EFFECTS OF AG-348, A PYRUVATE KINASE ACTIVATOR, ON ANEMIA AND HEMOLYSIS IN PATIENTS WITH PYRUVATE KINASE DEFICIENCY: EARLY DATA FROM THE DRIVE PK STUDY
(Abstract release date: 05/19/16)
EHA Library. F Grace R. 06/11/16; 135222; S466
Dr. Rachael F Grace
Contributions
Contributions
Abstract
Abstract: S466
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Hall C14
Background
Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by deficiency of the glycolytic enzyme red cell PK (PK-R), required for maintenance of adenosine triphosphate (ATP) in red blood cells. AG-348 is an orally-available, small molecule, allosteric activator of PK-R that activates wild-type and a range of mutated PK-R enzymes in vitro and increases PK-R activity and restores ATP levels in red blood cells from patients with PK deficiency ex vivo.
Aims
To describe early data from the ongoing DRIVE PK study (NCT02476916), an open-label, dose-ranging trial of AG-348 in transfusion-independent adults with PK deficiency.
Methods
After providing informed consent, patients are randomized to AG-348 50 mg or 300 mg orally twice daily (BID) for 6 months. Transfusion independence is defined as no more than 3 units of red blood cells transfused in the 12 months preceding first dose and no transfusions in the 4 months preceding first dose. Patients are followed weekly for Weeks 1–3, then every 3 weeks until Week 12, and then monthly until Week 24. Hormone and iron status are evaluated at Baseline, Week 12 and End of Study.
Results
As of 15 Jan 2016, 10 patients have received treatment for between 1 and 24 weeks. Adverse events (AEs) have been mild-to-moderate, with nausea (CTCAE Grade 1–2) the most commonly reported AE: 2 out of 5 (40%) patients in the 50 mg BID arm and 3 out of 5 (60%) patients in the 300 mg BID arm. No serious AEs have been reported. There have been no dose modifications for AEs. A single patient has had dose modifications for an increase in hemoglobin (Hb) above the protocol mandated maximum. Dosing was temporarily interrupted and reduced twice (100 mg BID, then 50 mg BID) and the patient has since been maintained on 50 mg BID for several weeks. Pharmacokinetic data showed exposure in line with expectations from earlier healthy volunteer studies with AG-348 for both doses. At data cutoff, pharmacodynamic analysis of 2,3-diphosphoglycerate (2,3-DPG) and ATP was available for 5 patients. Baseline 2,3-DPG levels were elevated in 4 of 5 patients, as expected. All patients with a Hb response of ≥1.5 g/dL also showed a substantial decrease in 2,3-DPG levels. Further data are being collected to evaluate relationships between hematological parameters and pharmacodynamic markers (2,3-DPG and ATP). Genotype–response relationships are also being assessed.
Conclusion
Early clinical data from DRIVE-PK indicate that AG-348 is well tolerated. Data on all patients (n~15–20), including safety, hematological responses, pharmacodynamic effects and genotype–response relationships will be presented.
Session topic: Red blood cells and iron - Clinical
Keyword(s): Clinical trial, Hemolytic anemia, Treatment
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Hall C14
Background
Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by deficiency of the glycolytic enzyme red cell PK (PK-R), required for maintenance of adenosine triphosphate (ATP) in red blood cells. AG-348 is an orally-available, small molecule, allosteric activator of PK-R that activates wild-type and a range of mutated PK-R enzymes in vitro and increases PK-R activity and restores ATP levels in red blood cells from patients with PK deficiency ex vivo.
Aims
To describe early data from the ongoing DRIVE PK study (NCT02476916), an open-label, dose-ranging trial of AG-348 in transfusion-independent adults with PK deficiency.
Methods
After providing informed consent, patients are randomized to AG-348 50 mg or 300 mg orally twice daily (BID) for 6 months. Transfusion independence is defined as no more than 3 units of red blood cells transfused in the 12 months preceding first dose and no transfusions in the 4 months preceding first dose. Patients are followed weekly for Weeks 1–3, then every 3 weeks until Week 12, and then monthly until Week 24. Hormone and iron status are evaluated at Baseline, Week 12 and End of Study.
Results
As of 15 Jan 2016, 10 patients have received treatment for between 1 and 24 weeks. Adverse events (AEs) have been mild-to-moderate, with nausea (CTCAE Grade 1–2) the most commonly reported AE: 2 out of 5 (40%) patients in the 50 mg BID arm and 3 out of 5 (60%) patients in the 300 mg BID arm. No serious AEs have been reported. There have been no dose modifications for AEs. A single patient has had dose modifications for an increase in hemoglobin (Hb) above the protocol mandated maximum. Dosing was temporarily interrupted and reduced twice (100 mg BID, then 50 mg BID) and the patient has since been maintained on 50 mg BID for several weeks. Pharmacokinetic data showed exposure in line with expectations from earlier healthy volunteer studies with AG-348 for both doses. At data cutoff, pharmacodynamic analysis of 2,3-diphosphoglycerate (2,3-DPG) and ATP was available for 5 patients. Baseline 2,3-DPG levels were elevated in 4 of 5 patients, as expected. All patients with a Hb response of ≥1.5 g/dL also showed a substantial decrease in 2,3-DPG levels. Further data are being collected to evaluate relationships between hematological parameters and pharmacodynamic markers (2,3-DPG and ATP). Genotype–response relationships are also being assessed.
Conclusion
Early clinical data from DRIVE-PK indicate that AG-348 is well tolerated. Data on all patients (n~15–20), including safety, hematological responses, pharmacodynamic effects and genotype–response relationships will be presented.
Session topic: Red blood cells and iron - Clinical
Keyword(s): Clinical trial, Hemolytic anemia, Treatment
Abstract: S466
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Hall C14
Background
Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by deficiency of the glycolytic enzyme red cell PK (PK-R), required for maintenance of adenosine triphosphate (ATP) in red blood cells. AG-348 is an orally-available, small molecule, allosteric activator of PK-R that activates wild-type and a range of mutated PK-R enzymes in vitro and increases PK-R activity and restores ATP levels in red blood cells from patients with PK deficiency ex vivo.
Aims
To describe early data from the ongoing DRIVE PK study (NCT02476916), an open-label, dose-ranging trial of AG-348 in transfusion-independent adults with PK deficiency.
Methods
After providing informed consent, patients are randomized to AG-348 50 mg or 300 mg orally twice daily (BID) for 6 months. Transfusion independence is defined as no more than 3 units of red blood cells transfused in the 12 months preceding first dose and no transfusions in the 4 months preceding first dose. Patients are followed weekly for Weeks 1–3, then every 3 weeks until Week 12, and then monthly until Week 24. Hormone and iron status are evaluated at Baseline, Week 12 and End of Study.
Results
As of 15 Jan 2016, 10 patients have received treatment for between 1 and 24 weeks. Adverse events (AEs) have been mild-to-moderate, with nausea (CTCAE Grade 1–2) the most commonly reported AE: 2 out of 5 (40%) patients in the 50 mg BID arm and 3 out of 5 (60%) patients in the 300 mg BID arm. No serious AEs have been reported. There have been no dose modifications for AEs. A single patient has had dose modifications for an increase in hemoglobin (Hb) above the protocol mandated maximum. Dosing was temporarily interrupted and reduced twice (100 mg BID, then 50 mg BID) and the patient has since been maintained on 50 mg BID for several weeks. Pharmacokinetic data showed exposure in line with expectations from earlier healthy volunteer studies with AG-348 for both doses. At data cutoff, pharmacodynamic analysis of 2,3-diphosphoglycerate (2,3-DPG) and ATP was available for 5 patients. Baseline 2,3-DPG levels were elevated in 4 of 5 patients, as expected. All patients with a Hb response of ≥1.5 g/dL also showed a substantial decrease in 2,3-DPG levels. Further data are being collected to evaluate relationships between hematological parameters and pharmacodynamic markers (2,3-DPG and ATP). Genotype–response relationships are also being assessed.
Conclusion
Early clinical data from DRIVE-PK indicate that AG-348 is well tolerated. Data on all patients (n~15–20), including safety, hematological responses, pharmacodynamic effects and genotype–response relationships will be presented.
Session topic: Red blood cells and iron - Clinical
Keyword(s): Clinical trial, Hemolytic anemia, Treatment
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Hall C14
Background
Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by deficiency of the glycolytic enzyme red cell PK (PK-R), required for maintenance of adenosine triphosphate (ATP) in red blood cells. AG-348 is an orally-available, small molecule, allosteric activator of PK-R that activates wild-type and a range of mutated PK-R enzymes in vitro and increases PK-R activity and restores ATP levels in red blood cells from patients with PK deficiency ex vivo.
Aims
To describe early data from the ongoing DRIVE PK study (NCT02476916), an open-label, dose-ranging trial of AG-348 in transfusion-independent adults with PK deficiency.
Methods
After providing informed consent, patients are randomized to AG-348 50 mg or 300 mg orally twice daily (BID) for 6 months. Transfusion independence is defined as no more than 3 units of red blood cells transfused in the 12 months preceding first dose and no transfusions in the 4 months preceding first dose. Patients are followed weekly for Weeks 1–3, then every 3 weeks until Week 12, and then monthly until Week 24. Hormone and iron status are evaluated at Baseline, Week 12 and End of Study.
Results
As of 15 Jan 2016, 10 patients have received treatment for between 1 and 24 weeks. Adverse events (AEs) have been mild-to-moderate, with nausea (CTCAE Grade 1–2) the most commonly reported AE: 2 out of 5 (40%) patients in the 50 mg BID arm and 3 out of 5 (60%) patients in the 300 mg BID arm. No serious AEs have been reported. There have been no dose modifications for AEs. A single patient has had dose modifications for an increase in hemoglobin (Hb) above the protocol mandated maximum. Dosing was temporarily interrupted and reduced twice (100 mg BID, then 50 mg BID) and the patient has since been maintained on 50 mg BID for several weeks. Pharmacokinetic data showed exposure in line with expectations from earlier healthy volunteer studies with AG-348 for both doses. At data cutoff, pharmacodynamic analysis of 2,3-diphosphoglycerate (2,3-DPG) and ATP was available for 5 patients. Baseline 2,3-DPG levels were elevated in 4 of 5 patients, as expected. All patients with a Hb response of ≥1.5 g/dL also showed a substantial decrease in 2,3-DPG levels. Further data are being collected to evaluate relationships between hematological parameters and pharmacodynamic markers (2,3-DPG and ATP). Genotype–response relationships are also being assessed.
Conclusion
Early clinical data from DRIVE-PK indicate that AG-348 is well tolerated. Data on all patients (n~15–20), including safety, hematological responses, pharmacodynamic effects and genotype–response relationships will be presented.
Session topic: Red blood cells and iron - Clinical
Keyword(s): Clinical trial, Hemolytic anemia, Treatment
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