Anemia, Hemolytic, Pyruvate Kinase Deficiency
Conditions
Brief summary
Study AG348-C-006 evaluated the efficacy and safety of orally administered AG-348 as compared with placebo in participants with pyruvate kinase (PK) deficiency, who were not regularly receiving blood transfusions. Participants were randomized 1:1 to receive either AG-348 or a matching placebo.
Interventions
DRUGPlacebo
Placebo matching AG-348 tablets, administered to maintain the blind.
DRUGAG-348
AG-348 tablets.
Sponsors
Agios Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Informed consent; * Male or female, aged 18 years or older; * Documented clinical laboratory confirmation of pyruvate kinase (PK) deficiency, defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation; * Hemoglobin (Hb) concentration less than or equal to 10.0 grams per deciliter (g/dL) regardless of gender (average of at least 2 Hb measurements \[separated by a minimum of 7 days\] during the Screening Period) * Considered not regularly transfused, defined as having had no more than 4 transfusion episodes in the 12-month period up to the first day of study treatment and no transfusions in the 3 months prior to the first day of study treatment; * Received at least 0.8 mg oral folic acid daily for at least 21 days prior to the first dose of study treatment, to be continued daily during study participation. * Adequate organ function; * Women of reproductive potential, have a negative serum pregnancy test; * For women of reproductive potential as well as men with partners who are women of reproductive potential, be abstinent as part of their usual lifestyle, or agree to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of giving informed consent, during the study, and for 28 days following the last dose of study treatment for women and 90 days for men following the last dose of study treatment; * Willing to comply with all study procedures for the duration of the study;
Exclusion criteria
* Homozygous for the R479H mutation or have 2 non-missense mutations, without the presence of another missense mutation, in the PKLR gene; * Significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound the interpretation of the study data; * Splenectomy scheduled during the study treatment period or have undergone splenectomy within 12 months prior to signing informed consent; * Currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Prior and subsequent participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted however, concurrent participation is not; participants enrolling in this current study will be expected to temporarily suspend participation in the NHS or Registry; * Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study treatment; * Prior treatment with a pyruvate kinase activator; * Prior bone marrow or stem cell transplant; * Currently pregnant or breastfeeding; * History of major surgery within 6 months of signing informed consent; * Currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to the first dose of study treatment; * Currently receiving hematopoietic stimulating agents that have not been stopped for a duration of at least 28 days prior to the first dose of study treatment; * History of allergy to sulfonamides if characterized by acute hemolytic anemia, drug induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis, or other serious clinical manifestations; * History of allergy to AG-348 or its excipients; * Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR) | Baseline, Weeks 16, 20, 24 | Hemoglobin response (HR) is defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24. The baseline Hb concentration is the average of all available Hb concentrations for a participant during the Screening Period up to the first dose of study treatment. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24 | Baseline, Week 24 | The PKDD is a 7-item patient reported outcome (PRO) measure of the core signs and symptoms associated with PK deficiency in adults. Participants rate their experience with symptoms of PK deficiency on the present day. The symptoms include those associated with tiredness, jaundice, bone pain, shortness of breath, and energy level. The score ranges from 25 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDD weekly scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). |
| Time to Last Measurable Concentration (Tlast) for AG-348 | Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12) | — |
| Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | From first dose of mitapivat to the end of study, including follow-up (up to Day 197) | Predicted probability of experiencing all grade hot flush at the doses of 5, 20, and 50 mg mitapivat BID based on exposure-response model. |
| Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | Baseline, Week 24 | Predicted percent change from baseline at Week 24 in the sex hormone measures (total testosterone, free testosterone, and estrone) at the doses of 5, 20, and 50 mg mitapivat BID in male participants. |
| Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24 | Baseline, Weeks 16, 20, 24 | This is the change in Hb concentration at Weeks 16, 20 and 24 compared to baseline. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). |
| Maximum Change From Baseline in Hb Concentration | Baseline, up to Week 24 | This is the maximum change from baseline in Hb concentration up to Week 24. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). |
| Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More | Baseline, up to Week 24 | This is the time taken to first achieve an increase of hemoglobin concentration of 1.5 g/dL or more from baseline. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). |
| Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24 | Baseline, Weeks 16, 20, 24 | The change from baseline in indirect bilirubin levels was summarized. Indirect bilirubin is a marker for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). |
| Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24 | Baseline, Weeks 16, 20, 24 | The change from baseline in LDH levels was summarized. LDH is a marker for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). |
| Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24 | Baseline, Weeks 16, 20, 24 | The change from baseline in haptoglobin levels was summarized. Haptoglobin levels are markers for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). |
| Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24 | Baseline, Weeks 16, 20, 24 | The change from baseline in reticulocyte percentage was summarized. Reticulocyte levels are markers for hematopoietic activity. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). |
| Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24 | Baseline, Week 24 | The PKDIA is a 12-item patient reported outcome (PRO) measure of the common impacts of PK deficiency on activities of daily living. Participants rate how PK deficiency has impacted aspects of daily living in the past 7 days, including impacts on relationships; perceived appearance; work performance; and leisure, social, mental, and physical activities. The score range is 30 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDIA scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo). |
| Percentage of Participants With Adverse Events | From signing of informed consent form to the end of study, including follow-up (up to Day 197) | An AE is any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12 | Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12) | — |
| Maximum Plasma Concentration (Cmax) for AG-348 | Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12) | — |
| Time to Cmax (Tmax) for AG-348 | Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12) | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Bone Mineral Density T-Score at Week 24 | Baseline, Week 24 | — |
| Change From Baseline in Bone Mineral Density Z-Score at Week 24 | Baseline, Week 24 | — |
| Percentage of Participants With Adverse Events of Special Interest (AESI) | Through 4 weeks after last dose (approximately Week 31) | An AE is any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AESI can be serious or non-serious. |
Countries
Brazil, Canada, Czechia, Denmark, France, Germany, Italy, Japan, Netherlands, South Korea, Spain, Switzerland, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
A total of 80 participants were randomized in the study, which was conducted across multiple sites in 14 countries: Brazil, Canada, Denmark, France, Germany, Italy, Japan, Republic of Korea, Netherlands, Spain, Switzerland, Turkey, United Kingdom, and United States. The study was conducted from 9 August 2018 to 9 October 2020.
Pre-assignment details
Screening was done for a period of 42 days after the participant provided the informed consent. Investigators determined if the participants met all the inclusion criteria and none of the exclusion criteria to receive AG-348 or placebo to determine the optimized dose to be received for 12 weeks as fixed-dose.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Comparator: Placebo Participants received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose. | 40 |
| Experimental: AG-348, 5 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose. | 2 |
| Experimental: AG-348, 20 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose. | 3 |
| Experimental: AG-348, 50 mg Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose. | 35 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo Comparator: Placebo | Experimental: AG-348, 5 mg | Experimental: AG-348, 20 mg | Experimental: AG-348, 50 mg |
|---|---|---|---|---|---|
| Age, Continuous | 36.6 years STANDARD_DEVIATION 15.47 | 37.2 years STANDARD_DEVIATION 15.92 | 21.5 years STANDARD_DEVIATION 4.95 | 48.0 years STANDARD_DEVIATION 26.21 | 35.8 years STANDARD_DEVIATION 14.07 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 62 Participants | 34 Participants | 1 Participants | 2 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants | 5 Participants | 1 Participants | 1 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 3 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 4 Participants | 0 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) White | 60 Participants | 32 Participants | 2 Participants | 3 Participants | 23 Participants |
| Sex: Female, Male Female | 48 Participants | 24 Participants | 0 Participants | 2 Participants | 22 Participants |
| Sex: Female, Male Male | 32 Participants | 16 Participants | 2 Participants | 1 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 39 | 0 / 2 | 0 / 3 | 0 / 35 |
| other Total, other adverse events | 35 / 39 | 1 / 2 | 3 / 3 | 31 / 35 |
| serious Total, serious adverse events | 2 / 39 | 0 / 2 | 1 / 3 | 3 / 35 |
Outcome results
Primary
Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR)
Hemoglobin response (HR) is defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24. The baseline Hb concentration is the average of all available Hb concentrations for a participant during the Screening Period up to the first dose of study treatment. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time frame: Baseline, Weeks 16, 20, 24
Population: Full analysis set included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Comparator: Placebo | Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR) | 0 percentage of participants |
| Experimental: AG-348 | Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR) | 40.0 percentage of participants |
p-value: <0.0001Exact Cochran-Mantel-Haenszel
Secondary
Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12
Time frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Population: Pharmacokinetic analysis population consisted of all participants who were enrolled and received a dose of study medication (mitapivat) with at least 1 non-zero pharmacokinetic plasma concentration of mitapivat at the Week 12 visit. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: Placebo | Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12 | 565.9 h*ng/mL | — |
| Experimental: AG-348 | Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12 | 1481.2 h*ng/mL | Geometric Coefficient of Variation 26.9 |
| Experimental: AG-348 20 mg | Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12 | 2973.3 h*ng/mL | Geometric Coefficient of Variation 35.6 |
Secondary
Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24
The change from baseline in haptoglobin levels was summarized. Haptoglobin levels are markers for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time frame: Baseline, Weeks 16, 20, 24
Population: Full analysis set included all participants who were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: Placebo | Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24 | 0.012 g/L | Standard Error 0.0412 |
| Experimental: AG-348 | Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24 | 0.169 g/L | Standard Error 0.0408 |
p-value: 0.007995% CI: [0.043, 0.273]Mixed-effect Model Repeated Measure
Secondary
Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24
This is the change in Hb concentration at Weeks 16, 20 and 24 compared to baseline. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time frame: Baseline, Weeks 16, 20, 24
Population: Full analysis set included all participants who were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: Placebo | Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24 | -1.48 grams per liter (g/L) | Standard Error 2.082 |
| Experimental: AG-348 | Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24 | 16.73 grams per liter (g/L) | Standard Error 2.075 |
p-value: <0.000195% CI: [12.41, 24.01]Mixed-effect Model Repeated Measure
Secondary
Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24
The change from baseline in indirect bilirubin levels was summarized. Indirect bilirubin is a marker for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time frame: Baseline, Weeks 16, 20, 24
Population: Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: Placebo | Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24 | 5.10 micromoles per liter (μmol/L) | Standard Error 4.061 |
| Experimental: AG-348 | Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24 | -21.16 micromoles per liter (μmol/L) | Standard Error 4.228 |
p-value: <0.000195% CI: [-37.82, -14.7]Mixed-effect Model Repeated Measure
Secondary
Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24
The change from baseline in LDH levels was summarized. LDH is a marker for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time frame: Baseline, Weeks 16, 20, 24
Population: Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: Placebo | Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24 | -21.18 units per litre (U/L) | Standard Error 16.04 |
| Experimental: AG-348 | Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24 | -91.99 units per litre (U/L) | Standard Error 16.222 |
p-value: 0.002795% CI: [-115.88, -25.74]Mixed-effect Model Repeated Measure
Secondary
Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24
The change from baseline in reticulocyte percentage was summarized. Reticulocyte levels are markers for hematopoietic activity. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time frame: Baseline, Weeks 16, 20, 24
Population: Full analysis set included all participants who were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: Placebo | Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24 | 0.0038 Reticulocyte percentages | Standard Error 0.0139 |
| Experimental: AG-348 | Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24 | -0.0973 Reticulocyte percentages | Standard Error 0.01401 |
p-value: <0.000195% CI: [-0.1391, -0.0632]Mixed-effect Model Repeated Measure
Secondary
Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24
The PKDD is a 7-item patient reported outcome (PRO) measure of the core signs and symptoms associated with PK deficiency in adults. Participants rate their experience with symptoms of PK deficiency on the present day. The symptoms include those associated with tiredness, jaundice, bone pain, shortness of breath, and energy level. The score ranges from 25 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDD weekly scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time frame: Baseline, Week 24
Population: Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: Placebo | Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24 | -2.05 score on a scale | Standard Error 0.976 |
| Experimental: AG-348 | Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24 | -5.16 score on a scale | Standard Error 0.955 |
p-value: 0.024795% CI: [-5.8, -0.41]Mixed-effect Model Repeated Measure
Secondary
Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24
The PKDIA is a 12-item patient reported outcome (PRO) measure of the common impacts of PK deficiency on activities of daily living. Participants rate how PK deficiency has impacted aspects of daily living in the past 7 days, including impacts on relationships; perceived appearance; work performance; and leisure, social, mental, and physical activities. The score range is 30 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDIA scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time frame: Baseline, Week 24
Population: Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: Placebo | Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24 | -1.39 score on a scale | Standard Error 1.157 |
| Experimental: AG-348 | Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24 | -4.65 score on a scale | Standard Error 1.123 |
p-value: 0.042195% CI: [-6.39, -0.12]Mixed-effect Model Repeated Measure
Secondary
Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
Predicted percent change from baseline at Week 24 in the sex hormone measures (total testosterone, free testosterone, and estrone) at the doses of 5, 20, and 50 mg mitapivat BID in male participants.
Time frame: Baseline, Week 24
Population: Safety Set: Participants who were administered the study drug. Male participants who received mitapivat in studies: study AG348-C-003 (NCT02476916): 32 participants; study AG348-C-006 (NCT03548220):15 participants; study AG348-C-007 (NCT03559699): 7 participants; and study AG348-C-011 (NCT03853798): 14 participants were pooled for analysis of this outcome measure.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo Comparator: Placebo | Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | Free Testosterone | 6.01 Percent change |
| Placebo Comparator: Placebo | Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | Total Testosterone | 0.877 Percent change |
| Placebo Comparator: Placebo | Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | Estrone | -31.5 Percent change |
| Experimental: AG-348 | Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | Free Testosterone | 14.1 Percent change |
| Experimental: AG-348 | Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | Total Testosterone | 3.18 Percent change |
| Experimental: AG-348 | Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | Estrone | -56.5 Percent change |
| Experimental: AG-348 20 mg | Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | Total Testosterone | 7.59 Percent change |
| Experimental: AG-348 20 mg | Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | Estrone | -68.2 Percent change |
| Experimental: AG-348 20 mg | Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | Free Testosterone | 26 Percent change |
Secondary
Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
Predicted probability of experiencing all grade hot flush at the doses of 5, 20, and 50 mg mitapivat BID based on exposure-response model.
Time frame: From first dose of mitapivat to the end of study, including follow-up (up to Day 197)
Population: Safety Set: Participants who were administered the study drug. Participants who received mitapivat in studies: study AG348-C-003 (NCT02476916): 52 participants; study AG348-C-006 (NCT03548220): 40 participants; study AG348-C-007 (NCT03559699): 27 participants; and study AG348-C-011 (NCT03853798): 36 participants, were pooled for the analysis of this outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Comparator: Placebo | Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | 3.37 Percent probability |
| Experimental: AG-348 | Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | 4.03 Percent probability |
| Experimental: AG-348 20 mg | Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters | 5.5 Percent probability |
Secondary
Maximum Change From Baseline in Hb Concentration
This is the maximum change from baseline in Hb concentration up to Week 24. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time frame: Baseline, up to Week 24
Population: Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: Placebo | Maximum Change From Baseline in Hb Concentration | 4.76 g/L | Standard Deviation 4.217 |
| Experimental: AG-348 | Maximum Change From Baseline in Hb Concentration | 23.94 g/L | Standard Deviation 21.367 |
Secondary
Maximum Plasma Concentration (Cmax) for AG-348
Time frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Population: Pharmacokinetic analysis population consisted of all participants who were enrolled and received a dose of study medication (mitapivat) with at least 1 non-zero pharmacokinetic plasma concentration of mitapivat at the Week 12 visit. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: Placebo | Maximum Plasma Concentration (Cmax) for AG-348 | 156.9 Nanograms per milliliter (ng/mL) | — |
| Experimental: AG-348 | Maximum Plasma Concentration (Cmax) for AG-348 | 373.1 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 13.6 |
| Experimental: AG-348 20 mg | Maximum Plasma Concentration (Cmax) for AG-348 | 1033 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 31.2 |
Secondary
Percentage of Participants With Adverse Events
An AE is any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Time frame: From signing of informed consent form to the end of study, including follow-up (up to Day 197)
Population: Safety analysis set included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Comparator: Placebo | Percentage of Participants With Adverse Events | 89.7 percentage of participants |
| Experimental: AG-348 | Percentage of Participants With Adverse Events | 50.0 percentage of participants |
| Experimental: AG-348 20 mg | Percentage of Participants With Adverse Events | 100 percentage of participants |
| Experimental: AG-348 50 mg | Percentage of Participants With Adverse Events | 88.6 percentage of participants |
Secondary
Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More
This is the time taken to first achieve an increase of hemoglobin concentration of 1.5 g/dL or more from baseline. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time frame: Baseline, up to Week 24
Population: Full analysis set included all participants who were randomized. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: AG-348 | Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More | 7.66 weeks | Standard Deviation 4.05 |
Secondary
Time to Cmax (Tmax) for AG-348
Time frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Population: Pharmacokinetic analysis population consisted of all participants who were enrolled and received a dose of study medication (mitapivat) with at least 1 non-zero pharmacokinetic plasma concentration of mitapivat at the Week 12 visit. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo Comparator: Placebo | Time to Cmax (Tmax) for AG-348 | 0.75 hours (h) |
| Experimental: AG-348 | Time to Cmax (Tmax) for AG-348 | 1.02 hours (h) |
| Experimental: AG-348 20 mg | Time to Cmax (Tmax) for AG-348 | 0.50 hours (h) |
Secondary
Time to Last Measurable Concentration (Tlast) for AG-348
Time frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Population: Pharmacokinetic analysis population consisted of all participants who were enrolled and received a dose of study medication (mitapivat) with at least 1 non-zero pharmacokinetic plasma concentration of mitapivat at the Week 12 visit. Overall number of participants analyzed is the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: Placebo | Time to Last Measurable Concentration (Tlast) for AG-348 | 7.787 hours (h) | — |
| Experimental: AG-348 | Time to Last Measurable Concentration (Tlast) for AG-348 | 7.809 hours (h) | Geometric Coefficient of Variation 4.2 |
| Experimental: AG-348 20 mg | Time to Last Measurable Concentration (Tlast) for AG-348 | 7.162 hours (h) | Geometric Coefficient of Variation 28 |
Other Pre-specified
Change From Baseline in Bone Mineral Density T-Score at Week 24
Time frame: Baseline, Week 24
Other Pre-specified
Change From Baseline in Bone Mineral Density Z-Score at Week 24
Time frame: Baseline, Week 24
Other Pre-specified
Percentage of Participants With Adverse Events of Special Interest (AESI)
An AE is any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AESI can be serious or non-serious.
Time frame: Through 4 weeks after last dose (approximately Week 31)