Increased hemoglobin affinity for oxygen with GBT1118 improves hypoxia tolerance in sickle cell mice

Abstract

Voxelotor (also known as GBT440) is a hemoglobin S polymerization inhibitor that increases the hemoglobin (Hb) affinity for oxygen (O2) in blood and has been approved for the treatment of sickle cell disease (SCD). In this study, GBT1118, an analog of voxelotor, was used to assess the impact of increasing Hb affinity for O2 on brain tissue oxygenation, blood pressure, heart rate, O2 delivery, and tolerance to hypoxia in Townes transgenic SCD mice. Brain oxygenation and O2 delivery were studied during normoxia and severe hypoxic challenges. GBT1118's pharmacokinetics in SCD mice allowed it to achieve the degree of Hb modification that voxelotor targets clinically. Chronic treatment with GBT1118 increased Hb affinity for O2, reducing the PO2 for 50% Hb O2 saturation (P50) in SCD mice from 31 mmHg to 18 mmHg. Chronic treatment with GBT1118 significantly improved hematological, hemodynamic, and oxygenation parameters during hypoxia, preserved cortical oxygenation during normoxia and improved cortical oxygenation during hypoxia, and increased tolerance to severe hypoxia. Independent of hematological changes induced by chronic treatment, a single dose of GBT1118 significantly improved tolerance to hypoxia, highlighting the benefits of increasing Hb affinity for O2 in preventing the complete deoxygenation of blood and consequent RBC sickling during hypoxia in SCD.

Small molecule protein binding to correct cellular folding or stabilize the native state against misfolding and aggregation

“…Thus, the FDA approved GBT440 as a first-in-class medicine for the treatment of SCD in 2019, sold under the brand name OxbrytaÒ by Global Blood Therapeutics (press release by FDA, URL). This clinical success encouraged others to design related compounds that may offer additional benefits, including non-covalent stabilizers of the R state of HbS [56,57]. At present, four drugs are available to treat SCD, hydroxyurea (HydreaÒ, DroxiaÒ, SiklosÒ, MylocelÒ), voxelotor or GBT440 (OxbrytaÒ), L-glutamine (EndariÒ), and crizanlizumab or SEG101 (AdakveoÒ).…”

Effects of GBT1118, a voxelotor analog, on intestinal pathophysiology in sickle cell disease

“…This strategy of incorporating the GBT1118 into chow has previously been shown to provide the dose of the Hb allosteric modifier that resulted in a Hb occupancy of around 30% in mice, comparable to that obtained in voxelotor‐treated patients 18 . GBT1118 improved oxygen delivery to hypoxic tissues in various mouse models of hypoxic tissue injury 19,20 . It also protects SCD mice from renal damage due to chronic haemolysis and haemoglobinuria by reducing the urine reactive oxygen species 21 .…”

GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model

“…Cardiac output, blood gases, total Hb and lactate were measured in normoxia (21% fraction of inspired O 2 [FiO 2 ]) and hypoxia (10% FiO 2 ) as described previously 8 . O 2 delivery (DO 2 ) and O 2 consumption (VO 2 ) were calculated from the cardiac output, total Hb, and arterial (SaO 2 ) and venous O 2 saturation (SvO 2 ) as described previously 8 . Tolerance to hypoxia was determined as described previously 8 …”

“…O 2 delivery (DO 2 ) and O 2 consumption (VO 2 ) were calculated from the cardiac output, total Hb, and arterial (SaO 2 ) and venous O 2 saturation (SvO 2 ) as described previously 8 . Tolerance to hypoxia was determined as described previously 8 …”