<scp>GBT</scp>440 increases haemoglobin oxygen affinity, reduces sickling and prolongs <scp>RBC</scp> half‐life in a murine model of sickle cell disease

<jats:title>Summary</jats:title><jats:p>A major driver of the pathophysiology of sickle cell disease (<jats:styled-content style="fixed-case">SCD</jats:styled-content>) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (<jats:styled-content style="fixed-case">RBC</jats:styled-content>s) and end‐organ damage. Pharmacologically increasing the proportion of oxygenated HbS in <jats:styled-content style="fixed-case">RBC</jats:styled-content>s may inhibit polymerization, prevent sickling and provide long term disease modification. We report that <jats:styled-content style="fixed-case">GBT</jats:styled-content>440, a small molecule which binds to the N‐terminal α chain of Hb, increases HbS affinity for oxygen, delays <jats:italic>in vitro</jats:italic> HbS polymerization and prevents sickling of <jats:styled-content style="fixed-case">RBC</jats:styled-content>s. Moreover, in a murine model of <jats:styled-content style="fixed-case">SCD</jats:styled-content>,<jats:styled-content style="fixed-case"> GBT</jats:styled-content>440 extends the half‐life of <jats:styled-content style="fixed-case">RBC</jats:styled-content>s, reduces reticulocyte counts and prevents <jats:italic>ex vivo </jats:italic><jats:styled-content style="fixed-case">RBC</jats:styled-content> sickling. Importantly, oral dosing of <jats:styled-content style="fixed-case">GBT</jats:styled-content>440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into <jats:styled-content style="fixed-case">RBC</jats:styled-content>s, which is a key therapeutic safety attribute. Thus, <jats:styled-content style="fixed-case">GBT</jats:styled-content>440 has the potential for clinical use as a disease‐modifying agent in sickle cell patients.</jats:p>