Table 1.
Completed clinical trials evaluating mitapivat for the treatment of hereditary hemolytic anemias.
| Study | Patient number (n) | Design, location | Study population | Major results |
|---|---|---|---|---|
| Yang et al. 11 (NCT04000165) | (n = 48 (SAD) (n = 48 (MAD) |
Phase I SAD and MAD, The United States | Healthy subjects | Mitapivat safe, with AEs more frequent at doses ⩾700 mg Pharmacokinetics favorable with low variability Dose-dependent changes in blood glycolytic intermediates consistent with glycolysis activation (increased ATP, reduced 2,3-DPG) |
| Grace et al. 25 (DRIVE-PK, NCT02476916) | Mitapivat (n = 52) | Phase II, North America and Europe | Adults with PKD who were not regularly transfused | Mitapivat safe and well-tolerated, with mild headache, insomnia, and nausea as most common AEs reported PK/PD parameters similar to healthy subjects 50% of patients had Hgb increase ⩾1.0 g/dl from baseline; improvement not seen in patients with two non-missense mutations or two R479H mutations Markers of hemolysis and erythropoiesis improved |
| Al-Samkari et al. 26 (ACTIVATE, NCT03548220) | Mitapivat (n = 40) Placebo (n = 40) |
Phase III randomized, Worldwide | Adults with PKD who were not regularly transfused with at least one non-R479H missense mutation | Met primary efficacy endpoint: mitapivat superior to placebo in achieving Hgb improvement ⩾1.5 g/dl (40% versus 0%) Met all secondary efficacy endpoints: improvement in average hemoglobin, lactate dehydrogenase, bilirubin, haptoglobin, reticulocyte percentage, and PKD-specific PRO measures (PKDD and PKDIA), all significantly greater in mitapivat arm than placebo arm Excellent safety profile; no patients on mitapivat discontinued treatment for any reason, including AEs; most common AEs in mitapivat arm were nausea and headache, and both were more common in placebo-treated patients PKDD and PKDIA underwent successful internal validation in this study |
| Glenthoj et al. 27 (ACTIVATE-T, NCT03559699) | Mitapivat (n = 27) | Phase III nonrandomized, Worldwide | Adults with PKD who were regularly transfused with at least one non-R479H missense mutation | Met primary efficacy endpoint: mitapivat reduced transfusion burden ⩾33% in 37% of enrolled patients Annualized number of RBC transfusions declined 39% 22% of patients rendered transfusion-free No AEs leading to treatment discontinuation |
| Kuo et al. 28 (NCT03692052) | Mitapivat (n = 20) | Phase II, The United States, Canada, and Europe | Adults with alpha- or beta-thalassemia who were not regularly transfused | Met primary efficacy endpoint: 16 patients (11/15 with beta-thalassemia and 5/5 with alpha-thalassemia) achieved Hgb increase ⩾1.0 g/dl Hemolytic and erythropoietic markers improved Responses were sustained with continued treatment Mitapivat well-tolerated with safety profile similar to prior studies |
| Xu et al. 29 (NCT04610866) | Mitapivat (n = 17) | Phase I MAD, The United States | Adults with sickle cell disease (HbSS) | Mitapivat safe and well-tolerated Mean hemoglobin change of +1.2 g/dl with mitapivat 50 mg twice daily Hemolytic markers improved Decreased mean 2,3-DPG and p50 and increased ATP in dose-dependent fashion |
AEs, adverse events; ATP, adenosine triphosphate; 2,3-DPG, 2.3-diphosphoglycerate; MAD, multiple ascending dose; PKD, pyruvate kinase deficiency; PK/PD, pharmacokinetic/pharmacodynamic; PKDD, pyruvate kinase deficiency diary; PKDIA, pyruvate kinase deficiency impact assessment; PRO, patient-reported outcome; SAD, single ascending dose.