs was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE. |
| Open-label Extension Period: Number of Participants With TEAEs, Serious TEAEs, Related TEAEs, Related TEAEs and TEAEs With Severity of Greater Than or Equal to 3 | Open-Label Extension Period: From Week 48 up to end of study (approximately 5 years) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and includes both serious \& non-serious TEAEs. Severity of abnormalities was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE. |
| Double-blind Period: Plasma Concentrations of Mitapivat | Double-blind Period: Pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36 | — |
| Double-blind Period: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of Mitapivat | Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36 | Area under the concentration-time curve from time zero to Tlast on dosing day, calculated using the linear-log trapezoidal rule. |
| Double-blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat | Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36 | — |
| Double-blind Period: Time to Reach of Maximum Observed Plasma Concentration (Tmax) of Mitapivat | Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36 | — |
| Double-blind Period: Time of Last Quantifiable Concentration (Tlast) of Mitapivat | Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36 | — |
| Double-blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat | Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36 | Clast is the last quantifiable concentration after a single dose or within the dosing interval (tau) for multiple doses. |
| Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | Double-blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36 | — |
| Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Double-blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36 | — |
Countries
Brazil, Bulgaria, Canada, Denmark, France, Germany, Greece, Italy, Lebanon, Malaysia, Netherlands, Saudi Arabia, Spain, Taiwan, Thailand, Turkey (Türkiye), United Arab Emirates, United Kingdom, United States
Contacts
STUDY_CHAIRMedical Affairs
Agios Pharmaceuticals, Inc.
Participant flow
Recruitment details
Participants took part at 81 study sites in Malaysia,Taiwan,Thailand,Bulgaria,Brazil,Lebanon,Saudi Arabia,Turkey,United Arab Emirates,Canada, the United States,Denmark,France,Germany,Greece,Italy,Netherlands,Spain and the United Kingdom.Results are reported for 48-week DB period until primary completion date.Analysis of data for OLE period is still ongoing with anticipated completion in June 2029.Results for OLE period will be reported by June 2030.
Pre-assignment details
A total of 305 participants with a diagnosis of Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-TDT) were screened. Of which, 258 were randomized and 257 received study treatment in this study.
Participants by arm
| Arm | Count |
|---|---|
| Mitapivat Participants randomized to receive mitapivat 100 mg, orally, BID for 48 weeks in double-blind period. | 171 |
| Placebo Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in double-blind period. | 87 |
| Total | 258 |
Baseline characteristics
| Characteristic | Total | Placebo | Mitapivat |
|---|---|---|---|
| Age, Continuous | 35.5 years STANDARD_DEVIATION 11.02 | 34.7 years STANDARD_DEVIATION 9.77 | 35.8 years STANDARD_DEVIATION 11.61 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 237 Participants | 79 Participants | 158 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 13 Participants | 5 Participants | 8 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 78 Participants | 22 Participants | 56 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Multiracial | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not reported | 11 Participants | 5 Participants | 6 Participants |
| Race/Ethnicity, Customized Unknown | 10 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 155 Participants | 56 Participants | 99 Participants |
| Sex: Female, Male Female | 136 Participants | 43 Participants | 93 Participants |
| Sex: Female, Male Male | 122 Participants | 44 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 171 | 0 / 87 |
| other Total, other adverse events | 122 / 172 | 50 / 85 |
| serious Total, serious adverse events | 19 / 172 | 13 / 85 |
Outcome results
Primary
Double-blind Period: Percentage of Participants Who Achieved Transfusion Reduction Response (TRR)
TRR is defined as ≥50% reduction in transfused red blood cells (RBC) units with a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline transfusion burden standardized to 12 weeks. Baseline transfusion burden standardized to 12 weeks= (12/24) × total number of RBC units transfused during 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 12 (Day 85) were considered nonresponders.
Time frame: Double-blind Period: Baseline through Week 48
Population: FAS included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitapivat | Double-blind Period: Percentage of Participants Who Achieved Transfusion Reduction Response (TRR) | 30.4 percentage of participants |
| Placebo | Double-blind Period: Percentage of Participants Who Achieved Transfusion Reduction Response (TRR) | 12.6 percentage of participants |
Comparison: The p-value is based on the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors.p-value: 0.000395% CI: [8, 27.2]Mantel Haenszel
Secondary
Double-blind Period: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of Mitapivat
Area under the concentration-time curve from time zero to Tlast on dosing day, calculated using the linear-log trapezoidal rule.
Time frame: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
Population: PK analysis set is a subset of the safety analysis set and included all participants with at least 1 plasma mitapivat concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-blind Period: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of Mitapivat | 4365.84 hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 35.9 |
Secondary
Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG)
Time frame: Double-blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
Population: PD analysis set is a subset of the safety analysis set and included all participants with at least 1 blood 2,3-diphosphoglycerate (2,3-DPG) or adenosine triphosphate (ATP) concentration measurement ≥LLQ. Number analyzed signifies those participants who were evaluable at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mitapivat | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose at Week 12 | 274.25 µg/mL | Standard Deviation 76.114 |
| Mitapivat | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 1 Hour Post-dose at Week 36 | 281.73 µg/mL | Standard Deviation 80.276 |
| Mitapivat | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose at Week 36 | 289.11 µg/mL | Standard Deviation 78.658 |
| Mitapivat | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 3 Hours Post-dose at Week 36 | 280.93 µg/mL | Standard Deviation 76.916 |
| Mitapivat | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose at Week 24 | 275.60 µg/mL | Standard Deviation 78.307 |
| Mitapivat | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 5 Hours Post-dose at Week 36 | 272.73 µg/mL | Standard Deviation 65.327 |
| Mitapivat | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 0.5 Hour Post-dose at Week 36 | 286.06 µg/mL | Standard Deviation 73.409 |
| Mitapivat | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 7 Hours Post-dose at Week 36 | 268.17 µg/mL | Standard Deviation 65.942 |
| Mitapivat | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose at Day 1 | 426.67 µg/mL | Standard Deviation 75.055 |
| Placebo | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 7 Hours Post-dose at Week 36 | 369.19 µg/mL | Standard Deviation 75.546 |
| Placebo | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose at Day 1 | 417.13 µg/mL | Standard Deviation 87.448 |
| Placebo | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose at Week 12 | 365.88 µg/mL | Standard Deviation 67.238 |
| Placebo | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose at Week 24 | 355.57 µg/mL | Standard Deviation 59.42 |
| Placebo | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose at Week 36 | 368.81 µg/mL | Standard Deviation 71.481 |
| Placebo | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 0.5 Hour Post-dose at Week 36 | 367.74 µg/mL | Standard Deviation 62.673 |
| Placebo | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 1 Hour Post-dose at Week 36 | 368.67 µg/mL | Standard Deviation 66.037 |
| Placebo | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 3 Hours Post-dose at Week 36 | 383.00 µg/mL | Standard Deviation 91.727 |
| Placebo | Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG) | 5 Hours Post-dose at Week 36 | 359.09 µg/mL | Standard Deviation 72.144 |
Secondary
Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP)
Time frame: Double-blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
Population: Pharmacodynamic (PD) analysis set is a subset of the safety analysis set and included all participants with at least 1 blood 2,3-diphosphoglycerate (DPG) or ATP concentration measurement ≥ LLQ. Number analyzed signifies those participants who were evaluable at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mitapivat | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 0.5 Hour Post-dose at Week 36 | 274.75 µg/mL | Standard Deviation 63.513 |
| Mitapivat | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 3 Hours Post-dose at Week 36 | 281.70 µg/mL | Standard Deviation 61.262 |
| Mitapivat | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 5 Hours Post-dose at Week 36 | 283.76 µg/mL | Standard Deviation 61.216 |
| Mitapivat | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 7 Hours Post-dose at Week 36 | 281.47 µg/mL | Standard Deviation 57.163 |
| Mitapivat | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | Pre-dose at Day 1 | 224.33 µg/mL | Standard Deviation 40.031 |
| Mitapivat | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | Pre-dose at Week 12 | 283.39 µg/mL | Standard Deviation 59.217 |
| Mitapivat | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | Pre-dose at Week 24 | 279.16 µg/mL | Standard Deviation 53.652 |
| Mitapivat | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | Pre-dose at Week 36 | 280.72 µg/mL | Standard Deviation 61.834 |
| Mitapivat | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 1 Hour Post-dose at Week 36 | 277.45 µg/mL | Standard Deviation 58.668 |
| Placebo | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | Pre-dose at Week 36 | 210.47 µg/mL | Standard Deviation 43.33 |
| Placebo | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 1 Hour Post-dose at Week 36 | 209.92 µg/mL | Standard Deviation 38.597 |
| Placebo | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | Pre-dose at Day 1 | 236.23 µg/mL | Standard Deviation 47.368 |
| Placebo | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 3 Hours Post-dose at Week 36 | 213.63 µg/mL | Standard Deviation 43.949 |
| Placebo | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | Pre-dose at Week 24 | 200.84 µg/mL | Standard Deviation 30.333 |
| Placebo | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 5 Hours Post-dose at Week 36 | 208.18 µg/mL | Standard Deviation 40.965 |
| Placebo | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | Pre-dose at Week 12 | 204.19 µg/mL | Standard Deviation 33.207 |
| Placebo | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 7 Hours Post-dose at Week 36 | 212.02 µg/mL | Standard Deviation 45.767 |
| Placebo | Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP) | 0.5 Hour Post-dose at Week 36 | 206.83 µg/mL | Standard Deviation 39.389 |
Secondary
Double-blind Period: Change From Baseline in Iron Levels
Iron metabolism was assessed based on Iron levels.
Time frame: Double-blind Period: Baseline through Week 48
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-blind Period: Change From Baseline in Iron Levels | -4.57 micromoles per liter (µmol/L) | Standard Error 0.949 |
| Placebo | Double-blind Period: Change From Baseline in Iron Levels | 2.06 micromoles per liter (µmol/L) | Standard Error 1.28 |
Secondary
Double-blind Period: Change From Baseline in Serum Ferritin Levels
Iron metabolism was assessed based on serum ferritin levels.
Time frame: Double-blind Period: Baseline through Week 48
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-blind Period: Change From Baseline in Serum Ferritin Levels | 45.3 micrograms per liter (µg/L) | Standard Error 88.9 |
| Placebo | Double-blind Period: Change From Baseline in Serum Ferritin Levels | 76.3 micrograms per liter (µg/L) | Standard Error 119.84 |
Secondary
Double-blind Period: Change From Baseline in Total Iron Binding Capacity
Iron metabolism was assessed based on total iron binding capacity.
Time frame: Double-blind Period: Baseline through Week 48
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-blind Period: Change From Baseline in Total Iron Binding Capacity | -21.80 µmol/L | Standard Error 3.597 |
| Placebo | Double-blind Period: Change From Baseline in Total Iron Binding Capacity | -1.23 µmol/L | Standard Error 5.053 |
Secondary
Double-blind Period: Change From Baseline in Transferrin Saturation (TSAT) Levels
Iron metabolism was assessed based on TSAT levels. Transferrin saturation is reported by dividing value of serum iron by total iron binding capacity.
Time frame: Double-blind Period: Baseline through Week 48
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-blind Period: Change From Baseline in Transferrin Saturation (TSAT) Levels | 0.079 Ratio | Standard Error 0.0261 |
| Placebo | Double-blind Period: Change From Baseline in Transferrin Saturation (TSAT) Levels | -0.013 Ratio | Standard Error 0.0371 |
Secondary
Double-blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat
Clast is the last quantifiable concentration after a single dose or within the dosing interval (tau) for multiple doses.
Time frame: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Population: PK analysis set is a subset of the safety analysis set and included all participants with at least 1 plasma mitapivat concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat | 175.76 ng/mL | Geometric Coefficient of Variation 85.1 |
Secondary
Double-blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat
Time frame: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Population: PK analysis set is a subset of the safety analysis set and included all participants with at least 1 plasma mitapivat concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat | 1603.00 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 45.6 |
Secondary
Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and includes both serious & non-serious TEAEs. Severity of AEs was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE.
Time frame: Double-blind Period: From first dose of study drug up to week 48
Population: Safety Analysis Set (SAS) included all participants who had received at least 1 dose of study treatment. Participants were classified according to the treatment received. If a participant was randomized to placebo and received at least 1 dose of mitapivat in the double-blind period, then the participant was classified to the mitapivat arm. One subject, randomized to placebo, received mitapivat and was classified in the mitapivat arm in the safety analysis set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mitapivat | Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with TEAEs | 155 Participants |
| Mitapivat | Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with TEAEs related to study drug | 65 Participants |
| Mitapivat | Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with serious TEAEs | 19 Participants |
| Mitapivat | Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with any TEAE of Grade ≥ 3 | 32 Participants |
| Placebo | Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with any TEAE of Grade ≥ 3 | 12 Participants |
| Placebo | Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with TEAEs | 71 Participants |
| Placebo | Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with serious TEAEs | 13 Participants |
| Placebo | Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3 | Participants with TEAEs related to study drug | 16 Participants |
Secondary
Double-blind Period: Percentage of Participants Who Achieved Transfusion-Independence
Transfusion-independence is defined as transfusion-free for ≥8 consecutive weeks through Week 48 in the double-blind period.
Time frame: Double-blind Period: Baseline through Week 48
Population: FAS included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitapivat | Double-blind Period: Percentage of Participants Who Achieved Transfusion-Independence | 9.9 percentage of participants |
| Placebo | Double-blind Period: Percentage of Participants Who Achieved Transfusion-Independence | 1.1 percentage of participants |
Secondary
Double-blind Period: Percentage of Participants Who Achieved TRR2
TRR2, defined as a ≥50% reduction in transfused RBC units in any consecutive 24-week period through Week 48 compared with the 24-week baseline transfusion burden, is reported. Baseline transfusion burden standardized to 24 weeks is the total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 24 (Day 169) were considered nonresponders.
Time frame: Double-blind period: Baseline through Week 48
Population: FAS included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitapivat | Double-blind Period: Percentage of Participants Who Achieved TRR2 | 13.5 percentage of participants |
| Placebo | Double-blind Period: Percentage of Participants Who Achieved TRR2 | 2.3 percentage of participants |
Comparison: The p-value is based on the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors.p-value: 0.000395% CI: [5.1, 17]Mantel Haenszel
Secondary
Double-blind Period: Percentage of Participants Who Achieved TRR3
TRR3, defined as a ≥33% reduction in transfused RBC units from Week 13 through Week 48 compared with the baseline transfusion burden standardized to 36 weeks, is reported. Baseline transfusion burden standardized to 36 weeks= (36/24) × total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 48 were considered nonresponders.
Time frame: Double-blind period: Baseline up to Week 13 through Week 48
Population: FAS included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitapivat | Double-blind Period: Percentage of Participants Who Achieved TRR3 | 14.6 percentage of participants |
| Placebo | Double-blind Period: Percentage of Participants Who Achieved TRR3 | 1.1 percentage of participants |
Comparison: The p-value is based on the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors.p-value: <0.000195% CI: [7.7, 19.1]Mantel Haenszel
Secondary
Double-blind Period: Percentage of Participants Who Achieved TRR4
TRR4, defined as a ≥50% reduction in transfused RBC units from Week 13 through Week 48 compared with the baseline transfusion burden standardized to 36 weeks, is reported. Baseline transfusion burden standardized to 36 weeks = (36/24) × total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 48 were considered nonresponders.
Time frame: Double-blind period: Baseline up to Week 13 through Week 48
Population: FAS included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitapivat | Double-blind Period: Percentage of Participants Who Achieved TRR4 | 7.6 percentage of participants |
| Placebo | Double-blind Period: Percentage of Participants Who Achieved TRR4 | 1.1 percentage of participants |
Comparison: The p-value is based on the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors.p-value: 0.005695% CI: [1.9, 10.9]Mantel Haenszel
Secondary
Double-blind Period: Percent Change From Baseline in Transfused RBC Units
Transfusion burden from Week 13 through Week 48 standardized to 36 weeks is defined as number of transfused RBC units from Day 85 through Week 48 in the Double-blind Period ×36/(Number of days from Day 85 through Week 48 in the Double-blind Period/7). Baseline transfusion burden standardized to 36 weeks= (36/24)× is the total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or within 168 days before the start of study treatment for participants randomized and dosed.
Time frame: Double-blind Period: Baseline, Week 13 through Week 48
Population: FAS included all participants who were randomized. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mitapivat | Double-blind Period: Percent Change From Baseline in Transfused RBC Units | 10.96 percent change | Standard Error 2.149 |
| Placebo | Double-blind Period: Percent Change From Baseline in Transfused RBC Units | 3.32 percent change | Standard Error 2.846 |
Secondary
Double-blind Period: Plasma Concentrations of Mitapivat
Time frame: Double-blind Period: Pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
Population: Pharmacokinetic (PK) Analysis Set included a subset of the safety analysis set and included all participants with at least 1 mitapivat plasma concentration measurement ≥ lower limit of quantification (LLQ). Number analyzed signifies those participants who were evaluable at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mitapivat | Double-blind Period: Plasma Concentrations of Mitapivat | Pre-dose at Week 36 | 129.31 nanograms per milliliter (ng/mL) | Standard Deviation 260.61 |
| Mitapivat | Double-blind Period: Plasma Concentrations of Mitapivat | 0.5 Hour Post-dose at Week 36 | 1282.21 nanograms per milliliter (ng/mL) | Standard Deviation 1007.068 |
| Mitapivat | Double-blind Period: Plasma Concentrations of Mitapivat | 1 Hour Post-dose at Week 36 | 1468.69 nanograms per milliliter (ng/mL) | Standard Deviation 713.248 |
| Mitapivat | Double-blind Period: Plasma Concentrations of Mitapivat | 3 Hours Post-dose at Week 36 | 765.32 nanograms per milliliter (ng/mL) | Standard Deviation 372.719 |
| Mitapivat | Double-blind Period: Plasma Concentrations of Mitapivat | 5 Hours Post-dose at Week 36 | 371.11 nanograms per milliliter (ng/mL) | Standard Deviation 232.556 |
| Mitapivat | Double-blind Period: Plasma Concentrations of Mitapivat | Pre-dose at Week 12 | 122.90 nanograms per milliliter (ng/mL) | Standard Deviation 252.666 |
| Mitapivat | Double-blind Period: Plasma Concentrations of Mitapivat | Pre-dose at Week 24 | 96.55 nanograms per milliliter (ng/mL) | Standard Deviation 184.835 |
| Mitapivat | Double-blind Period: Plasma Concentrations of Mitapivat | 7 Hours Post-dose at Week 36 | 221.78 nanograms per milliliter (ng/mL) | Standard Deviation 172.845 |
Secondary
Double-blind Period: Time of Last Quantifiable Concentration (Tlast) of Mitapivat
Time frame: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Population: PK analysis set is a subset of the safety analysis set and included all participants with at least 1 plasma mitapivat concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mitapivat | Double-blind Period: Time of Last Quantifiable Concentration (Tlast) of Mitapivat | 6.750 Hours |
Secondary
Double-blind Period: Time to Reach of Maximum Observed Plasma Concentration (Tmax) of Mitapivat
Time frame: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Population: PK analysis set is a subset of the safety analysis set and included all participants with at least 1 plasma mitapivat concentration measurement ≥LLQ. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mitapivat | Double-blind Period: Time to Reach of Maximum Observed Plasma Concentration (Tmax) of Mitapivat | 1.000 Hours |
Secondary
Open-label Extension Period: Number of Participants With TEAEs, Serious TEAEs, Related TEAEs, Related TEAEs and TEAEs With Severity of Greater Than or Equal to 3
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and includes both serious & non-serious TEAEs. Severity of abnormalities was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE.
Time frame: Open-Label Extension Period: From Week 48 up to end of study (approximately 5 years)