Clinical trial data of PK activators for treatment of PK deficiency
| Clinical trial . | Study information . | Summary of main findings . | Authors, reference . |
|---|---|---|---|
| Healthy Volunteer Trial of Mitapivat | Phase 1, healthy volunteers | • One grade 3 TEAE in multiple ascending dose study at a dose of 700 mg every 12 hours (abnormal liver function tests). Hormone changes consistent with reversible, dose-dependent aromatase inhibition. • Pharmacodynamic profile: maximal decrease 2,3-BPG 24 hours postdose; maximal increase in ATP between 8-14 days of dosing, durable for 48-72 h after dosing supporting twice daily dosing. | Yang H, Merica E, Chen Y, et al.26 |
| Healthy Volunteer Trial of Etavopivat | Phase 1, healthy volunteers | • Treatment emergent events were mild to moderate; none led to discontinuation. No changes in hormone levels. • Pharmacodynamic profile: maximal decrease 2,3-BPG 24 hours postdose; maximal increase in ATP by day 8 of dosing, durable for 120 h after dosing supporting once daily dosing | Forsyth S, Schroeder P, Geib J, et al.37 |
| DRIVE-PK trial (mitapivat) | Phase 2, adults with PK deficiency, not regularly transfused (<4 transfusions in prior 12 months) | • 26/52 (50%) of adults had an increase in Hb ≥1 g/dL; mean maximum Hb increase 3.4 g/dL • Increase in Hb occurred in median of 10 days. • Genotype-hemoglobin response relationship with all Hb responders with at least one missense PKLR mutation. • Well-tolerated, most common adverse events were headaches, insomnia, nausea, generally resolving within 1 week. Rebound hemolysis seen with abrupt discontinuation of drug. | Grace RF, Rose C, Layton MD, et al.29 |
| ACTIVATE trial (mitapivat) | Phase 3, adults with PK deficiency, not regularly transfused (<4 transfusions in prior 12 months) and at least one missense PKLR mutation | • 16/40 (40%) receiving mitapivat met the primary endpoint (Hb ≥1.5 g/dL, at least 2 timepoints) compared with 0/40 (0%) receiving placebo • Hemoglobin increase correlated with improvements in markers of hemolysis and hematopoiesis and disease-specific patient reported outcome measures. • Well-tolerated; adverse events (most common: nausea, headache) were similar in the placebo and mitapivat arms. | Al-Samkari H, Galactéros F, Glenthøj A, et al.30 |
| ACTIVATE-T trial (mitapivat) | Phase 3, adults with PK deficiency receiving ≥6 transfusions in prior 12 months and at least 1 missense PKLR mutation | • 10/27 (37%) of adults receiving mitapivat with ≥33% reduction in transfusion burden. • 6/27 (22%) transfusion free after starting mitapivat. • Adverse events included headache, nausea, increase in liver enzymes. | Glenthøj A, van Beers EJ, Al-Samkari H, et al.31 |
| ACTIVATE/ACTIVATE-T open label long-term extension study (mitapivat) | Extension study of ACTIVATE/ACTIVATE-T trials | • ACTIVATE: 39.5% (15/38) randomized to placebo had a Hb response after switching to mitapivat; response by hemoglobin, hemolytic markers, and patient-reported outcomes has been sustained for more than 3 years in the majority. • ACTIVATE-T: 37% (10/27) have met criteria for transfusion response for more than 3 years; 6 patients have remained transfusion free for more than 3 years. • Well-tolerated, no new safety findings. • Decrease in iron overload by liver iron concentration and other iron markers seen in both studies with ongoing improvements over time. • Sustained stability in bone mineral density by DXA scan. | Multiple references32-36 |
| Clinical trial . | Study information . | Summary of main findings . | Authors, reference . |
|---|---|---|---|
| Healthy Volunteer Trial of Mitapivat | Phase 1, healthy volunteers | • One grade 3 TEAE in multiple ascending dose study at a dose of 700 mg every 12 hours (abnormal liver function tests). Hormone changes consistent with reversible, dose-dependent aromatase inhibition. • Pharmacodynamic profile: maximal decrease 2,3-BPG 24 hours postdose; maximal increase in ATP between 8-14 days of dosing, durable for 48-72 h after dosing supporting twice daily dosing. | Yang H, Merica E, Chen Y, et al.26 |
| Healthy Volunteer Trial of Etavopivat | Phase 1, healthy volunteers | • Treatment emergent events were mild to moderate; none led to discontinuation. No changes in hormone levels. • Pharmacodynamic profile: maximal decrease 2,3-BPG 24 hours postdose; maximal increase in ATP by day 8 of dosing, durable for 120 h after dosing supporting once daily dosing | Forsyth S, Schroeder P, Geib J, et al.37 |
| DRIVE-PK trial (mitapivat) | Phase 2, adults with PK deficiency, not regularly transfused (<4 transfusions in prior 12 months) | • 26/52 (50%) of adults had an increase in Hb ≥1 g/dL; mean maximum Hb increase 3.4 g/dL • Increase in Hb occurred in median of 10 days. • Genotype-hemoglobin response relationship with all Hb responders with at least one missense PKLR mutation. • Well-tolerated, most common adverse events were headaches, insomnia, nausea, generally resolving within 1 week. Rebound hemolysis seen with abrupt discontinuation of drug. | Grace RF, Rose C, Layton MD, et al.29 |
| ACTIVATE trial (mitapivat) | Phase 3, adults with PK deficiency, not regularly transfused (<4 transfusions in prior 12 months) and at least one missense PKLR mutation | • 16/40 (40%) receiving mitapivat met the primary endpoint (Hb ≥1.5 g/dL, at least 2 timepoints) compared with 0/40 (0%) receiving placebo • Hemoglobin increase correlated with improvements in markers of hemolysis and hematopoiesis and disease-specific patient reported outcome measures. • Well-tolerated; adverse events (most common: nausea, headache) were similar in the placebo and mitapivat arms. | Al-Samkari H, Galactéros F, Glenthøj A, et al.30 |
| ACTIVATE-T trial (mitapivat) | Phase 3, adults with PK deficiency receiving ≥6 transfusions in prior 12 months and at least 1 missense PKLR mutation | • 10/27 (37%) of adults receiving mitapivat with ≥33% reduction in transfusion burden. • 6/27 (22%) transfusion free after starting mitapivat. • Adverse events included headache, nausea, increase in liver enzymes. | Glenthøj A, van Beers EJ, Al-Samkari H, et al.31 |
| ACTIVATE/ACTIVATE-T open label long-term extension study (mitapivat) | Extension study of ACTIVATE/ACTIVATE-T trials | • ACTIVATE: 39.5% (15/38) randomized to placebo had a Hb response after switching to mitapivat; response by hemoglobin, hemolytic markers, and patient-reported outcomes has been sustained for more than 3 years in the majority. • ACTIVATE-T: 37% (10/27) have met criteria for transfusion response for more than 3 years; 6 patients have remained transfusion free for more than 3 years. • Well-tolerated, no new safety findings. • Decrease in iron overload by liver iron concentration and other iron markers seen in both studies with ongoing improvements over time. • Sustained stability in bone mineral density by DXA scan. | Multiple references32-36 |
DXA, dual energy x-ray absorptiometry; TEAE, treatment-emergent adverse event.