Abstract
Etavopivat is an investigational, oral, small molecule activator of erythrocyte pyruvate kinase (PKR) in development for the treatment of sickle cell disease (SCD) and other hemoglobinopathies. PKR activation is proposed to ameliorate the sickling of SCD red blood cells (RBCs) through multiple mechanisms, including reduction of 2,3-diphosphoglycerate (2,3-DPG), which consequently increases hemoglobin (Hb)-oxygen affinity; increased binding of oxygen reduces sickle hemoglobin polymerization and sickling. In addition, PKR activation increases adenosine triphosphate (ATP) produced via glycolytic flux, which helps preserve membrane integrity and RBC deformability. We evaluated the pharmacodynamic response to etavopivat in nonhuman primates (NHPs) and in healthy human subjects and evaluated the effects in RBCs from patients with SCD after ex vivo treatment with etavopivat. A single dose of etavopivat decreased 2,3-DPG in NHPs and healthy subjects. Hb-oxygen affinity was significantly increased in healthy subjects after 24 hours. After daily dosing of etavopivat over 5 consecutive days in NHPs, ATP was increased by 38% from baseline. Etavopivat increased Hb-oxygen affinity and reduced sickling in RBCs collected from patients with SCD with either homozygous hemoglobin S or hemoglobin S and C disease. Collectively, these results demonstrate the ability of etavopivat to decrease 2,3-DPG and increase ATP, resulting in increased Hb-oxygen affinity and improved sickle RBC function. Etavopivat is currently being evaluated in clinical trials for the treatment of SCD. SIGNIFICANCE STATEMENT: Etavopivat, a small molecule activator of the glycolytic enzyme erythrocyte pyruvate kinase, decreased 2,3-diphosphoglycerate in red blood cells (RBCs) from nonhuman primates and healthy subjects and significantly increased hemoglobin (Hb)-oxygen affinity in healthy subjects. Using ex vivo RBCs from donors with sickle cell disease (SCD) (homozygous hemoglobin S or hemoglobin S and C genotype), etavopivat increased Hb-oxygen affinity and reduced sickling under deoxygenation. Etavopivat shows promise as a treatment for SCD that could potentially reduce vaso-occlusion and improve anemia.
Highlights
Sickle cell disease (SCD) is an autosomal recessive blood disorder caused by a single point mutation in the beta globin gene resulting in the expression of sickle hemoglobin (HbS)
Etavopivat Modulates 2,3-DPG and adenosine triphosphate (ATP) in Cynomolgus Monkeys Following the administration of a single 50-mg/kg dose of etavopivat in non-human primates (NHP), the etavopivat plasma concentration reached its maximal value (Cmax) between 1- and 2-hours post-dose, and 2,3-DPG declined to 47% of the baseline concentration between 12- and 24-hours post-dose (P=0.04) (Fig. 1), which approaches the theoretical maximum calculated by 2,3-DPG PK/PD
Targeting Pyruvate kinase-R (PKR) activation to reduce the concentration of 2,3-DPG is based on the ratelimiting role that PKR plays in regulating glycolysis in red blood cells (RBC)
Summary
Sickle cell disease (SCD) is an autosomal recessive blood disorder caused by a single point mutation in the beta globin gene resulting in the expression of sickle hemoglobin (HbS). HbS tends to polymerize when deoxygenated in the low oxygen tension of capillaries, or even in arterioles. HbS polymerization alters red blood cell (RBC) morphology and negatively affects their function (Sundd et al, 2019). The formation of cytoplasmic HbS polymers causes the RBC to adopt a rigid, sickle-like shape that is the defining characteristic of SCD (Kato et al, 2018). Repeated HbS polymerization and depolymerization with changing oxygen pressure, as well as oxidative damage, alters the RBC membrane, leading to a significantly shortened RBC lifespan, i.e., hemolysis (Sundd et al, 2019)
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