GBT021601: Targeting HbS Polymerization to Mitigate Sickle Cell Disease Pathophysiology in a Murine Model

Sickle cell disease (SCD) results from a genetic mutation in the β globin gene, causing red blood cells (RBCs) to sickle and leading to a range of clinical issues. A drug called voxelotor, which inhibits the polymerization of hemoglobin S (HbS) and increases oxygenated Hb, has been shown to be effective and well-tolerated in SCD patients, reducing hemolytic anemia.

GBT021601 is a second-generation HbS polymerization inhibitor being developed to potentially achieve higher hemoglobin modification at lower doses. In a study involving Townes SCD mice, GBT021601 was administered orally for 21 days at varying doses. The drug led to a dose-dependent increase in hemoglobin occupancy and a significant reduction in the p50 value, indicating improved oxygen affinity.

At the highest dose, GBT021601 significantly decreased the number of circulating sickled cells and the sickling of mouse blood under hypoxic conditions. The drug also reduced hemolysis, as evidenced by an increase in hemoglobin levels and a decrease in reticulocyte percentages. Furthermore, GBT021601 improved RBC health, as indicated by an increase in mature RBCs and a decrease in mitochondria-containing RBCs.

GBT021601 also dose-dependently increased the RBC half-life, from 1.3 days in control mice to 7.4 days in those treated with the highest dose of the drug. Additionally, the treatment led to a significant reduction in spleen weight, suggesting improved blood flow and organ function.

In summary, GBT021601 has demonstrated the potential to normalize hemoglobin levels, reduce hemolysis, and significantly improve RBC health and lifespan, as well as organ function in a mouse model of SCD. These findings support the further clinical development of GBT021601 as a promising treatment for SCD patients.