According to results of a multiple-dose studies at the 2021 ASH Annual Meeting, treatment with etavopivat, a small molecule activator of erythrocyte pyruvate kinase, improved anemia and decreased intravascular hemolysis in patients with sickle cell disease (SCD) treated for up to 12 weeks.
Previous studies demonstrated that etavopivat resulted in decreased levels of 2,3-disphosphoglyceric acid (2,3-DPG) and increased levels of adenosine triphosphate (ATP) in red blood cells (RBCs) of healthy volunteers and patients with SCD. In the present analysis, researchers evaluated the effects of etavopivat in two-week multiple ascending dose (MD) cohorts and a 12-week open-label study.
In the completed MD cohorts, 20 patients were randomized 8:2 to receive etavopivat 300 mg then 600 mg or placebo once daily for two weeks. In the open-label cohort, up to 20 patients will receive etavopivat 400 mg once daily for 12 weeks.
The MD cohorts included 17 patients with HbSS SCD, two patients with HbS?+thalassemia, and one patient with HbSC disease. As of July 2021, 11 patients had been treated in the open-label cohort.
Among patients treated in the MD cohorts, 73% achieved a hemoglobin (Hb) increase of ?1 g/dL from baseline (p < 0.004), with an average increase of 1.1 g/dL. In addition, decreases in absolute reticulocyte count (ARC), indirect bilirubin, and lactate dehydrogenase (LDH) were observed.
“Increased Hb and a significant reduction in ARC indicated that etavopivat enhanced survival of sickle RBCs and significantly improved the severe anemia associated with SCD,” the authors reported.
The investigators also observed significant improvements in hematologic and hemolytic parameters in both cohorts of patients. All the initial improvements in hemoglobin, ARC, indirect bilirubin, and LDH seen in the MD cohorts were sustained in patients that received up to 12 weeks of etavopivat in the open-label cohort.
Of the six patients in the open-label cohort who have completed 12 weeks of treatment, five (83%) achieved an Hb increase of ?1 g/dL from baseline. The highest increase in hemoglobin was 1.81 g/dL.
The etavopivat-treated RBCs from MD patients had improved functional health, including point of sickling and deformability. This improvement persisted up to one week after treatment in more than one-third (36%) of patients.
According to the researchers “these long-living red blood cells have improved membrane health that may further reduce the risk of vaso-occlusive crises [VOC] and end-organ damage.”
Etavopivat was well-tolerated in both study groups, they added, and the safety profile was consistent with underlying SCD. Most adverse events (AEs) were grade 1/2. Serious AEs included grade 3 acute chest syndrome and unrelated VOC (n = 1), grade 3 deep vein thrombosis (n = 1), and grade 4 transient blood creatine phosphokinase increase that was unrelated to the study drug (n = 1)